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J Appl Physiol 103: 8-16, 2007. First published March 22, 2007; doi:10.1152/japplphysiol.01162.2006
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Cardiac atrophy in women following bed rest

Todd A. Dorfman,1,2 Benjamin D. Levine,1,2,* Tommy Tillery,2 Ronald M. Peshock,2 Jeff L. Hastings,1,2 Suzanne M. Schneider,3 Brandon R. Macias,5 Gianni Biolo,4 and Alan R. Hargens5,*

1Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, and 2Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; 3Division of Physical Performance and Development, University of New Mexico, Albuquerque, New Mexico; 4Department of Clinical, Technological and Morphological Sciences, and Division of Internal Medicine, University of Trieste, Trieste, Italy; and 5Department of Orthopaedic Surgery, University of California, San Diego, California

Submitted 14 October 2006 ; accepted in final form 15 March 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Both chronic microgravity exposure and long-duration bed rest induce cardiac atrophy, which leads to reduced standing stroke volume and orthostatic intolerance. However, despite the fact that women appear to be more susceptible to postspaceflight presyncope and orthostatic hypotension than male astronauts, most previous high-resolution studies of cardiac morphology following microgravity have been performed only in men. Because female athletes have less physiological hypertrophy than male athletes, we reasoned that they also might have altered physiological cardiac atrophy after bed rest. Magnetic resonance imaging was performed in 24 healthy young women (32.1 ± 4 yr) to measure left ventricular (LV) and right ventricular (RV) mass, volumes, and morphology accurately before and after 60 days of 6° head-down tilt (HDT) bed rest. Subjects were matched and then randomly assigned to sedentary bed rest (controls, n = 8) or two treatment groups consisting of 1) exercise training using supine treadmill running within lower body negative pressure plus resistive training (n = 8), or 2) protein (0.45 g·kg–1·day–1 increase) plus branched-chain amino acid (BCAA) (7.2 g/day) supplementation (n = 8). After sedentary bed rest without nutritional supplementation, there were significant reductions in LV (96 ± 26 to 77 ± 25 ml; P = 0.03) and RV volumes (104 ± 33 to 86 ± 25 ml; P = 0.02), LV (2.2 ± 0.2 to 2.0 ± 0.2 g/kg; P = 0.003) and RV masses (0.8 ± 0.1 to 0.6 ± 0.1 g/kg; P < 0.001), and the length of the major axis of the LV (90 ± 6 to 84 ± 7 mm. P < 0.001), similar to what has been observed previously in men (8.0%; Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist Zerwekh JE, Peshock RM, Weatherall PT, Levine BD. J Appl Physiol 91: 645–653, 2001). In contrast, there were no significant reductions in LV or RV volumes in the exercise-trained group, and the length of the major axis was preserved. Moreover, there were significant increases in LV (1.9 ± 0.4 to 2.3 ± 0.3 g/kg; P < 0.001) and RV masses (0.7 ± 0.1 to 0.8 ± 0.2 g/kg; P = 0.002), as well as mean wall thickness (9 ± 2 to 11 ± 1 mm; P = 0.02). The interaction between sedentary and exercise LV and RV masses was highly significant (P < 0.0001). Protein and BCAA supplementation led to an intermediate phenotype with no change in LV or RV mass after bed rest, but there remained a significant reduction in LV volume (103 ± 14 to 80 ± 16 ml; P = 0.02) and major-axis length (91 ± 5 to 88 ± 7 mm; P = 0.003). All subjects lost an equivalent amount of body mass (3.4 ± 0.2 kg control; 3.1 ± 0.04 kg exercise; 2.8 ± 0.1 kg protein). Cardiac atrophy occurs in women similar to men following sedentary 60 days HDT bed rest. However, exercise training and, to a lesser extent, protein supplementation may be potential countermeasures to the cardiac atrophy associated with chronic unloading conditions such as in spaceflight and prolonged bed rest.

sex differences; microgravity exposure; cardiac atrophy; exercise; protein supplementation; magnetic resonance imaging

BOTH CHRONIC MICROGRAVITY exposure and long-duration bed rest result in eccentric cardiac atrophy and impaired cardiac compliance, leading to a prominent reduction in upright stroke volume (SV) and orthostatic intolerance (13, 34, 45, 58, 68). Although women appear to be more susceptible to postspaceflight presyncope and orthostatic hypotension than men (25), there are relatively few high-resolution studies of female cardiac structure after gravitational unloading. Currently, women account for 20% of the astronauts in the United States. The increased incidence of orthostatic intolerance in women following gravitational unloading has been attributed to a hypoadrenergic sympathetic system (16, 65), a greater dependence on plasma volume (16, 65), and a smaller SV secondary to a smaller and less compliant left ventricle (LV) (16, 19, 20), but the impact of microgravity on cardiac morphology in women remains poorly understood.

Following head-down-tilt (HDT) bed rest, there is a cephalic and intrathoracic redistribution of intravascular volume and a transient increase in SV secondary to the loss of hydrostatic and gravitational gradients. A diuresis ensues, resulting in a new hemodynamic steady state that is halfway between the upright and supine positions (34) and a prominent drop in LV filling (34, 45, 47). With the restoration of gravitational gradients, orthostatic hypotension occurs, but the reduction in SV after gravitational unloading cannot be attributed entirely to hypovolemia (11, 21, 35, 47). In fact, cardiac atrophy occurs in men following as little as 14 days of bed rest, and this adaptive response likely contributes to the orthostatic intolerance associated with microgravity exposure by reducing cardiac distensibility and thereby SV at any given filling pressure (34, 45, 47). Previous reports show a reduction of LV mass in men of 4.7, 8.0, and 15.6% after 2, 6, and 12 wk respectively (14, 45).

Endurance exercise training clearly causes eccentric LV hypertrophy and improved cardiac compliance (33) in previous male bed rest models (4). Furthermore, male athletes have more physiological hypertrophy than female athletes (38, 44, 57). Whether sex similarly affects the magnitude of myocardial atrophy following cardiovascular unloading, however, is unclear. The purpose of this study was to use magnetic resonance imaging (MRI) to measure precise changes in female cardiac morphology following bed rest deconditioning. We hypothesized that HDT bed rest induces cardiac atrophy in women and that exercise training in women prevents the adaptive cardiac remodeling associated with gravitational unloading.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects

Twenty-four healthy female subjects aged 32.1 ± 4 yr (range 25–40 yr) participated in this study, which was part of an international collaboration among the French, European, Canadian, and American space agencies. The subjects represented a wide range of nationalities including Czech, Dutch, French, English, Finish, Polish, Scottish, German, and Swiss. All subjects had to be physically active with at least "average" aerobic fitness (mean ± SD maximal oxygen uptake 39 ± 4 ml·kg–1·min–1), but competitive athletes were excluded. Subjects were 59 ± 4 kg and 1.66 ± 0.07 m. The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki 1964 and all its applicable amendments, and each subject signed an informed consent form meeting the requirements of the Good Clinical Practice recommendations of the International Conference on Harmonisation, and approved by the Institutional Review Boards of NASA Johnson Space Center and University of California, San Diego.

Study Design (Bed Rest)

All twenty-four subjects completed 60 days of strict 6° HDT bed rest. The eight subjects randomized to exercise walked/ran for 40 min on a vertical treadmill in a lower body negative pressure (LBNP) chamber (Fig. 1) at 1–1.15 body weights (50–60 mmHg LBNP) followed by 10 min of resting LBNP three to four times per week depending on their graded oxygen uptake; exercise intensity varied from 40 to 80% pre-bed rest maximal oxygen uptake in an "interval" fashion over the course of each session as previously described (8, 12, 24, 56). This mode of exercise was chosen because supine treadmill exercise within LBNP provides weight bearing, muscle loads, and cardiovascular responses equivalent to upright treadmill exercise on Earth and simulates metabolic and kinetic features of upright exercise (8, 38). Furthermore, this exercise paradigm has maintained peak oxygen consumption in men exposed to 5 and 15 days of HDT bed rest (32, 64).


Figure 1
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  		Fig. 1. Schematic depicting supine treadmill running in a lower body negative pressure (LBNP) chamber, and the inertial forces on the heart during supine treadmill running in a LBNP chamber are similar to the forces during upright endurance training on Earth.

 
Resistive training of the knee extensor and plantar flexor muscle groups was conducted on a flywheel ergometer modified for bed rest every third day, and each training session included four sets of seven repetitions with each leg performed with maximal effort using both concentric and eccentric contractions with a 2-min resting period between each set (1, 52). Protein content in the diet was 1 g·kg–1·day–1 in the control and exercise groups. In the nutrition group, dietary protein content was increased to 1.45 g/kg. Free branched-chain amino acids (BCAA) (3.6 g/day free leucine, 1.8 g/day free isoleucine, and 1.8 g/day free valine) were added as a supplement (Friliver, Bracco, Italy), which was given at the main meals. With the exception of the exercise session, all subjects were restricted to the HDT position at all times except for during meals when they were allowed to elevate on one elbow.

Subjects were housed and supervised in the Institut de Médecine et de Physiologie Spatlates (MEDES) Space Clinic located within the Toulouse Rangueil Hospital. Each subject was given a diet of 110% of their resting metabolic rate, which was determined before bed rest and adjusted every 15 days by indirect calorimetry and impedance measures of body composition. The maximum liquid intake of the sedentary and protein supplementation group was 60 ml·kg–1·day–1, and the maximum liquid intake for the exercise group was 60 ml·kg–1·day–1 on the days without training and 75 ml·kg–1·day–1 on days with exercise training. Intake and urine output were recorded, and caloric intake was increased as needed for the exercise subjects with the goal of preventing changes in body composition. For all subjects, sodium intake was 1.2 to 1.6 mmol·kg–1·day–1, potassium intake was 0.9 to 1.1 mmol·kg–1·day–1, calcium intake was 1 g/day, and phosphorus intake was 1.2 to 1.6 mmol·kg–1·day–1.

MRI Imaging

Parameters protocol.   MRI was performed on all subjects immediately before and just before the end of bed rest at the Rangueil Hospital in Toulouse, France, and all images were acquired by a 1.5-T Phillips MRI scanner. After completing the standard imaging protocol for the assessment of mass and volume (23, 28, 30, 48), gradient echo, cine long- and short-axis MRI sequences with a temporal resolution of ~42 ms, a repetition time of ~4 ms, an echo time of ~2 ms, and a flip angle of 55° were obtained. The heart was sectioned in 6 mm slices with a gap of 4 mm spanning from the apex to the base, and the image resolution was 256 x 256 with a 330-mm field of view.

Image analysis.   One observer who was blinded to the group assignments read the cardiac MRI studies. Short axis slices were used for volume, mass, and mean wall thickness (MWT) calculations using the MRI-MR Analytical Software System (MEDIS, Leiden, The Netherlands) (41). LV end-diastolic volumes were determined by manually identifying the endocardial border at both end diastole and end systole. End diastole was the first frame in every sequence, and end systole was defined as the frame with the smallest endocardial (chamber) area. LV volumes were then calculated by summation using Simpson's rule (28, 48). The difference between endocardial and epicardial volumes were computed and multiplied by 1.05 g/ml, which is the density of cardiac muscle, to calculate the LV mass (30). This technique has been shown to be extremely accurate and reproducible in our laboratory (30, 34, 45) with an intraobserver variability for LV mass and right ventricular (RV) mass of r = 0.98 with a SE of estimate of 3.8 g and r = 0.97 with a SE of estimate of 2.1 g, respectively (45).

The RV end-diastolic volume was determined by manually identifying the endocardial border at end diastole, which was the first frame in every sequence, and then it was computed by summation as described above for the calculation of LV end-diastolic volume (45). RV mass was calculated by manually outlining the endocardial and epicardial borders of the RV free wall in each slice at end diastole, and the sum of the differences between endocardial and epicardial areas was multiplied by the density of myocardial muscle, which is 1.05 g/ml (9, 43, 45). The moderator band and the interventricular septum were not included in the measurement of RV free wall mass (9, 43).

The MWT of the LV including papillary muscles was calculated by the MRI-MASS software system, which measures the distance between manually determined endocardial and epicardial borders of each segment at end diastole using the modified centerline method (26, 27). Calculations were performed from the base of the heart to the apex, and the slices at the valvular level as well as the lowest apical slice without blood volume at end systole were excluded (26). Using long-axis four-chamber slices, the major axis was measured from the mitral valve to the apex (50), and the minor axis was determined by measuring the widest distance from the interventricular septum to the lateral wall of the LV perpendicular to the major axis.

Statistical Analysis

The numerical data are presented as means ± SD. The differences between before bed rest (pre) and end of bed rest (post) LV and RV end-diastolic volumes, masses, MWT, and linear dimensions for the sedentary, exercise, and protein supplementation groups were compared with a two-way, mixed-design ANOVA with pre-post bed rest as the paired comparison and sedentary vs. exercise vs. protein supplementation as the unpaired comparison. Significant F values were followed by Newman-Keuls post hoc test or Bonferroni correct t-tests for multiple comparisons. Because of the relatively small sample size, all individual P values are reported as per recommendation of the American Physiological Society (45, 47). LV and RV masses (g) were adjusted for body size by dividing myocardial mass by body mass (kg) at the start of the study.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
All subjects lost an equivalent amount of body mass (3.4 ± 0.2 kg control; 3.1 ± 0.04 kg exercise; 2.8 ± 0.1 kg protein).

LV End-Diastolic volume, LV Mass, and MWT

After sedentary prolonged bed rest without protein supplementation, there was a significant reduction in LV volume (96 ± 26 to 77 ± 25 ml; P = 0.03), LV mass (126 ± 14 to 113 ± 18 g; P = 0.003), and adjusted LV mass (2.2 ± 0.2 to 2.0 ± 0.2 g/kg; P = 0.003) (Fig. 2A), similar to what has been observed previously in men (Fig. 3). In contrast, when exercise was performed while the subjects were confined to bed rest, there was not a significant reduction in LV volume, and there was a significant increase in LV mass (115 ± 31 to 136 ± 27 g; P < 0.001), adjusted LV mass (1.9 ± 0.4 to 2.3 ± 0.3 g/kg; P < 0.001) (Fig. 2B), and MWT (9 ± 2 to 11 ± 1 mm; P = 0.01). After receiving protein supplementation during bed rest, LV mass and adjusted LV mass were preserved (Fig. 2C), but a significant reduction in LV volume (103 ± 14 to 80 ± 16 ml; P = 0.02) remained. The interaction among groups was highly significant for LV mass (P < 0.0001) although it did not achieve conventional significance for LV volume.


Figure 2
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  		Fig. 2. A: adjusted left ventricular (LV) mass at baseline (pre) and after sedentary prolonged bed rest (post). B: adjusted LV mass at baseline and following exercise during bed rest. C: adjusted LV mass and protein supplementation during bed rest. *P < 0.05.

 

Figure 3
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  		Fig. 3. LV mass measured by magnetic resonance imaging after 2, 6, 8, and 12 wk of sedentary head-down-tilt bed rest. Values are means ± SE, and linear regressions are calculated from mean values of percent reduction in LV mass.

 
RV End-Diastolic Volume and RV Mass

At the end of HDT bed rest without protein supplementation, there was a significant reduction in RV volume (104 ± 33 to 86 ± 25 ml; P = 0.02), RV mass (44 ± 8 to 34 ± 6 g; P < 0.001), and adjusted RV mass (0.8 ± 0.1 to 0.6 ± 0.1 g/kg; P < 0.001) (Fig. 4 A). In contrast, when exercise was performed during bed rest, there was not a significant reduction in RV volume, and there was a significant increase in RV mass (40 ± 9 g to 47 ± 10 g; P = 0.005; interaction P < 0.0001) as well as adjusted RV mass (0.7 ± 0.1 to 0.8 ± 0.2 g/kg; P = 0.002) (Fig. 4B). Furthermore, RV volume, RV mass, and adjusted RV mass (Fig. 4C) were preserved following protein supplementation during sedentary bed rest.


Figure 4
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  		Fig. 4. A: adjusted right ventricular (RV) mass at baseline and after sedentary prolonged bed rest. B: adjusted RV mass at baseline and following exercise during bed rest. C: adjusted RV mass and protein supplementation during bed rest. *P < 0.05.

 
Changes in Cardiac Morphology

There was a significant reduction in the length of the major axis of the LV following sedentary bed rest with (91 ± 5 to 88 ± 7 mm, P = 0.003; Fig. 5C) or without protein supplementation (90 ± 6 to 84 ± 7 mm; P < 0.001; Fig. 5A). In contrast, the major axis of the LV was preserved after exercise while the subjects were confined to bed (Fig. 5B; interaction P = 0.006). The length of the minor axis was not statistically different following sedentary bed rest with or without exercise or protein supplementation. The LV mass-to-volume ratio did not change significantly at the end of strict bed rest without protein supplementation (1.4 ± 0.2 to 1.6 ± 0.5 g/ml; P = 0.17) consistent with an eccentric atrophy, but there were significant increases in the mass-to-volume ratio at the end of bed rest with protein supplementation (1.3 ± 0.3 to 1.7 ± 0.4 g/ml; P = 0.02) and exercise training (1.3 ± 0.4 to 1.7 ± 0.4 g/ml; P = 0.009).


Figure 5
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  		Fig. 5. A: length of the major axis of the LV at baseline and after sedentary prolonged bed rest. B: length of the major axis of the LV baseline and following exercise during bed rest. C: length of the major axis of the LV and protein supplementation during bed rest. *P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The principal new findings of this study include the following: 1) sedentary HDT bed rest for 60 days results in cardiac atrophy in women to a degree that is similar to what has been observed previously in men (8.0%; Ref. 45); 2) exercise training and to a lesser extent protein supplementation prevent the adaptive cardiac atrophy associated with bed rest and preserve or even increase myocardial mass. As a result, exercise and to a lesser degree amino acid supplementation are effective countermeasures against the physiological cardiac remodeling following cardiovascular unloading.

Sex and Orthostatic Intolerance

Women appear to be more susceptible than men to presyncope and symptomatic orthostatic hypotension following microgravity exposure (16, 18–20, 25, 65), but the mechanism remains unclear. Although some argue that there are sex differences in sympathetic responses following cardiovascular unloading, the data are controversial and inconclusive (16, 17, 19, 20, 65), and the impact of cardiac atrophy in this setting is poorly defined.

Sex-specific cardiovascular responses to gravitational stress have been described (17, 25). For example, some reports have suggested that women have a blunted increase in vascular resistance and a greater augmentation in heart rate during LBNP compared with men, which has been attributed to the vasodilatory effects of estrogen (17, 27, 65). Furthermore, sympathetic nerve activity is decreased in post menopausal women following hormone replacement therapy (65). In contrast, Fu and coworkers (20) recently showed that men and women have similar increases in both total peripheral resistance and heart rate during head up tilt (20), and similar increases in total peripheral resistance during maximal LBNP to presyncope (19). Heart rate was elevated in this study because of a greater and more precipitous decline in SV and/or stroke index in women consistent with a primary difference in diastolic function. Furthermore, Fu and coworkers demonstrated that sex does not affect mean sympathetic nerve activity (bursts/min), plasma norepinephrine levels, systemic vascular resistance, or diastolic blood pressure following graded head-up tilt under both normovolemic or hypovolemic conditions. This study also showed that relative to men, women have significantly lower systolic blood pressures under both conditions, suggesting that women have smaller SV and less cardiac filling during gravitational stress (19, 20, 65).

Although the majority of high-resolution studies on cardiac morphology after gravitational unloading have been performed on men, cardiovascular structural differences between sexes without unloading have been described (41, 50, 51). For example, LV end-diastolic volume, RV end-diastolic volume, LV mass, RV mass, and LV cavity length are all greater for men than women despite adjustments for body size (41, 50, 51). Moreover, women have a smaller SV secondary to a smaller and stiffer LV than men during orthostatic stress (19, 20), and female athletes have less physiological hypertrophy than male athletes (38, 44, 57). Given the sex-specific morphological differences, high-resolution studies on female cardiac structure after microgravity exposure are necessary to understand the mechanisms behind the increased incidence of orthostatic intolerance in women after spaceflight.

Cardiac Remodeling Following Bed Rest in Men

Cardiac atrophy occurs after as short as 10 days of spaceflight in men (45). Although small animal models have been controversial (49), there is a prominent reduction in LV mass after thoracic inferior vena caval constriction in canines (37) consistent with the concept that chronic unloading of the heart of large mammals leads to cardiac atrophy. A recent study in our laboratory demonstrated that there was a 5% reduction in LV mass following 2 wk of bed rest deconditioning in men (14) and that LV mass decreased by 8% after 6 wk with an additional reduction of 8% after 12 wk (45, 46). Similar to what has been observed previously in men, this study found a 10% reduction in LV mass following 8 wk of bed rest in women (Fig. 3). Moreover, after 6 wk of HDT bed rest in men (45, 46), LV end-diastolic volume decreased by ~14% (P = 0.002), MWT decreased by ~4% (P = 0.01), RV end-diastolic volume decreased by ~16% (P = 0.06), and RV mass decreased by ~10% (P = 0.06), all qualitatively and quantitatively similar to the reductions observed in this study in healthy premenopausal women.

Implications for Exercise Training During Bed Rest

To prevent the physiological cardiac remodeling following microgravity exposure, effective countermeasures such as exercise must be implemented during spaceflight. Endurance exercise prevents the cardiac adaptations associated with gravitational unloading while preserving myocardial mass (14) and diastolic filling (34, 35, 39, 53). Not only does exercise prevent the reduction in LV compliance associated with aging (4, 34), LV end-diastolic volume, LV mass, and LV distensibility are all greater in Masters endurance athletes compared with age-matched sedentary seniors (4). Exercise training augments early filling rates, lowers peak atrial filling velocities (34, 53), and increases diastolic untwisting rates (14, 39). Moreover, preliminary reports using supine cycle ergometry alone (90 min/day, twice as long as the LBNP treadmill exercise in the present study) showed that while there was a significant reduction in LV mass (5%) after 18 days of sedentary –6° HDT bed rest, exercise training during bed actually resulted in a 4% increase in LV mass (14). Furthermore, endurance training prevents a decline in diastolic suction associated with HDT bed rest (14). The principal new findings of this study extend the previous research on the protective role for exercise during bed rest and demonstrate that despite a significant reduction in LV mass (10%) and RV mass (23%) following 60 days of HDT bed rest in women, there was a significant increase in LV mass (18%) and RV mass (18%) following exercise training during bed rest. Although the mechanisms behind the beneficial effects of exercise during gravitational unloading remain unclear, endurance exercise, with or without strength training certainly prevents cardiac atrophy, preserves myocardial viscoelastic properties, increases LV mass, optimizes LV chamber geometry (eccentric ventricular hypertrophy), and improves LV compliance (4, 35, 45).

Although the exercise protocol in this study consisted of dynamic treadmill running within an LBNP chamber and short episodes of resistive training on a flywheel ergometer, it is likely that any mode or combination of modes of exercise that increases cardiac work for an adequate duration and intensity by augmenting heart rate, preload, afterload, and/or contractility may cause physiological hypertrophy and prevent myocardial atrophy following bed rest or spaceflight. In fact, an earlier study that evaluated 947 elite athletes demonstrated that 27 different sports resulted in larger LV diastolic dimensions (57). However, cycling, rowing, and swimming are associated with larger LV dimensions and MWT than a purely static sport such as weightlifting, consistent with the eccentric physiological hypertrophy of endurance athletes (57).

Implications for Protein Supplementation During Bed Rest

This study was only a small part of a very large collaboration between the French, European, Canadian, and American space agencies, and the goal of the International Space Life Sciences Working Group was to design a protocol that would ensure the safety and health of female astronauts both during and after spaceflight. As a result, protein supplementation was implemented as an additional and separate countermeasure to the peripheral muscle wasting (5, 7, 58, 59, 60) associated with spaceflight. However, interestingly, LV and RV mass were preserved in this study following a 0.45 g/kg daily increase in dietary protein, which was supplemented with 7.2 g/kg of BCAA. Although this finding was quite surprising, there is a plethora of data supporting the notion that protein intake and BCAA supplementation stimulate protein synthesis, suppress protein breakdown, and prevent nitrogen loss in skeletal muscle and myocardium (2, 3, 5, 15, 59, 61, 66). Despite an intravenous infusion of amino acids, a recent study showed that there is less synthesis of lean-body protein after 14 days of bed rest compared with ambulatory controls (5, 6), but a significant increase in protein intake might achieve the same postabsorptive anabolic effect during best rest as seen during ambulatory periods (7). Moreover protein stimulation is augmented by BCAA by enhancing the production and function of proteins involved in mRNA translation (2, 3), and a recent study demonstrated that a 30 mmol/day increase of BCAA attenuated nitrogen loss following 6 days of bed rest compared with the group receiving nonessential amino acids (59), providing further evidence that there maybe a beneficial effect of branched-chain amino acid supplementation during bed rest. It should be noted that virtually all of these studies have examined protein balance in skeletal muscle. To our knowledge, detailed studies of protein balance during unloading have not been performed in cardiac muscle.

Myocardial Atrophy vs. Interstitial Fluid Volume

Numerous male bed rest models have established that cardiac remodeling occurs following microgravity exposure (11, 21, 34, 45, 47), but controversy still exists. Critics maintain that the apparent reduction in myocardial mass following microgravity exposure is a function of a reduction in myocardial interstitial fluid volume rather than a true cardiac atrophy (62). These authors' argument was based on the assertion that the reduction in LV mass (9.1%) measured by echocardiography after spaceflight was normalized after a 3-day recovery period, and it was also based on the observation that there was a small reduction in LV mass (3.7%) after dialysis as assessed by MRI (29, 62). Several lines of evidence suggest that this hypothesis is not correct.

First, after HDT bed rest, there is a greater leftward shift in the pressure-volume relationship than after a similar degree of hypovolemia due to intravenous furosemide (47), and volume replacement alone does not prevent the orthostatic intolerance observed following cardiovascular unloading (11, 21, 34, 47). In fact, after HDT bed rest, there is a reduction in the equilibrium volume and a significant decline in diastolic untwisting rates, suggesting a reduction in diastolic suction from true cardiac remodeling rather than exclusively hypovolemia (14, 31).

Moreover, in previous spaceflight studies, ventricular mass was measured using a mixed combination of two-dimensional echocardiography and two-dimensional guided M-mode echocardiography based on the Teicholz formula, which calculates mass from a single dimension raised to the third power. However, such echocardiographic measurements of myocardial mass are highly variable and imprecise (41, 50, 51), and thus echocardiography is not likely to be sensitive enough to detect small changes in cardiovascular structure (41, 50, 51). Although echocardiography is commonly used in clinical practice, its ability to measure cardiac mass is poorly reproducible and inaccurate (41, 50, 51). Two-dimensional echocardiography requires good acoustic windows for imaging and accurate delineation of endocardial borders, which is quite difficult given its limited resolution (41). Moreover, foreshortening is quite common with echo measurements (41), and echocardiography measurements of myocardial mass are dependent on ventricular volume. In fact, mass and volume calculations obtained from echocardiography are frequently discrepant from those values that were measured by cardiac MRI (40, 41, 51).

In comparison, MRI is very accurate and precise, and it is the gold standard for the assessment of LV mass and volume (45). Cardiac MRI does not rely on geometric assumptions, and it offers very high temporal and spatial resolution independent of patient size and operator skill (41, 50, 51). A recent study addressing the ability of MRI to assess LV and RV volume as well as LV and RV mass reported that intraobserver and interobserver variability ranged from 1.4 to 5.9% (51). In the previously mentioned dialysis study, LV mass only decreased by 3.7% despite an enormous 2- to 3-liter loss of volume after dialysis (29). In contrast, after losing only 200 ml of volume during spaceflight, the measured reduction in LV mass was three times greater than the reduction in LV mass after dialysis (29, 62). As a result, the authors of this study concluded that MRI measures LV mass both reliably and independently of LV loading (29). Hence, even extreme dehydration minimally impacts LV mass when assessed by appropriate techniques, although standard echocardiographic techniques may indeed be too sensitive to changes in LV volume to be reliably used to measure LV mass under these circumstances.

Furthermore, in this study LV volumes decreased similarly after bed rest with (22%) and without protein supplementation (20%), but these groups of subjects had drastically different changes in LV mass. Whereas LV mass decreased by 10% after sedentary bed rest, LV mass was preserved after subjects received protein supplementation during bed rest despite an equivalent loss of volume, providing further evidence that the apparent reduction in cardiac mass following microgravity exposure results from cardiac remodeling rather than hypovolemia.

Limitations

Perhaps, another limitation of our study is the fact that the subjects underwent only pre- and post-bed rest cardiac MRI studies, instead of a protocol with interval measurements of myocardial volumes and mass. Thus we cannot comment on the exact time course of the physiological atrophy associated with HDT bed rest in women. However, using a linear regression of LV mass after 2, 6, and 12 wk of bed rest in men, women appear to have the same degree of cardiac atrophy (Fig. 3).

Although this study did not directly address whether or not exercise and protein supplementation would decrease the incidence of orthostatic intolerance test associated with HDT bed rest, it did clearly show that exercise and to a lesser extent protein supplementation prevent the cardiac atrophy observed during HDT bed rest.

Furthermore, sympathoactivation is an important trophic signal in the heart, and it is possible that LBNP-induced sympathetic activation may contribute to limiting cardiac atrophy independent of exercise. However, it is likely that exercise during LBNP would minimize the sympathetic activation produced by LBNP alone by virtue of the muscle pump.

Finally, the exercise intervention used in this study incorporated a combination of dynamic and static exercise rather than either type of exercise independently. This type of training is typical of competitive athletes but precludes us from attributing the prevention of cardiac atrophy to either the endurance or the strength component of the intervention by itself. Additional studies with a more direct comparison are necessary to answer this question explicitly.

In conclusion, using the gold standard for the measurement of cardiac mass, this study found that women have the same relative degree of cardiac atrophy as do men following 60 days of sedentary long-term HDT bed rest, and this myocardial atrophy likely contributes to the reduction in cardiac filling and the prominent drop in upright SV observed after microgravity exposure. However, a combined program of dynamic and static exercise training during bed rest prevents this adaptive cardiac remodeling and increases myocardial mass. Although dietary protein with BCAA supplementation is less effective than exercise training, this study suggested that an increased intake of protein enriched with BCAA preserved cardiac mass and suppressed the physiological cardiac atrophy associated with cardiovascular unloading. We speculate that an exercise regimen coupled with protein and BCAA supplementation might offer the best protection from the myocardial wasting associated with microgravity exposure.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This study, Women International Space Simulation for Exploration 2005, was sponsored by the European Space Agency, the National Aeronautics and Space Administration of the USA (NASA), the Canadian Space Agency, and the French "Centre National d'Etudes Spatiales," which has been the "Promoteur" of the study according to French law. The study has been performed by MEDES, Institute for Space Physiology and Medicine in Toulouse, France. This study was also supported by NASA Grant NNJ04HF71G (to A. R. Hargens) and by NASA/NSBRI Grants NNJ04H01A and CA00701 (to B. J. Levine).


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Stuart M. C. Lee, R. Scott Meyer, Scott M. Smith, Don Watenpaugh, Yvonne Moutier, Scott Trappe, Dieter Blottner, Angèle Choppard, Jacques Mercier, Maurice Hayot, Pierre Barbe, Don Ranney, Laurence Stevens, Bruno Bastide, Todd Trappe, Per A. Tesch, Benedikt Schoser, Jean-François Marini, Claude Dechesne, and Murielle Mutin for establishing and executing the exercise protocol. We also must thank Beniamino Ciocchi, Raffaella Antonione, Francesca Zorat, Elena Caliandro, Arianna Piccoli, Mariella Sturma, and Anna De Santis for their assistance with the protein supplementation protocol. Moreover, we thank the nurses, staff, and entire research team at the MEDES Space Clinic (Toulouse Rangueil Hospital) for their exceptional care of the subjects during bed rest and exercise. Finally, we thank the outstanding 24 women who volunteered for this bed rest investigation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. D. Levine, Institute for Exercise and Environmental Medicine, 7232 Greenville Ave., Suite 435, Dallas, TX 75231 (e-mail: BenjaminLevine{at}TexasHealth.org)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* Both B. D. Levine and A. R. Hargens are senior authors on this paper. Back


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