Brief overview of the Literature

Introduction

Gravity has important effects on cardiovascular mechanisms and their response to exercise, specifically in terms of filling pressures and intravascular fluid distribution. The upright position at 1-G (earth) defines the normal operating conditions for the human cardiovascular system (Buckey et al., 1996b). The removal of all hydrostatic gradients when entering space (0-G at microgravity) causes a headward shift of fluids, resulting in facial edema (Thornton et al., 1977) and decreased leg volume (Moore and Thornton, 1987). This fluid shift is believed to be the primary stimulus for many of the physiological effects of space flight, including reductions in plasma volume and orthostatic intolerance on return to gravity. (Blomqvist and Stone, 1983).

The most important physiological changes caused by microgravity include bone demineralization (Shaw et al., 1988; Vailas et al., 1992), skeletal muscle atrophy (Riley et al., 1996; Caiozzo et al., 1996), vestibular problems causing space motion sickness (Oman et al., 1986), cardiovascular problems resulting in orthostatic intolerance (Buckey et al., 1996a; Shykoff et al., 1996) and reductions in plasma volume and red cell mass (Alfrey et al., 1996).

What follows is a brief review of the literature that has investigated cardiovascular responses to microgravity, post-flight orthostatic intolerance, cardiovascular response to exercise in a microgravity environment and skeletal muscle response to microgravity. The review also focuses on measurements of the autonomic nervous system, specifically heart rate variability and energy expenditure.

Cardiovascular response to microgravity and post-flight orthostatic intolerance

As the force of gravity is reduced, there is a progressive shift of fluid from the lower extremities to the upper body (Thornton et al., 1977; West, 2000). This causes an increase in the central fluid volume resulting in diuresis, a negative fluid balance and a reduction in the circulating blood volume (West, 2000). Accordingly, cardiac output increases on initial exposure to microgravity, but then decreases as the circulating blood volume drops. Specifically, reported erythrocyte mass and blood volume losses are recorded at approximately 1%/day (Alfrey, 1994), while cardiac stroke volume reportedly decreases by 10% relative to 1G supine conditions (Fritsch-Yelle et al., 1996). Shykoff et al. (1996) have shown that in-flight cardiac output at rest was an average of 1.5L.min-1 lower than standing pre flight values, but was not different to supine pre-flight values. While some studies have shown that heart rate remains relatively unchanged in a microgravity environment (Levine et al., 1996), others have shown significant decreases in both heart rate and blood pressure (Fritsch-Yelle et al., 1996) during space flight. These studies have reported that in-flight resting heart rate was an average of 15 beats.min-1 lower than standing heart rate and 5 beats.min-1 lower than preflight supine conditions (Shykoff et al., 1996). Similarly, mean arterial blood pressure was approximately 6mmHg lower in-flight than standing values but was not different to pre-flight supine conditions. Systolic blood pressure was not different to pre-flight values, while in-flight diastolic blood pressure at rest was an average of 11mmHg less than standing pre-flight values while not different from supine measurements (Shykoff et al., 1996). With the exception of losses in red blood cell mass, these reductions in cardiovascular variables are similar to those responses elicited on earth after the assumption of an upright posture from a supine position (Watenpaugh and Hargens, 1996).

Post-flight orthostatic intolerance has been reported widely. The symptoms of this cardiovascular deconditioning syndrome include minor decreases in blood pressure, inappropriate increases in resting heart rate and exercise intolerance (Levine et al., 1996). This condition exists when there is either an excessive postural decrease in cardiac filling and stroke volume and/or an inadequate compensatory neurohumoral response, resulting in a failure to maintain adequate brain perfusion in an upright position (Blomqvist, 1990).

The pathophysiology of post-flight orthostatic intolerance can be explained in terms of the complex cardiovascular regulatory mechanisms that exist on earth and the factors that are associated with cardiovascular adaptations in a microgravity environment. On earth, the cardiovascular system has developed both structural and regulatory mechanisms to maintain cerebral perfusion and prevent lower extremity fluid accumulation while in upright postures. These complex mechanisms include leg vasoconstriction in an upright posture relative to supine conditions via baroreflexes, local venoarteriolar reflexes and myogenic vascoconstriction (Henriksen and Sejrsen, 1976; Jepsen and Gaehtgens, 1995; Vissing, 1997), relatively low venous compliance in the legs (Watenbaugh et al., 1993) and capillary basement membrane thickening in the lower body (Williamson et al., 1975).

Recent research has focused on identifying the changes that occur to these regulatory systems in microgravity, and has attempted to provide some insight into the underlying cause of post-flight orthostatic hypotension. In-flight cardiovascular adaptations include a 10-15% fall in total blood volume (Blomqvist and Stone, 1983; Johnson et al., 1977), which results in a decrease in cardiac filling in the supine position and a larger postural reduction in stroke volume (Blomqvist, 1990). A second adaptation is a significant increase in venous compliance and a decrease in standing vasoconstrictor responses, causing an increase in peripheral pooling and contributing to the reported reduced upright, post-flight stroke volume (Beck et al., 1992; Buckey et al., 1992; Convertino et al., 1989). Finally, there is also an inadequate compensation for a posture-induced reduction in stroke volume, which causes a decrease in standing blood pressure. Altered cardiovascular neurohumoral regulation, including a blunted carotid-cardiac baroreflex, have been reported in post-flight studies and have also been suggested as possible mechanisms contributing to an inappropriate increase in heart rate with standing (Fritsch et al., 1992; Fritsch-Yelle et al., 1994). Other factors that may be associated with orthostatic intolerance include increased abdominal pooling and changes in ventricular pressure-volume relationships (Buckey et al., 1996a). Additional studies have also suggested that there is a centrally mediated hypoadrenergic responsiveness that may be a contributing factor to post-flight orthostatic intolerance (Fritsch-Yelle et al 1996). Initially, an increased standing heart rate and the total peripheral resistance compensates for the lower stroke volume, which maintains blood pressure for a relatively short period of time (5 minutes). Thereafter, however, blood pressure decreases and heart rate increases. This provides evidence to suggest that initially, baroreflex mechanisms are intact, but with prolonged standing, there seems to be an overwhelming of these compensatory mechanisms (Buckey et al, 1996a).

Accordingly, it could be suggested that microgravity itself does not act as a stressor to the cardiovascular system, but it is rather the adaptive changes that occur in response to the in-flight environment that result in the adverse effects on the cardiovascular system that have been reported.

Neuromuscular response to microgravity

Information regarding the functional and morphological changes in human skeletal muscle after space flight is relatively limited and studies in this area have predominantly used rats orbited in Russian biosatellites and American space shuttles (Caiozzo et al., 1994; Ilyina-Kakueva et al., 1976; Martin et al., 1988; Riley et al., 1992; Riley et al., 1990). Nevertheless, marked decrements in muscle strength and size have been reported in both humans and rats after space flight. Astronauts aboard Skylab (28, 56 and 84 days) averaged a 5-26% decline in whole muscle strength of the knee extensors and flexors (Rummel et al., 1975). Soviet cosmonauts also experienced a significant decline in ankle extensor strength after both short- (7 days) and long-duration (110-237 days) exposure to weightlessness (Grigor'yeva and Kozlovskaya, 1987; Kozlovskaya et al., 1984). Despite in-flight exercise countermeasures in these studies, decreases in muscle strength were still recorded.

Since all skeletal muscles respond to the presence or absence of motor activity, it is not surprising that muscle atrophy is a feature of microgravity (West, 2000). Post-flight gait reflects changes in electromyographic activity indicating muscle fatigue, weakness and poor co-ordination as a result of an in-flight loss of anticipatory activation of certain muscles (Clement et al., 1984; Kozlovskaya et al., 1990) and changes in protein metabolism (West, 2000). LeBlanc et al. (1995) used magnetic resonance imaging (MRI) to assess leg and back muscle volumes before and after an 8-day space flight. They observed equal volume losses of 6.3% and 6.0% for the calf and quadriceps respectively, whereas the anterior compartment of the lower leg showed less of a decline in volume of 3.9%. Other studies, however, have found no differences in calf strength and morphology after a 17-day space flight (Trappe et al., 2001). Trappe et al (2001), however, acknowledge that their testing protocol may have served as a training stimulus for the subjects in this study and thus may have attenuated the loss in muscle strength that may have ordinarily been observed.

The reduction in muscular strength appears to be accompanied by a decline in whole muscle size, specifically in those muscles involved primarily in the maintenance of an upright posture (West, 2000). Accordingly, microgravity also reduces the peak force of limb skeletal muscles (Convertino, 1990; Greenleaf et al., 1989). In one study, after 28 days of space flight, there was a greater drop in thigh compared to arm and extensor compared to flexor torque, with the peak extensor torque of the thigh declining by 20% compared with a 10% loss in thigh flexor and arm extensor groups (Convertino, 1990; Greenleaf et al., 1989). These changes were increased linearly with an increase in time, most likely due to a preferential reliance on the upper limbs, in both humans and rats, in order to maintain stability during space flight (Riley et al., 1996). MRI techniques have also revealed decreases in the cross sectional area of muscle fibers of approximately 11 and 24% in type 1 and type 2 fibers respectively (West, 2000). These data demonstrate that human skeletal muscle becomes weaker as a result of the length of time spent in microgravity. In most studies, however, after reloading periods comparable to flight duration, post-flight muscle strength ratios approximate the results measured before space flight (Riley et al. 1996). Similarly, the rapid post-flight improvement of walking indicates a retaining of motor and sensory commands, rather than recovery of myofiber size (Riley et al., 1996).

Studies performed on rats indicate that eccentric contraction-like sarcomere lesions, absent in flight, occur post-flight after approximately 5 hours of reloading (Riley et al., 1996). Muscle fiber damage has been suggested as being primarily a post-flight phenomenon, likely to result from eccentric contractions that occur with joint loading in a 1-G environment (Riley et al., 1990; Riley et al., 1992; Riley et al., 1995). Strenuous, eccentric contraction exercise that produces these sarcomere lesions in humans is associated with immediate, severe and often long-standing decrements in force (Clarkson and Tremblay, 1988; Friden and Leiber, 1992) as well as significant swelling, pain and tenderness (Newham et al., 1983; Eston et al., 1996) These results, therefore suggest that space flight unloading, although not causing structural damage, may render atrophic antigravity muscles susceptible to this reloading sarcomere disruption.

Exercise in a microgravity environment

(a) Cardiovascular exercise

The literature provides few studies investigating cardiovascular response to exercise during space flight and tends to focus predominantly on the effects of exercise on post-flight variables. Studies investigating maximal exercise performance after adaptation to microgravity have shown that peak power output and oxygen consumption are well maintained during space flight and are not significantly different from pre-flight values (Levine et al., 1996). In their study, Levine et al. (1996) reported a reduction of 22% in peak oxygen consumption after 14 days of space flight, which was contributed solely to a decrease in peak stroke volume and cardiac output. Peak oxygen consumption was still significantly below pre-flight values when measured 24-48 hours after landing, but had recovered to baseline values after 7 days. Levine et al (1996) reported that peak heart rate and blood pressure did not differ between pre-, in- or post-flight tests and these authors thus concluded that the reduction in post-flight oxygen consumption was most likely due to a decrease in intravascular blood volume, stroke volume and cardiac output.

Studies have also been performed to investigate whether in-flight exercises performed during short duration space flights would affect heart rate and blood pressure responses within 2-4 hours of landing (Lee et al., 1999). Subjects in this study were required to perform low, moderate or high levels of exercise during the flight. The results of this study showed that in all groups, post-flight supine heart rate was similar to pre-flight values and that the increases in heart rate after standing were significantly greater in those subjects who had performed lower levels of exercise. These authors therefore concluded that moderate to high levels of in-flight exercise attenuates the altered heart rate response to standing after space flight.

Studies investigating in-flight responses to exercise have shown that an increase in heart rate contributes to the positive linear relationship observed between cardiac output and oxygen consumption (Shykoff et al. 1996). This group showed that heart rate, as a function of oxygen consumption, was linear without a difference among gravity and microgravity conditions (Shykoff et al. 1996). If this is the case, then it may be possible to use heart rate as an indication of workload and heart rate values will be comparable between pre-flight and in-flight workloads. This group has also suggested that during erect exercise at 1G, cardiac output might be elevated over that needed for muscle perfusion to maintain a driving force for venous return from the legs (Shykoff et al. 1996). In microgravity, however, the cardiac output might rather be set by the needs of the working muscle alone. Perhaps the redistribution of blood volume and flow means that all perfused tissues are adequately but not wastefully perfused, thereby allowing more optimal oxygen extraction which would be required due to the loss of red cell mass.

(b) Resistance training exercise

The countermeasures that have been employed during space flight, in an attempt to avoid the adverse affects on muscle structure and function, include vigorous exercise programmes and in some Soviet studies, wearing a “penguin suit” (West, 2000). The results of these studies, however, have shown that there is considerable variation in training response between individuals and thus the efficacy of these measurements remains somewhat contentious.

These exercise countermeasures have been used extensively during both long-duration (Skylab and Mir) and short-duration (Spacelab) space flights (Convertino, 1990; Greenleaf et al., 1989). For the most part, the exercise has consisted of aerobic activities using cycle ergometers and treadmills. It has been difficult to determine the effectiveness of these programs because non-exercising controls have not been included in the trials, and the specific exercise protocols have generally not been well described. Accordingly, many studies have used simulated environments of bed-rest to approximate the disuse atrophy that occurs in a real microgravity environment. The primary finding from these studies is that high-resistance exercise training is effective in preventing muscle wasting and reduced muscular performance (Bamman et al., 1997; Greenleaf et al., 1994). Specifically, previous research on rats has suggested that exercise programmes should include eccentric loading and lower body negative pressure to counter susceptibility to sarcomere disruption and interstitial edema as discussed above (Riley et al., 1996). Reacclimatization protocols should thus consider both vascular and myogenic factors to minimize post-flight muscle weakness and delayed-onset muscle soreness.

Heart rate variability (R-R interval recording)

Observations of heart rate intervals have indicated significant variation between beats. This variability has been examined in an attempt to determine if the frequency characteristics contributing to this variability can be used as a non-invasive probe for the autonomic control mechanism of the human cardiovascular system (Yamamoto et al., 1991).

Heart rate is controlled by the balance between the autonomic parasympathetic (PNS) and sympathetic nervous system (SNS) activity to the sinoatrial node. Accordingly, on a beat-to-beat basis, heart rate is not constant and there are periodical fluctuations in heart rate that are indicative of the relative contributions of each of these 2 components of the autonomic nervous system (Saul, 1990). This can be determined by analyzing the time intervals between each QRS complex (R-R variability). This R-R interval has been shown to be variable and easily influenced by a variety of factors that include respiration, blood pressure regulation, thermoregulation and circadian rhythms (Stein et al., 1994).

Various methods have been proposed in an attempt to determine the relative contributions of the SNS and the PSNS to heart rate. Linear time domain and frequency domain measures of heart rate variability (HRV) have been used most commonly in the noninvasive assessment of the autonomic modulation of heart rate (Akselrod et al., 1985; Arai et al., 1989; Breuer et al., 1993; Yamamoto et al., 1991). Time domain analysis calculates variability based on interbeat intervals, while frequency domain analysis is used to partition the total variance of heart rate into the variances accounted for by underlying groups of frequencies (Stein et al., 1994). This method assigns different frequency components to the different contribution of the SNS and the PSNS to heart rate control. High frequency components are associated solely with cardiac PNS activity, while lower frequencies are more likely to be associated with both PNS and SNS activity (Yamomoto et al, 1991). A ratio of high to low frequency components has been associated with the SNS. The importance of being able to identify these different contributions is applicable in terms of being a non-invasive method to identify autonomic neural balance and input to the heart in a number of physiological settings (Yamamoto et al., 1991).

During dynamic exercise, the initial rise in heart rate is due to the withdrawal of vagal tone followed by an increase in the activity of the cardiac sympathetic nerves (Tulppo et al., 1996). Exercise heart rate has also been studied using spectral analysis of HRV. In studies using pharmacological modalities to manipulate heart rate response, results have shown a clear reduction in PNS activity that occurs linearly with an increase in exercise intensity, although the results of this specific study provided no evidence to show an increase in SNS activity (Arai et al., 1989). Other studies have shown that different work intensities result in different changes in the contributions of the SNS and the PSNS. Yamamoto et al. (1991) showed a significant and progressive decrease in PNS activity, as well as overall HRV during exercise until the exercise intensity reached approximately 60% of a predetermined maximal workload. SNS contributions, however, only increased during high intensity exercise. These results suggest, as may be expected, that there is a gradual withdrawal of PNS activity as heart rate increases during exercise, and that only at relatively higher workloads is there an increase in SNS contribution to heart rate.

There have been few studies that have examined R-R variability in a microgravity environment. Cooke and Dowlyn (2000) used R-R data, in the frequency domain with spectral analysis, as an index of sympathetic activity in a simulated microgravity environment using the head-down tilt position. These authors concluded that a non-invasive frequency domain estimate, such as heart rate variability, did not adequately reveal subtle changes in sympathetic traffic during acute microgravity. Shykoff et al. (1996) have suggested that results from studies employing simulated microgravity environments should be interpreted with caution as true microgravity environments cause a cardiovascular response that is significantly different to that observed during simulations.

Fritsch-Yelle et al (1994) measured R-R intervals in astronauts before and after shuttle missions lasting between 8-14 days. Between pre-flight and post-flight measurements, R-R interval spectral power in the high frequency range did not change, while there was an increase in low-frequency band and increases of the ratio of low- and high-frequency R-R interval power. It was suggested that these results reflect increases of sympathetic-cardiac neural traffic. This suggestion has been supported by the finding of an increase in circulating norepinepherine on landing day, which correlates closely to muscle sympathetic activity (Eckberg et al., 1988). These changes from pre-flight values persisted for several days after landing and provide some evidence of post-flight increases in sympathetic influences on arterial pressure control (Fritsch-Yelle et al., 1994).

Other cardiovascular studies have focused mainly on mean heart rate and blood pressure data. The results of these studies have been equivocal, with some showing decreases in in-flight heart rate (Bungo and Johnson, 1983; Kasting et al., 1987) while others showing increases in heart rate (Eckberg et al., 1992; Goldstein et al., 1982). Those studies showing decreases in heart rate suggest that the cardiovascular system operates with reduced in-flight sympathetic activity and vascular resistance (Fritsch-Yelle et al., 1996).

Physical activity energy expenditure measurement

The accurate measurement of 24 hours free living energy expenditure is key in many health related areas. It is known that physical activity plays an important protective role in many of the chronic diseases of lifestyles: such as coronary artery disease, certain forms of cancers, and more importantly obesity, which in itself opens up a whole myriad of other health related diseases, such as Type II diabetes. Currently, there are many assessment tools available in the field for the measurement of physical activity. However, the accuracy of the tools varies widely, as does the sample population able to be tested depending on the type of tool being used. In addition, the validity of the assessment tool is dependent on the limitations and assumptions associated with the validation technique.

Assessment methods include questionnaires, indirect calorimetry, the doubly labeled water technique, heart rate monitoring, and motion sensors. Of these, both heart rate monitoring and motion sensors have been widely used as they provide relatively inexpensive, accurate and reliable methods for the objective measurement of physical activity out in the field.

The use of heart rate in the prediction of energy expenditure has previously demonstrated a day to day coefficient of variation of 15% using the heart rate monitoring method in eight fit, healthy men (Van Den Oever et al., unpublished data, 1996). Ceesay et al. (1989) validated the technique in a group of volunteers (mean age 25 years), and found a significant correlation between the heart rate (HR) method and indirect calorimetry method. In this study, they found that the HR method provided individual estimates of energy expenditure that were within 10 % of those calculated according to the indirect calorimetry method.

The measurement of energy expenditure in microgravity

Numerous studies have investigated the impact of micro-gravity on total energy expenditure (TEE) and its effects on astronauts. Most recently Lane et al. (1997) used the doubly labeled water technique to investigate the TEE in 13 male astronauts participating in 8 – 14 day Space Shuttle missions during 1992 – 1994. In this study it was found that there was no difference in the TEE between the ground-based studies and the in-flight-based studies. However, the total energy intake is significantly lower during the in-flight versus the ground-based studies. This significant difference is attributed to the motion sickness, which the astronauts experience during the mission. Body weight is also significantly different between the ground- and in-flight-based studies. This is as a result of the negative energy balance of the astronauts.

In another study, Stein et al. (1999) compared the 16-day in-flight 1996 LMS mission with a 16-day 6º bed-tilt bed-rest, using the doubly labeled water technique. In this study it was found that there was a significant difference in body weight, nitrogen retention and energy intake. During bed-rest, body weight, water, fat and energy balance remained unchanged, while during the space flight, there were significant decreases in weight and nitrogen retention, in addition dietary intake was also reduced, while energy expenditure remained unchanged in-flight, resulting in a significant loss in overall body weight