Supine cycling plus volume loading prevent cardiovascular deconditioning during bed rest
Abstract
There are two possible mechanisms contributing to the excessive fall of stroke volume (and its contribution to orthostatic intolerance) in the upright position after bed rest or spaceflight: reduced cardiac filling due to hypovolemia and/or a less distensible heart due to cardiac atrophy. We hypothesized that preservation of cardiac mechanical function by exercise training, plus normalization of cardiac filling with volume infusion, would prevent orthostatic intolerance after bed rest. Eighteen men and three women were assigned to 1) exercise countermeasure (n = 14) and 2) no exercise countermeasure (n = 7) groups during bed rest. Bed rest occurred in the 6° head-down tilt position for 18 days. The exercise regimen was prescribed to compensate for the estimated cardiac work reduction between bed rest and ambulatory periods. At the end of bed rest, the subjects were further divided into two additional groups for post-bed rest testing: 1) volume loading with intravenous dextran to normalize cardiac filling pressure and 2) no volume loading. Dextran infusion was given to half of the exercise group and all of the sedentary group after bed rest, leading ultimately to three groups: 1) exercise plus volume infusion; 2) exercise alone; and 3) volume infusion alone. Exercise training alone preserved left ventricular mass and distensibility as well as upright exercise capacity, but lower body negative pressure (LBNP) tolerance was still depressed. LBNP tolerance was maintained only when exercise training was accompanied by dextran infusion. Dextran infusion alone following bed rest without exercise maintained neither orthostatic tolerance nor upright exercise capacity. We conclude that daily supine cycle exercise sufficient to prevent cardiac atrophy can prevent orthostatic intolerance after bed rest only when combined with plasma volume restoration. This maintenance of orthostatic tolerance was achieved by neither exercise nor dextran infusion alone. Cardiac atrophy and hypovolemia are likely to contribute independently to orthostatic intolerance after bed rest.
the circulatory adaptation to microgravity or ground-based simulations such as head-down tilt bed rest is initiated by an acute cephalic shift of intravascular volume due to a loss of gravitational hydrostatic gradients, resulting in an increase in cardiac preload relative to the upright position on Earth (2). Immediate neurohumoral modulation of this enhanced central blood volume induces a salt and water diuresis and reduces cardiac filling and stroke volume (SV) to the level approximately one-half between the supine and standing postures within 48 h during head-down tilt bed rest (24, 27, 30). When exposure to bed rest is more prolonged, adaptive cardiac remodeling occurs because of continuous cardiac unloading and thus reduced cardiac work, which leads to eccentric cardiac atrophy (9, 10, 31) and a less distensible left ventricle (LV) (27, 32) within as little as 2 wk. When gravitational load is restored, orthostatic hypotension may ensue when the upright SV is too small for the available vasoconstrictor reserve (13, 26, 27). An upright SV that is lower after compared with before bed rest or spaceflight has been observed in virtually all microgravity investigations and is the sine qua non of the cardiovascular adaptation to microgravity.
The mechanism underlying this very low upright SV is multifactorial. SV is largely regulated by cardiac filling via the Starling mechanism (29, 33). While the plasma volume loss associated with bed rest clearly reduces cardiac filling (23, 32) and contributes to orthostatic intolerance after microgravity exposure, our previous observations have shown that the cardiac atrophy exacerbates this fall in SV by changing the operating characteristics of the Starling mechanism—LV end-diastolic volumes (LVEDV) and thus SV are smaller at any given cardiac filling pressure, especially below baseline when pericardial constraint is minimal (27, 32). As a consequence, there are two possible physiological mechanisms contributing to the excessive fall in SV after bed rest: 1) lower cardiac filling due to hypovolemia and 2) a less distensible heart due to cardiac atrophy.
It is well known that endurance athletes with LV eccentric hypertrophy have hearts that are more compliant and distensible than those of nonathletes (25, 35). Conversely, prolonged physical inactivity is accompanied by cardiac atrophy and is particularly pronounced in patients with high-level spinal cord injury, an example of long-term and extreme physical inactivity (8). These observations strongly suggest that physical activity is a critical component that determines cardiac mass by modulating cardiac work.
This study therefore had two independent but related hypotheses: 1) that endurance exercise training sufficient to compensate for the cardiac work reduction during bed rest would maintain LV structure and function including LV compliance and the Starling mechanism and 2) that acute volume restoration carefully calibrated to eliminate hypovolemia and normalize cardiac preload, when combined with preserved cardiac mechanics, would prevent orthostatic intolerance after bed rest by eliminating the excessive fall in SV.
METHODS
Subjects
Sedentary, nonsmoking, healthy men (n = 18) and women (n = 3) participated in this study. Subjects were randomly assigned in a 2:1 balanced randomization (by sex, age within 5 yr, and physical activity) to exercise countermeasure (12 men and 2 women) and sedentary (6 men and 1 woman) groups. All subjects were normotensive with a normal ECG at rest and during 24 h of ambulatory blood pressure and Holter recordings. They had normal echocardiograms, did not use any regular medication, and were free of drugs.
All subjects signed an informed consent form to participate in protocols approved by the Institutional Review Boards of the University of Texas Southwestern Medical Center at Dallas and Texas Health Presbyterian Hospital Dallas.
Bed Rest and Exercise Countermeasure
An overview of the study is provided in Fig. 1. The overall structure began with a pre-bed rest period during which all experiments were conducted in a set order. Subjects were provided a standard diet of fixed sodium and calorie content with ad libitum fluids for 3 days before each testing session.
Fig. 1.Detailed study design for 18 days of 6° head-down tilt bed rest and 2 kinds of countermeasures: 1) supine cycle exercise training and 2) intravenous dextran infusion. ExDex (n = 7) and ExNoVol (n = 7) are groups with or without dextran infusion, respectively, after exercise countermeasure (Exercise, n = 14) during bed rest. SedDex (n = 7) is the group with dextran infusion after sedentary bed rest. PCWP, pulmonary capillary wedge pressure.
The pretesting was followed by a bed rest period of 14 days during which hypothesis 1 was tested with the random assignment to exercise intervention. Bed rest occurred in the 6° degree head-down tilt position at all times, although subjects were allowed to elevate on one elbow for meals. Day-night cycles were strictly monitored and controlled. Subjects were housed in the General Clinical Research Center at the University of Texas Southwestern Medical Center/Parkland Hospital and given a standard diet. Calories were supplemented in the exercising subjects to account for increased caloric expenditure from exercise, and to prevent weight loss beyond that achieved after the first 72 h in bed. Fluids were allowed ad libitum during this period.
On day 15, subjects returned to the lab for post-bed rest hemodynamic assessment and exact titration of LV preload restoration as described below. Subjects remained in bed for an additional 3 days, with ongoing countermeasure implementation for a total of 18 days of bed rest, after which orthostatic tolerance and exercise testing were repeated for the testing of hypothesis 2 by random assignment (of the exercising subjects) to volume infusion.
Exercise was performed in the supine position on a supine cycle ergometer three times a day. The quantity of exercise training was determined based on a calculation of cardiac work assuming that cumulative cardiac stroke work would be the primary determinant of LV mass. We previously (27) estimated a reduction of 24-h cardiac work by ∼18% during bed rest compared with ambulatory periods from our earlier bed rest study. We also estimated, on the basis of known increases in SV and blood pressure during submaximal exercise, that it would take ∼90 min of dynamic exercise per day at 75% of maximum heart rate to normalize stroke work while in bed compared with ambulatory periods (27). Therefore, subjects in the exercise group exercised three times a day, 30 min a session, at 75% of maximal heart rate. Subjects used Polar heart rate monitors (Polar Electro) to monitor and record their heart rates during exercise. A training program with individual target heart rates was given to each subject and strictly controlled.
Pre-Bed Rest Testing Protocol
Day 1: baseline hemodynamics and cardiac mechanics.
baseline hemodynamics.
A 6-Fr balloon-tipped, fluid-filled catheter (Swan-Ganz, Baxter) was placed through an antecubital vein into the pulmonary artery under fluoroscopic guidance. All intracardiac pressures were referenced to atmospheric pressure, with the pressure transducer (Transpac IV, Abbott) zero reading set at 5 cm below the sternal angle. Heart rate was monitored continuously with the ECG (Hewlett-Packard). Blood pressure was measured continuously in the finger with photoplethysmography (Finapres, Ohmeda) and intermittently by an arm cuff with electrosphygmomanometry (Suntech 4240). Cardiac output was measured every 5 min with a modification of the foreign gas rebreathing technique using acetylene as the soluble and helium as the insoluble gas (20, 27, 32). SV was calculated from the cardiac output and corresponding heart rate during rebreathing. Hemodynamic stability was confirmed after >30 min of quiet supine rest by at least two sequential stable cardiac outputs with <10% difference between each other, which was used for baseline SV calculation. After a confirmation of baseline hemodynamic stability, plasma volume was measured with the Evans blue dye technique (12). Hematocrit was measured via microcentrifuge techniques; blood volume was calculated from the plasma volume and hematocrit. Baseline measurements of pulmonary capillary wedge pressure (PCWP) and LVEDV followed. The mean PCWP was determined visually at end expiration and was used as an index of LV end-diastolic pressure (5). LVEDV was estimated with two-dimensional echocardiography using standard views and formulas, as recommended by the American Society of Echocardiography (ATL HDI 5000) (36). Images were obtained with an annular phased-array transducer using a frequency of 2.5–3.5 MHz. Measurements of LV endocardial areas were made from the parasternal short-axis window at the level of the mitral valve and papillary muscles and from the apical window in the four-chamber view, where the major-axis distance was measured from apex to the mitral annulus. To calculate LVEDV for each subject, either a modified Simpson's rule or the area-length method was chosen based on the optimal endocardial definition. The same formula was used for each individual subject throughout the study.
cardiac mechanics.
Lower body negative pressure (LBNP) was used to decrease cardiac filling as previously described (27, 32). Briefly, LBNP was implemented with a Plexiglas tank sealed at the level of the iliac crests in the supine position. Measurements of cardiac output, cuff blood pressure, PCWP, and LVEDV were obtained after 5 min each of −15 and −30 mmHg LBNP while finger blood pressure and heart rate were continuously monitored. After LBNP was released, repeat baseline measurements were made to confirm a return to the hemodynamic steady state. Cardiac filling was then increased by a rapid (100–200 ml/min) infusion of warm (37°C) isotonic saline. The same hemodynamic measurements as at LBNP were repeated immediately after 15 and 30 ml/kg saline had been infused. These six data points (2 baselines, LBNP −15 and −30 mmHg, and saline infusion of 15 and 30 ml/kg) were used to construct Starling and LV pressure-volume curves as previously described (25, 27, 32).
Day 2: maximal orthostatic tolerance and exercise tests.
Maximal orthostatic tolerance and exercise testing was performed at least 3 days after the invasive pressure-volume measurement in order to minimize the effects of the volume infusion during the assessment of cardiac mechanics on day 1.
maximal orthostatic tolerance.
Maximal orthostatic tolerance was measured with a ramped LBNP test, beginning at −15 mmHg for 5 min and then increasing to −30 and −40 mmHg for 5 min each, followed by an increase in LBNP by −10 mmHg every 3 min until signs or symptoms of presyncope were observed according to previously described criteria (27). Maximal orthostatic tolerance was calculated from the summed product of the absolute magnitude of LBNP multiplied by time at each stage (mmHg·min). These tests were always performed first thing in the morning on all testing days.
maximal exercise tests.
Maximal exercise tests were performed in the upright position on a cycle ergometer. Exercise testing always occurred in the early afternoon at least 2 h after the maximal LBNP testing. This order was set to prevent the effects of a single bout of maximal exercise on orthostatic tolerance (7). Heart rate was monitored continuously by 12-lead ECG, and blood pressure was monitored every 2 min by arm cuff (Suntech 4240). Gas exchange analysis was performed by the technique of Douglas with CO2, N2, and O2 concentrations determined by mass spectrometry (Marquette MGA 1100) and ventilation volumes by Tissot spirometer. Cardiac output was determined with the modified acetylene rebreathing technique. Oxygen uptake and cardiac output were determined at rest and at maximal effort. At rest, Douglas bags were collected for 3 min, and cardiac output was measured in triplicate and averaged. After the rest data collection, subjects started cycling at an individually determined initial workload (watts) and the workload was increased 20–25 W every 2 min to achieve maximal effort within ∼10–12 min. The initial workload was determined by a screening exercise test for each subject. During maximal exercise testing, Douglas bags were collected in the second minute of each of the final three stages as predicted from screening test data, with consecutive 45-s collections when the subject was nearing maximal effort. Cardiac output was measured during the final 20 s of maximal exercise. Maximal exercise was defined as an inability to continue exercise despite vigorous encouragement. Cardiac output was divided by heart rate during rebreathing to calculate SV. Oxygen uptake (V̇o2) was divided by cardiac output to calculate arteriovenous oxygen content difference according to the Fick equation.
Post-Bed Rest Testing Protocol
The same order and timing of testing as during pre-bed rest testing was used for post-bed rest testing.
Day 1: baseline hemodynamics and cardiac mechanics.
baseline hemodynamics.
First, to evaluate the effects of the exercise countermeasure (exercise vs. sedentary, hypothesis 1) on baseline hemodynamics, measurements of blood volume, cardiac output, heart rate, blood pressure, PCWP, and LVEDV were made in both exercise and sedentary groups (Fig. 1).
Next, to test hypothesis 2, dextran 40 was infused in half of the exercise countermeasure subjects (6 men and 1 woman, random balanced assignment) (ExDex) and all of the sedentary subjects (6 men and 1 woman) (SedDex) to restore both plasma volume and LV filling pressures up to the pre-bed rest level. Dextran was not infused in the other half of the exercise countermeasure subjects (ExNoVol) (Fig. 1); thus the only difference between the two exercise countermeasure groups was the dextran infusion after bed rest on testing days. Specifically, with continuous monitoring of PCWP, the amount of dextran equivalent to the plasma loss estimated by the Evans blue dye technique was infused rapidly (∼1,000 ml/h) and allowed to equilibrate for 30 min, followed by repeat assessment of PCWP. If the mean PCWP was still below the pre-bed rest baseline value, additional dextran was infused in 100- to 250-ml increments until the baseline PCWP was achieved. Hemodynamic measurements were repeated 30 min after the completion of the last dextran infusion to provide a second “baseline” value.
cardiac mechanics.
The same protocol of LBNP and normal saline infusion as performed before bed rest was then followed to construct LV pressure-volume and Starling curves after baseline hemodynamic measurements in the non-dextran infusion group (ExNoVol) and after the second “baseline” hemodynamic measurements following normalization of preload with dextran infusion in the dextran infusion groups (ExDex and SedDex).
Day 2: maximal orthostatic tolerance and exercise tests.
Maximal orthostatic tolerance and exercise testing was performed 3 days after the invasive pressure-volume measurement in order to minimize the effects of the day 1 dextran (for plasma volume normalization) and saline (as part of cardiac mechanics protocol) infusions and to keep the order identical to that for the pre-bed rest testing. As noted above, subjects remained in head-down tilt bed rest between day 1 and day 2 (Fig. 1).
maximal orthostatic tolerance.
Because no right heart catheterization was performed on the maximal orthostatic tolerance testing day, the same amount of dextran that was infused in the precisely calibrated day 1 protocol was reinfused in each subject designated for plasma volume restoration (ExDex + SedDex groups). As on day 1, dextran was not infused in the ExNoVol group. The same protocol of the maximal orthostatic tolerance test with LBNP used in pre-bed rest testing was performed 30 min after the completion of dextran infusion.
maximal exercise tests.
After a break following the maximal LBNP test, during which subjects were allowed to be seated upright and walk to the bathroom, maximal exercise tests were performed in the upright position by cycle ergometry with the same protocol as used for the pre-bed rest testing. As with pre-bed rest testing, maximal exercise occurred ∼2 h after completion of the maximal orthostatic tolerance testing.
Left Ventricular Mass
LV mass was quantified by MRI (1.5-T Philips NT MRI scanner, Best, The Netherlands) before and after bed rest. Short-axis, gradient-echo, cine MRI sequences with a temporal resolution of 39 ms were obtained to calculate LV masses as previously described (19). LV mass was computed as the difference between epicardial and endocardial areas multiplied by the density of heart muscle, 1.05 g/ml (22). The data for LV mass in these subjects have been reported previously (10).
Data Analysis
Starling curves (PCWP vs. SV).
An index of the steepness of the Starling relationship during a decrease in cardiac filling was obtained by performing linear regression on the linear portion of the curve for each subject, including points obtained at baseline and during LBNP at −15 and −30 mmHg (27, 32). This characteristic has been shown in previous studies to predict a significant portion of the individual variation in LBNP tolerance (25). Starling curves were constructed for the grouped means of PCWP and SV. A grouped Starling curve was drawn by applying second-order linear regression to these mean data.
Left ventricular pressure-volume curves.
To evaluate chamber properties, we constructed pressure-volume curves relating LVEDV to PCWP, using the logarithmic equation described by Nikolic et al. (28): P = −S ln[(Vm − V)/(Vm − V0)], where P is PCWP, V is LVEDV, V0 is equilibrium volume or the volume at which P = 0, Vm is the maximal volume obtained by this chamber, and S is a stiffness constant that describes the shape of the entire curve. The key feature of this model is the ability to identify the equilibrium volume of the LV, which is the LV volume when filling pressure is zero. This characteristic identifies an important property of LV filling because it is this volume below which the LV must contract in systole to take advantage of diastolic suction (28, 42).
Modeling of the logarithmic curves was performed with the Marquardt-Levenberg algorithm and commercially available software (Sigmaplot 10.0, Jandel Scientific). Initial values for iterative determination of the logarithmic relationship were chosen for each individual subject as Vm = 1 ml above the maximum LVEDV observed during volume infusion and V0 = 1 ml below the minimum LVEDV observed during LBNP. Pressure-volume curves were calculated for each individual subject before and after bed rest for statistical comparisons as well as for grouped means for the composite curves. Operational slopes of pressure-volume curves were calculated from their derivatives: dP/dV = S/(Vm − V).
Statistics.
Data are presented as means ± SE. Statistical probability was assessed with Student's paired t-test to test the difference between values before and after the bed rest. One-way ANOVA was used for the comparison of percent changes between before and after bed rest to test interaction among groups, and a Tukey post hoc test was applied when the P value was <0.05. Student's t-test was used for the comparison of percent changes between before and after bed rest to test the interaction between the exercise groups (ExDex and ExNoVol) versus the nonexercise group (SedDex) only for baseline hemodynamics.
RESULTS
Baseline Hemodynamics
Comparison for hypothesis 1: exercise vs. sedentary.
All baseline measures of cardiac filling pressures [PCWP and right atrial pressure (RAP)] and volume (LVEDV) decreased in both groups after 2 wk of 6° head-down tilt bed rest, while the magnitude of the decrease in LVEDV was larger in the sedentary group than in the exercise group (Table 1). Consistent with lower cardiac filling, cardiac output and SV also decreased after the 2 wk of bed rest. The magnitude of the decrease in SV was larger in the sedentary group than in the exercise group (Table 1), similar to the pattern for cardiac filling pressures. These changes were accompanied by a reduction of plasma volume and blood volume with the same trend, such that the magnitude of the decrease was larger in the sedentary group while the reduction of blood volume was considerably smaller and of less statistical probability in the exercise countermeasure group (Table 1).
| Condition | Pre | Post | P Value | Change % | Interaction P Value |
|---|---|---|---|---|---|
| Exercise (n = 14) | |||||
| Weight, kg | 79 ± 4 | 76 ± 4 | <0.001* | −2.7 ± 0.4 | 0.759 |
| Plasma volume, liter | 3.39 ± 0.17 | 3.23 ± 0.17 | 0.015* | −4.5 ± 1.8 | 0.111 |
| Blood volume, liter | 5.48 ± 0.30 | 5.33 ± 0.31 | 0.154 | −2.5 ± 1.9 | 0.217 |
| MBP, mmHg | 85 ± 2 | 88 ± 11 | 0.195 | 3.4 ± 2.5 | 0.487 |
| Qc, liter | 7.2 ± 0.3 | 6.7 ± 0.3 | 0.087 | −5.6 ± 3.8 | 0.357 |
| SV, ml | 109 ± 6 | 105 ± 8 | 0.357 | −4.1 ± 3.5 | 0.037* |
| TPR, dyn·s·cm−5 | 976 ± 50 | 1,079 ± 59 | 0.029* | 11.5 ± 4.3 | 0.537 |
| PCWP, mmHg | 11.0 ± 0.4 | 9.5 ± 0.5 | 0.002* | −14.0 ± 3.6 | 0.221 |
| RAP, mmHg | 7.8 ± 0.5 | 6.7 ± 0.5 | 0.043* | −11.7 ± 6.5 | 0.368 |
| LVEDV, ml | 127 ± 8 | 120 ± 7 | 0.014* | −4.7 ± 1.9 | 0.021* |
| LV mass, g | 146 ± 9 | 154 ± 11 | 0.046* | 4.6 ± 2.2 | 0.021* |
| Sedentary (n = 7) | |||||
| Weight, kg | 78 ± 6 | 76 ± 5 | 0.036* | −2.4 ± 0.8 | |
| Plasma volume, liter | 3.4 ± 0.2 | 3.1 ± 0.2 | <0.001* | −8.8 ± 0.5 | |
| Blood volume, liter | 5.5 ± 0.3 | 5.2 ± 0.3 | <0.001* | −6.0 ± 0.7 | |
| MBP, mmHg | 85 ± 2 | 85 ± 3 | 0.958 | 0.4 ± 3.5 | |
| Qc, liter | 7.4 ± 0.2 | 6.5 ± 0.4 | 0.038* | −11.5 ± 4.4 | |
| SV, ml | 113 ± 7 | 95 ± 5 | <0.001* | −15.8 ± 2.0 | |
| TPR, dyn·s·cm−5 | 936 ± 38 | 1,081 ± 47 | 0.003* | 15.7 ± 3.3 | |
| PCWP, mmHg | 10.2 ± 0.6 | 7.9 ± 0.4 | 0.003* | −21.5 ± 4.2 | |
| RAP, mmHg | 6.6 ± 0.7 | 5.0 ± 0.3 | 0.019* | −21.0 ± 5.6 | |
| LVEDV, ml | 140 ± 7 | 123 ± 5 | <0.001* | −12.2 ± 1.7 | |
| LV mass, g | 158 ± 6 | 152 ± 6 | 0.064 | −3.8 ± 1.7 | |
LV mass quantified by MRI was slightly but statistically significantly increased in the exercise group, while it tended to be slightly decreased in the sedentary group (Table 1). As described previously, the differential response between exercise and sedentary groups was statistically significant (10).
Comparison for hypothesis 2: dextran infusion.
The post-bed rest baseline hemodynamics after dextran infusion was compared with the pre-bed rest baseline hemodynamics in the dextran infusion groups (ExDex and SedDex) (Table 2). Of note, all cardiac filling and output indexes were restored up to or even above pre-bed rest baseline levels in both dextran infusion groups (ExDex and SedDex), indicating the validity of the protocol. The amount of dextran infusion was 304 ± 53 ml in the ExDex group and 435 ± 80 ml in the SedDex group (P = 0.198).
| Pre | Post | % Change | P Value | Interaction P Value | |
|---|---|---|---|---|---|
| ExDex (n = 7) | |||||
| MBP, mmHg | 83 ± 3 | 82 ± 2 | −0.7 ± 2.0 | 0.659 | 0.183 |
| Qc, liter | 7.1 ± 0.4 | 7.5 ± 0.3 | 8.6 ± 7.5 | 0.367 | 0.704 |
| SV, ml | 106 ± 6 | 112 ± 8 | 6.1 ± 4.0 | 0.151 | 0.883 |
| TPR, dyn·s·cm−5 | 959 ± 66 | 881 ± 33 | −5.8 ± 6.9 | 0.302 | 0.900 |
| PCWP, mmHg | 11.2 ± 0.8 | 11.5 ± 0.8 | 3.0 ± 3.3 | 0.391 | 0.200 |
| RAP, mmHg | 7.7 ± 0.7 | 7.6 ± 0.4 | 1.8 ± 6.9 | 0.846 | 0.275 |
| LVEDV, ml | 129 ± 9 | 144 ± 9 | 13.3 ± 3.9 | 0.015* | 0.012* |
| SedDex (n = 7) | |||||
| MBP, mmHg | 85 ± 2 | 88 ± 3 | 3.3 ± 1.9 | 0.131 | |
| Qc, liter | 7.4 ± 0.2 | 8.2 ± 0.2 | 11.8 ± 3.4 | 0.011* | |
| SV, ml | 113 ± 7 | 118 ± 5 | 5.4 ± 2.4 | 0.054* | |
| TPR, dyn·s·cm−5 | 936 ± 39 | 869 ± 26 | −6.8 ± 2.0 | 0.019* | |
| PCWP, mmHg | 10.2 ± 0.6 | 11.0 ± 0.5 | 8.8 ± 2.7 | 0.009* | |
| RAP, mmHg | 6.6 ± 0.7 | 7.2 ± 0.5 | 11.9 ± 5.6 | 0.094 | |
| LVEDV, ml | 140 ± 7 | 138 ± 11 | −2.3 ± 3.6 | 0.669 | |
Orthostatic Tolerance
Maximal LBNP tolerance (orthostatic tolerance index, time·LBNP, mmHg·min) was preserved in the ExDex group even after 2 wk of bed rest (pre 839 ± 133, post 826 ± 85 mmHg·min; P = 0.921), while it was reduced 25 ± 7% (pre 879 ± 57, post 654 ± 66 mmHg·min; P = 0.008) in the SedDex group (Fig. 2). This decrease compares with a 24% decrease in our previously reported (27) bed rest study using exactly the same testing and bed rest protocols in which neither exercise countermeasure nor dextran infusion was given. To our surprise, the decrease in LBNP tolerance was not improved and may even have been worsened by exercise without volume infusion: ExNoVol group showed 43 ± 5% reduction (pre 1,157 ± 192, post 641 ± 95 mmHg·min; P = 0.004).
Fig. 2.Maximal lower body negative pressure (LBNP) tolerance before (pre) and after (post) head-down tilt bed rest in ExDex, ExNoVol, and SedDex groups.
Starling Curves
The post-bed rest Starling curves (Fig. 3) were virtually identical to the pre-bed rest curves in both exercise groups (ExDex and ExNoVol). However, there was one important difference. The post-bed rest individual data points for the ExDex group were superimposed on their pre-bed rest values, but for the ExNoVol group there was a reduction in the lowest PCWP achieved during LBNP and a commensurate reduction in SV such that they shifted to a lower point on the same curve. This difference was consistent with preserved cardiac mechanics but relative hypovolemia in the ExNoVol group compared with the ExDex group. In contrast, for the SedDex group there was a distinct reduction in SV for any given filling pressure below baseline, similar to that observed previously after sedentary bed rest without any countermeasure (27).
Fig. 3.Starling curves before (pre) and after (post) head-down tilt bed rest in ExDex, ExNoVol, and SedDex groups. Shown are mean ± SE group data for stroke volume (SV) at given PCWP. Six data points correspond to 2 degrees of LBNP, 2 baselines, and 2 saline infusions. Dextran infusion groups (ExDex and SedDex) have 7 data points in the post-bed rest results, including another data point from before dextran infusion. Curves were drawn by second-order linear regression based on mean values for each condition.
These differences among Starling curves could be quantified by the slopes of the linear part of the curves. These slopes were clearly steeper in the SedDex group (pre 6.2 ± 0.2, post 8.3 ± 0.8; P = 0.033) and probably steeper in the ExNoVol group (pre 5.4 ± 0.6, post 7.7 ± 1.4; P = 0.101) after bed rest even though cardiac filling pressure was normalized in the SedDex group. In contrast, the Starling curve slope was unchanged between before and after bed rest in the ExDex group (pre 6.6 ± 0.9, post 7.1 ± 1.8 ml/mmHg; P = 0.818).
Left Ventricular Pressure-Volume Curves
Like the Starling curves, the pressure-volume curves were identical between before and after bed rest in the exercise groups (ExDex and ExNoVol); in contrast, a leftward shift was observed in the sedentary group (SedDex) (Fig. 4). Consistent with this leftward shift, V0 and maximal volume (Vmax) were likely decreased in the SedDex group after 2 wk of bed rest (P = 0.069 and P = 0.077, respectively), while they were comparable in both ExDex (P = 0.647 and 0.619) and ExNoVol groups (P = 0.769 and 0.836; Table 3; note that V0 and Vmax in Fig. 4 are derived from the logarithmic model of the group mean data points of LVEDV and PCWP and thus differ from the mean of the individual values). The overall chamber stiffness constant was not significantly different between before and after bed rest in any group (Table 3). Operational slopes at baseline LVEDV were flatter in the sedentary group (SedDex; P = 0.05) and probably flatter in the exercise groups [ExDex (P = 0.088) and ExNoVol (P = 0.134)] after bed rest, while these were restored by dextran infusion in both groups (ExDex and SedDex) (Table 3). Even if an estimate of transmural pressure (PCWP − RAP) (1, 39) is used as the dependent variable to construct the pressure-volume curves, these differences before and after bed rest between groups remain the same.
Fig. 4.Left ventricular pressure-volume curves before (pre) and after (post) head-down tilt bed rest in ExDex, ExNoVol, and SedDex groups. Shown are mean ± SE group data. Six data points correspond to 2 degrees of LBNP, 2 baselines, and 2 saline infusions. Dextran infusion groups (ExDex and SedDex) have 7 data points in the post-bed rest results, including another data point from before dextran infusion. V0, Vmax, and Stiffness are equilibrium volume, maximum volume, and stiffness constant from the logarithmic model. These indexes are derived from group mean data points and thus differ from the mean of the individual values in Table 3. LVEDV, left ventricular end-diastolic volume.
| Pre | Post | P Value | |
|---|---|---|---|
| ExDex (n = 7) | |||
| V0, ml | 26 ± 6 | 22 ± 9 | 0.647 |
| Vmax, ml | 184 ± 7 | 191 ± 11 | 0.619 |
| S | 9.2 ± 0.9 | 9.0 ± 1.6 | 0.893 |
| dP/dV at BL | 0.20 ± 0.03 | 0.14 ± 0.02 | 0.088 |
| dP/dV at 2nd BL | N/A | 0.27 ± 0.08 | 0.313 |
| ExNoVol (n = 7) | |||
| V0, ml | 44 ± 10 | 55 ± 10 | 0.367 |
| Vmax, ml | 196 ± 25 | 188 ± 18 | 0.769 |
| S | 15.8 ± 2.1 | 16.8 ± 2.4 | 0.836 |
| dP/dV at BL | 0.26 ± 0.03 | 0.21 ± 0.01 | 0.134 |
| SedDex (n = 7) | |||
| V0, ml | 68 ± 10 | 26 ± 12 | 0.069 |
| Vmax, ml | 223 ± 23 | 187 ± 9 | 0.077 |
| S | 16.7 ± 3.1 | 9.8 ± 1.3 | 0.127 |
| dP/dV at BL | 0.22 ± 0.03 | 0.16 ± 0.03 | 0.050 |
| dP/dV at 2nd BL | N/A | 0.20 ± 0.03 | 0.582 |
Maximum Exercise Test
Maximal oxygen uptake (V̇o2max) decreased prominently in the sedentary group (SedDex: pre 2.54 ± 0.18, post 2.03 ± 0.13 l/min, −19 ± 5%; P = 0.012) despite volume loading, accompanied by an equivalent reduction in peak workload (SedDex: pre 203 ± 13, post 174 ± 13 W, −13 ± 5%; P = 0.07). In contrast, V̇o2max was unchanged [ExDex: pre 2.85 ± 0.26, post 2.81 ± 0.20 l/min (P = 0.624); ExNoVol: pre 2.96 ± 0.40, post 2.76 ± 0.30 ml (P = 0.343)] and peak upright workload was even slightly increased [ExDex: pre 217 ± 15, post 226 ± 14 W (P = 0.095); ExNoVol: pre 214 ± 26, post 216 ± 22 W (P = 0.928)] in the exercising groups. More comprehensive physiological variables from maximal exercise testing are provided in Supplemental Tables S1 and S2.1
DISCUSSION
The principal new findings from the present study were as follows: 1) Orthostatic tolerance was maintained after 2 wk of 6° head-down tilt bed rest by the combination of sufficient daily cycling to normalize cardiac work between bed rest and ambulatory periods plus the normalization of plasma volume by dextran infusion; 2) the mechanisms for this preservation appeared to be a combination of both preserving cardiac mechanical function (preventing cardiac atrophy and stiffening) plus restoration of cardiac filling volume; 3) however, neither exercise training nor the normalization of plasma volume alone maintained orthostatic tolerance after bed rest; and 4) this “dose” of exercise training was also sufficient to maintain exercise capacity in the upright position. To our knowledge, this study is the first to demonstrate the complete prevention of orthostatic intolerance after prolonged bed rest without gravitational countermeasures. The fact that exercise training or dextran infusion alone did not prevent the orthostatic intolerance suggests that insufficient cardiac filling and impaired cardiac mechanics both independently affect orthostatic intolerance after bed rest.
Exercise to Prevent Cardiovascular “Deconditioning” During Bed Rest
A number of investigators have used exercise training to prevent “cardiovascular deconditioning” associated with bed rest (7, 11, 15–17, 38, 40, 41). These studies have employed dynamic versus static exercise with supine cycling (38), large muscle mass dynamic exercise versus relatively small muscle mass isokinetic exercise (15–17), one bout of maximal exercise training (7, 11), or exercise in a centrifuge (21). Most recently, Watenpaugh and colleagues (40, 41) employed supine treadmill running during simultaneous LBNP to establish a similar cardiovascular stress to exercise training in the 1 G upright position. Although upright exercise capacity was preserved in these studies, protection from orthostatic intolerance remained incomplete. A similar observation was made with this specific countermeasure in the all-female subjects from the WISE study (18, 37). The present report is consistent with and extends these previous studies by demonstrating that it is not necessarily the type of exercise that is important—exercise training during bed rest that is sufficient to preserve cardiac structure is capable of preserving upright exercise capacity but not orthostatic tolerance.
Effect of Exercise on LV Morphology and Cardiac Mechanics
The present study confirmed that not only did this frequency, duration, and intensity of exercise training prevent the reduction of LV mass during bed rest but it also preserved the LV pressure-volume relationship and Starling mechanism. These findings implicate a strong link between LV morphology, function, and adaptation to microgravity.
One key observation was that despite the inadequate cardiac filling during orthostatic stress, the equilibrium volume (V0) was not reduced in the exercise-only group (ExNoVol) while it was clearly reduced after sedentary bed rest in this and other studies (27, 32). V0 represents the volume below which the heart must contract in systole to generate a recoil force during relaxation to cause diastolic suction (28). A reduction in V0 such as seen with sedentary bed rest may compromise diastolic suction since the heart must then contract to an even greater degree to support venous return. This process may be especially important to counteract gravity when standing. Since there is no evidence that contractility is augmented after bed rest (allowing a smaller end-systolic volume for the same afterload), a reduced V0 will impair diastolic suction, reduce end-diastolic volume, and contribute to the reduction in upright SV. Conversely, preservation of V0 (with exercise training) should preserve diastolic suction.
Indeed, the observation that V0 was preserved by daily exercise training is consistent with our previous finding (10) in these same subjects with MRI tagging that while LV untwisting in early diastole was impaired after 2 wk of sedentary bed rest, this impairment was prevented by exercise training. Moreover, a similar preservation of cardiac morphology with an exercise countermeasure was also observed in young women subjects during more prolonged 8-wk head-down tilt bed rest (9). Together these studies, ranging from 2 to 8 wk of bed rest and containing both men and women, have consistently shown that daily exercise training for up to 90 min at 75% maximal heart rate can prevent cardiac atrophy and preserve cardiac diastolic function including LV compliance, the Starling mechanism, and diastolic suction.
Plasma Volume Effects and Ventricular Filling
Confinement to bed reduces plasma and blood volume (6, 27, 32, 34), and this response was also observed in the present study in the group who performed no regular exercise. In contrast, increased physical activity is associated with an increase in blood volume and/or plasma volume, suggesting that exercise training may mitigate this reduction in blood volume during bed rest (6). Previous studies demonstrated that large muscle dynamic exercise training is more effective at preventing hypovolemia during bed rest than static or isokinetic exercise training (16, 38). Moreover, even one bout of maximal exercise has been shown to prevent the reduction of blood volume during bed rest (7). The present study used large muscle dynamic exercise training and appeared to similarly stabilize plasma and blood volume, consistent with previous studies (16, 38). Nevertheless, the exercise groups still showed significant reductions for all indexes of cardiac filling pressures (PCWP and RAP) and volume (LVEDV), indicating that regular exercise training alone cannot preserve blood volume enough to normalize cardiac filling following bed rest.
Therefore, the major findings with regard to hypothesis 1 and the effect of the exercise countermeasure on cardiac structure and function were twofold: 1) LV mass, compliance, distensibility, Starling mechanism, and diastolic suction were maintained after bed rest, but 2) cardiac filling pressure and volume were not completely preserved. These findings suggest that the failure to maintain orthostatic tolerance by the exercise countermeasure alone is explained by reduced cardiac filling despite normal cardiac diastolic function similar to what has been observed with acute hypovolemia (23, 32).
Dextran Infusion Alone
It has been reported that volume expansion by itself is not successful at restoring either supine (14) or upright (2) hemodynamics after prolonged exposure to bed rest. Combined with the failure of standard oral rehydration strategies to normalize orthostatic tolerance in astronauts (3, 4), these observations suggest that volume loading alone cannot prevent orthostatic hypotension following microgravity. However, oral volume loading is quite imprecise. For example, it is not clear how much volume is absorbed or retained within the vascular space. Even when saline has been given intravenously, it has never been precisely calibrated to unequivocally reverse the plasma volume loss as well as cardiac preload reduction observed after bed rest. One of the particular strengths of this study therefore is that we used precise and reliable methods to normalize both plasma volume and cardiac filling pressure, using a volume expander that has a long enough half-life to remain in the intravascular space for the duration of the experiment. Nevertheless, orthostatic tolerance was still not preserved by the dextran infusion alone following sedentary bed rest (SedDex), providing strong evidence that hypovolemia by itself is not responsible for the orthostatic intolerance after bed rest.
Contributing to this failure also appeared to be a fundamental change in LV distensibility after sedentary bed rest. As noted above, the Starling and pressure-volume curves showed that even though baseline PCWP was indeed normalized by the dextran infusion, the SV during LBNP was lower for any given PCWP due to a reduced LVEDV after compared with before bed rest. This observation provides evidence against impaired venous function being the primary problem: if that were true, SV should be appropriate for any given filling pressure (like our ExNoVol group), and filling pressure during LBNP should simply be too low. We demonstrated previously (13) that individuals have varying amounts of vasoconstrictor reserve available to counteract the reduction in SV during orthostatic stress. Since in the present study every subject was taken to his or her orthostatic tolerance limit by progressive LBNP, the reduction in SV even at the same filling pressure ultimately overwhelmed individual vasomotor reserve at a lower orthostatic stress after bed rest.
We were surprised to find that the SedDex group showed a reduction in orthostatic tolerance by 25%, which was comparable to the 24% reduction in orthostatic tolerance after 2 wk of sedentary bed rest without dextran infusion reported previously from this laboratory (27). Together these observations emphasize the important contribution of cardiac remodeling to the orthostatic intolerance after bed rest, regardless of central volume status.
Dextran Infusion Following Exercise Countermeasure
In contrast to when dextran was given after sedentary bed rest, orthostatic tolerance was maintained by dextran infusion when it followed the exercise countermeasure (ExDex). Since both Starling curves and LV pressure-volume curves were virtually identical after this combined countermeasure, it seems safe to conclude that preserved LV structure coupled with restored LV preload eliminated the excessive fall of SV during orthostatic stress. Together these data confirm the primacy of cardiac mechanics and ventricular filling independent of any changes in reflex control of the circulation as the primary mechanism of orthostatic intolerance after bed rest. As a consequence, prevention of this excessive fall of SV is likely to be the most effective strategy to prevent orthostatic intolerance after bed rest or spaceflight.
Conclusions
Cardiac atrophy, which is functionally characterized by a less distensible LV and impaired diastolic suction, during bed rest was prevented by a daily exercise training program sufficient to maintain not only ambulatory cardiac work but also upright exercise performance. By themselves, neither the restoration of plasma volume and cardiac filling pressures by dextran infusion nor the preservation of cardiac structure and mechanics by exercise training could prevent orthostatic intolerance after bed rest. However, when exercise training was combined with a calibrated volume infusion to normalize cardiac filling pressures, orthostatic intolerance was prevented by eliminating the excessive fall in SV. These findings suggest that hypovolemia and cardiac atrophy are independently responsible for orthostatic intolerance after bed rest.
GRANTS
This study was supported by National Aeronautics and Space Administration (NASA) Grant NAS 96-OLMSA-01B and National Space Biomedical Research Institute Grant NNH047ZUU003N and postdoctoral fellowship grant PR01101 through NASA NCC9 and Clinical and Translational Research Center (CTRC) [formerly General Clinical Research Center (GCRC)] Grant RR-00633.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
FOOTNOTES
1The online version of this manuscript contains supplemental material.
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