(Circulation. 1997;96:517-525.)
© 1997 American Heart Association, Inc.
Articles |
Cardiac Atrophy After Bed-Rest Deconditioning
A Nonneural Mechanism for Orthostatic Intolerance
From the Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas (Tex) and the University of Texas Southwestern Medical Center at Dallas.
Correspondence to Benjamin D. Levine, MD, Director, Institute for Exercise and Environmental Medicine, 7232 Greenville Ave, Dallas, TX 75321. E-mail Levineb{at}wpmail.phscare.org
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Background The cardiovascular adaptation to bed rest leads to orthostatic intolerance, characterized by an excessive fall in stroke volume (SV) in the upright position. We hypothesized that this large fall in SV is due to a change in cardiac mechanics.
Methods and Results We measured pulmonary capillary wedge pressure (PCWP), SV, left ventricular end-diastolic volume (LVEDV), and left ventricular mass (by echocardiography) at rest, during lower-body negative pressure, and after saline infusion before and after 2 weeks of bed rest with -6° head-down tilt (n=12 subjects aged 24±5 years). Pressure (P)-volume (V) curves were modeled exponentially by P=aekV+b and logarithmically by P=-Sln[(Vm-V)/(Vm-V0], where V0 indicates volume at P=0, and the constants k and S were used as indices of normalized chamber stiffness. Dynamic stiffness (dP/dV) was calculated at baseline LVEDV. The slope of the line relating SV to PCWP during lower-body negative pressure characterized the steepness of the Starling curve. We also measured plasma volume (with Evans blue dye) and maximal orthostatic tolerance. Bed rest led to a reduction in plasma volume (17%), baseline PCWP (18%), SV (12%), LVEDV (16%), V0 (33%), and orthostatic tolerance (24%) (all P<.05). The slope of the SV/PCWP curve increased from 4.6±0.4 to 8.8±0.9 mL/mm Hg (P<.01) owing to a parallel leftward shift in the P-V curve. Normalized chamber stiffness was unchanged, but dP/dV was reduced by 50% at baseline LVEDV, and cardiac mass tended to be reduced by 5% (P<.10).
Conclusions Two weeks of head-down–tilt bed rest leads to a smaller, less distensible left ventricle but a shift to a more compliant portion of the P-V curve. This results in a steeper Starling relationship, which contributes to orthostatic intolerance by causing an excessive reduction in SV during orthostasis.
Key Words: cardiac output • pressure • cardiac volume • diastole • syncope • elasticity
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Gravitational and hydrostatic gradients play an essential role in determining the distribution of pressure and volume within the cardiovascular system.1 When these gradients are removed or minimized, such as during exposure to spaceflight or ground-based simulations such as head-down–tilt bed rest, a central fluid shift occurs, initiating a neurohumorally mediated reduction in blood and plasma volume2 3 and a "normalization" of hemodynamic equilibrium in the direction of that observed in the upright posture.4 5 6 This adaptation is rapid and appears to be substantially complete within the first 24 to 48 hours of microgravity exposure.7 8 When head-to-foot gravitational forces are subsequently restored, orthostatic intolerance ensues.5 Upright SV is reduced in all individuals, and heart rate is increased, although the ability to increase vascular resistance is more variable.5 9 Although there are conflicting data regarding changes in baroreflex regulation of heart rate and vascular resistance that may limit the compensatory response to orthostasis,5 9 10 11 12 it is this excessive fall in SV that is the sine qua non of microgravity-induced orthostatic hypotension.
For any given level of LV contractility or afterload, SV is determined to a large extent by LV filling as a function of the Frank-Starling mechanism.13 LVEDP is determined by LVEDV, and this relationship is influenced by cardiac chamber stiffness. Because of the curvilinear nature of the LV pressure-volume relationship, cardiac stiffness is dynamic with the instantaneous stiffness, defined as dP/dV, dependent on the specific value of LV volume.14 We have hypothesized that spaceflight or microgravity simulated by bed rest leads to a reduction in LV volume and therefore a shift on the LV pressure-volume relationship to a more compliant region of the curve.15 Such a shift would lead to a greater reduction in LVEDV during orthostasis and a greater reduction in SV for any given change in LVEDP. To test this hypothesis, we directly measured LV pressure-volume relations and constructed Starling curves (SV versus LVEDP) to examine ventricular performance in 12 normal subjects before and after 2 weeks of complete bed rest with -6° head-down tilt.
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Subjects
Twelve healthy subjects (11 men, 1 woman) with a mean age of 24±5 years (range, 18 to 35 years), height of 185±23 cm, and weight of 79±3 kg were studied. No subject smoked, used recreational drugs, or had significant chronic medical problems. No subject was an endurance-trained athlete,16 and subjects were excluded if they exercised for >30 min/d more than 3 times per week (either dynamic or static exercise). Subjects were screened with a careful history and physical examination, ECG, and echocardiogram and were excluded if high-quality, two-dimensional echocardiographic images could not be obtained. Body composition was obtained by use of standard underwater weighing techniques.17 All subjects signed an informed consent form approved by the Institutional Review Boards of the University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas.
Instrumentation
All experiments were performed in the morning 
2 hours after a
light breakfast and >12 hours after the last caffeinated or alcoholic
beverage, in a quiet, environmentally controlled laboratory with an
ambient temperature of 25°C. A 6F balloon-tipped, flow-directed
pulmonary arterial catheter (Edwards Swan-Ganz,
Baxter) was placed under fluoroscopic guidance through an antecubital
vein into the pulmonary artery. With the balloon inflated, the
catheter was advanced into the pulmonary capillary wedge
position, which was confirmed both fluoroscopically and by the presence
of characteristic pressure waveforms. 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
in the supine position. Pressure waveforms were amplified
(Hewlett-Packard 78534A and Astromed ASC909) and displayed on a
strip-chart recorder (Astromed MT 95000) with 0.5 mm Hg
resolution. The mean PCWP was determined visually at end expiration and
was used as an index of LVEDP. Heart rate was continuously monitored by
electrocardiography (Hewlett-Packard), and
beat-by-beat blood pressure was measured in the finger by
photoplethysmography (Finapres, Ohmeda). Intermittent blood pressure
was also measured in the arm by electrosphygmomanometry (Suntech 4240)
with a microphone placed over the brachial artery and the Korotkoff
sounds gated to the ECG.
Cardiac Output
Cardiac output was measured with a modification of the
acetylene rebreathing technique using acetylene as the soluble gas and
helium as the insoluble gas.18 With this technique,
pulmonary blood flow is calculated from the disappearance rate
of acetylene in expired air, measured with a mass spectrometer
(Marquette), after adequate mixing in the lung has been confirmed by a
stable helium concentration. This method has been validated in our
laboratory against standard invasive techniques, including
thermodilution and direct Fick, over a range of cardiac outputs from
2.75 to 27.00 L/min, with an r2 of .91 and an
SEE of 1.1 L/min.19 We chose this technique to facilitate
comparison with our previous studies16 20 and to minimize
the requirement for multiple injections of iced saline, which could
influence cardiac pressure and volume. To confirm the accuracy of the
technique in the present study, we performed some thermodilution
measurements of cardiac output immediately after the rebreathing
maneuver. There was a close relationship between acetylene rebreathing
and thermodilution (n=145 observations; r=.99;
P<.0001; SEE=250 mL). SV was calculated from cardiac output
and heart rate measured during rebreathing.
Ventricular Volumes and Mass
LV mass and volumes were measured with two-dimensional
echocardiography using standard views and formulas
as described by the American Society of
Echocardiography.21 Images were
obtained with an annular phased-array transducer using a frequency of
2.5 to 3.5 MHz (Interspec Apogee CX) and stored on VCR tape for
off-line analysis by a skilled technician. Measurements of LV
endocardial and epicardial areas were made from the parasternal
short-axis window at the level of the mitral valve and the papillary
muscles and from the apical window in the four-chamber view, with care
taken to avoid foreshortening of the major axis. The major-axis
distance was measured from the apex to the mitral annulus. For the
calculation of LV volume for each subject, either a modified Simpson's
rule method, the area-length method, or the bullet model (cylinder
hemiellipsoid) was chosen on the basis of which views provided the most
optimal endocardial definition.22 The same formula was
used for each individual subject throughout the study. Two to three
beats were averaged from images recorded at end expiration. Using a
similar technique, we have previously reported20 an
interobserver variability of 10% and an SEE of 26 mL in comparison
with biplane angiography during cardiac
catheterization. In addition, to confirm the accuracy
of our volume measurements in the present study, we compared SV
measured by echocardiography (EDV-ESV) with that
calculated during rebreathing. The Pearson's correlation coefficient
of this comparison was .85, with an SEE of 10.9 mL.
Protocol
After 30 minutes of quiet rest in the supine position, plasma
volume was measured using Evans blue dye.23 To decrease
and increase ventricular filling, we used a sequence of
LBNP and rapid saline infusion, as previously reported.20
LBNP was achieved by placing the subject in an acrylic plastic box,
sealed at the level of the iliac crest. Suction was provided by a
vacuum pump controlled with a variable autotransformer.
Measurements of PCWP, cardiac output (and therefore SV), LVEDV, heart
rate, and blood pressure were made at baseline and then after 5 minutes
each of LBNP at -15 and -30 mm Hg. The LBNP was then
released. After repeat baseline measurements to confirm a return to
hemodynamic steady state (usually 20 to 30 minutes),
warm (37°C), isotonic saline was infused rapidly at a rate of 100
mL/min. Measurements were repeated after 15 and 30 mL/kg had been
infused.
Seventy-two hours after this session, maximal orthostatic tolerance was measured using a ramped LBNP test. No invasive measurements were made during this protocol. LBNP was begun at -15 mm Hg for 5 minutes, then increased to -30 and -40 mm Hg for 5 minutes each, followed by an increase in LBNP by -10 mm Hg every 3 minutes until signs or symptoms of presyncope were achieved. Presyncope was defined as a decrease in systolic blood pressure to <80 mm Hg; a decrease in systolic blood pressure to <90 mm Hg associated with symptoms of lightheadedness, nausea, or diaphoresis; or progressive symptoms of presyncope accompanied by a request from the subject to discontinue the test. In 24 tests, a true hemodynamic end point was reached in the majority (95%) of circumstances. A cumulative stress index was calculated for this specific protocol by summing the product of negative pressure and duration at each level of LBNP and was used as a continuous measure of orthostatic tolerance.
Microgravity Simulation With Head-Down–Tilt Bed Rest
After the initial series of experiments, head-to-foot
gravitational gradients were reduced by placing the subjects on
complete bed rest with -6° head-down tilt. Subjects were allowed to
elevate on one elbow for meals but otherwise were restricted to the
head-down position at all times. To characterize the acute adaptation
to head-down tilt, subjects first were brought into the laboratory in
the morning after being upright for 2 hours. Cardiac output, heart
rate, and blood pressure were measured in the standing position every 5
minutes until repeat values of cardiac output were within 500 mL.
Subjects then were placed in the supine position for 30 minutes of
quiet rest, after which hemodynamic measurements were
repeated. The head-down position was then assumed, and
hemodynamics were measured at 5, 15, 30, 60, 180, and
240 minutes and then repeated after 24 hours, 48 hours, 1 week, and 2
weeks of head-down tilt. Subjects were housed in the General Clinical
Research Center at the University of Texas Southwestern Medical Center
and given a standard diet that consisted of 2827±609 cal/d,
including 5.2±1.2 g/d of sodium. Fluids were allowed ad
libitum, but all fluid intake and urine output were carefully
recorded. The same series of experiments was repeated after 2 weeks
of head-down tilt. The head-down tilt was maintained during the 72
hours between the measurement of pressure-volume relations and the
orthostatic tolerance test for a total of 18 days.
Data Analysis
Starling Curves
To evaluate ventricular performance, we
constructed Starling curves relating PCWP to SV. An index of the
steepness of this relationship during decreases in cardiac filling was
obtained by performing linear regression on the linear portion of the
curve, including points obtained at baseline, and during LBNP at -15
and -30 mm Hg.20 This characteristic has been
shown in previous studies20 to predict a significant
portion of the individual variation in LBNP tolerance. Starling curves
were constructed before and after bed rest both for (1) the grouped
means for PCWP and SV and (2) each individual subject.
Pressure-Volume Relations
To evaluate chamber-stiffness properties, we constructed
pressure-volume curves relating LVEDV to PCWP. Two separate but related
models were constructed: an exponential model14 and a
logarithmic model.24 The exponential approach modeled the
curves according to the equation:
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Although this exponential relationship has been used frequently to
describe LV pressure-volume relations, it suffers from one important
limitation: it cannot identify the equilibrium volume of the LV, that
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.25 Therefore, to further
characterize LV pressure-volume relations and to allow the calculation
of equilibrium volume, we also modeled the data in the present
experiment according to the logarithmic model described by
Yellin25 :
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Modeling of both exponential and logarithmic curves was performed with the Marquardt-Levenberg algorithm using commercially available software (Sigmaplot 6.2, Jandel Scientific). Initial values for the exponential curve fitting were obtained from the group data previously reported in untrained normal subjects20 ; for the logarithmic relationship, initial values 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. All curves were calculated for each individual subject before and after bed rest for statistical comparison and for the composite curves relating the group mean LVEDV to the group mean PCWP for all subjects combined before and after bed rest. In addition, to determine instantaneous chamber stiffness at resting LVEDV, dP/dV was calculated for each curve at two discrete volumes: the supine baseline LVEDV before bed rest and the supine baseline LVEDV after bed rest.
Ventricular Function
Ventricular function normalized for LV volume was
assessed by comparing the relationship between LVEDV and SV. The slope
of this line was calculated by linear regression.
Statistics
Discrete variables were compared before and after bed rest
with the paired t test by use of a personal computer–based
statistical package (Winstar, AndersonBell). A value of
P<.05 was accepted as statistically significant.
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Results |
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Adaptation to Simulated Microgravity
When the upright posture was used as a reference, assumption of the supine position resulted in a doubling of SV (from 51±12 to 104±27 mL) and a compensatory bradycardia (from 94±10 to 69±5 bpm) and vasodilation (SVR decrease from 1559±291 to 900±231 d · s · cm-5) (all comparisons P<.001). Imposition of -6° head-down tilt increased SV by an additional 15% (115±40 mL; P<.05 compared with supine). This response peaked by 30 minutes, and SV declined thereafter, reaching a nadir at
48 hours (head-down position
SV=89±13 mL). (See Fig 1
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After 2 weeks of head-down tilt, supine SV declined to a value 50%
of the difference between supine and upright posture (80±15 mL;
P<.001 compared with supine position before head-down
tilt). All other measures of LV filling also decreased, including PCWP
and EDV, as shown in the Table. This
adaptation was accompanied by a reduction in plasma volume of 550±123
mL (P<.05) and a decrease in lean body mass of 1.5±0.6 kg
(P<.05). Of note, these adaptations are similar in
direction and magnitude to those observed after spaceflight missions of
9 to 14 days.5 Myocardial mass appeared to decrease by 5%
(P<.10), consistent with cardiac atrophy. LBNP
tolerance was reduced by 24% (P=.02), with a similar
directional response observed in all subjects (Fig 2).
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Starling Curves
Along with the reduction in resting supine PCWP and LVEDV, the
slope of the linear portion of the Starling curve (from baseline
through -30 mm Hg LBNP) doubled from 4.6±1.4 to 8.8±2.9
mL/mm Hg (P<.003; Fig 3).
Thus, there was nearly twice the fall in SV for the same fall in PCWP
after head-down–tilt bed rest. However, contrary to our original
hypothesis, this response was not simply due to a reduction in filling
pressure along the same Starling curve. For any given PCWP below
baseline, there was a smaller SV after versus before bed rest (ie, a
different Starling curve). Specifically, during LBNP before bed rest,
PCWP decreased to 6.2±2.6 mm Hg (at -15 mm Hg
LBNP) and 4.2±2.5 mm Hg (at -30 mm Hg LBNP),
whereas after bed rest, it similarly decreased to 6.1±2.4 and
4.5±2.1 mm Hg (P=NS for before/after
comparisons). However, SV was significantly less after bed rest
(P<.0001; Fig 3). To examine whether this observation was
due to reduced contractile function or reduced cardiac filling, SV was
plotted as a function of LVEDV (Fig 4).
The slope of this relationship (preload recruitable SV) was unchanged
after bed rest, suggesting that reduced filling rather than depressed
contractility was responsible for the smaller SV.
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Pressure-Volume Curves
Both the exponential and logarithmic models are plotted together
in Fig 5. As expected, over the range of
data measured in the experiment, the curves are similar, with similar
goodness of fit of the models (square root of the weighted sum of
squares=2.4 and 2.8 for the exponential model for before and after bed
rest curves, respectively, versus 2.1 and 2.8 for the logarithmic
model). Regardless of the model, after bed rest, pressure-volume
curves demonstrated a parallel shift to the left, resulting in a
decreased volume for any given pressure. This observation was
particularly prominent for pressures below baseline. However,
normalized chamber stiffness, as measured by either stiffness constant
(k or S) did not change. Therefore, the principal
mechanical adaptation to bed rest appeared to be decreased
distensibility (smaller volume for a given pressure) without a change
in overall chamber stiffness.26 However, because supine
LVEDV decreased (P<.01), there was a baseline shift to a
less stiff (more compliant) portion of a less distensible curve. Thus,
dP/dV at baseline for supine LVEDV after bed rest was only half the
dP/dV at baseline for supine LVEDV before bed rest (P<.05).
Logarithmic modeling revealed a significant decrease in equilibrium
volume (V0) (73±8 to 49±6 mL; P<.01),
consistent with decreased chamber size (Fig 6). Before bed rest, V0 was
larger than resting supine LVESV (53±4 mL; P<.05),
consistent with the use of diastolic suction to
facilitate LV filling. After bed rest, however, V0 was not
different from LVESV (41±2 mL; P=.23), suggesting that
diastolic suction had become less effective. These
adaptations were associated functionally with a lower SV at any given
level of LBNP, including maximal LBNP (Fig 7).
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The principal new findings from this study were that 2 weeks of -6° head-down–tilt bed rest led to a smaller, less distensible LV as manifested by a parallel, leftward shift in the LV pressure-volume relationship and a decrease in equilibrium volume. However, because supine LVEDV also decreased due to a decrease in plasma volume, there was a baseline shift to a less stiff (more compliant) portion of a less distensible curve. Thus, dP/dV at baseline for supine LVEDV after bed rest was only half the dP/dV at baseline for supine LVEDV before bed rest. This reduction in cardiac size coupled with the decreased dynamic stiffness led to a steeper Starling curve and a greater decrease in SV at any given level of orthostatic stress, ultimately leading to orthostatic intolerance.
There is voluminous literature regarding the effect of short-term real or simulated microgravity on the cardiovascular system, most of which focuses on the reflex control of the circulation. One prevailing opinion suggests that adaptations in the autonomic nervous system may present a unified hypothesis for the orthostatic intolerance observed after adaptation to microgravity.27 However, abnormalities of reflex control of the circulation have been difficult to implicate as the cause of orthostatic intolerance, with many studies reporting conflicting results. For example, the carotid baroreflex control of heart rate has been studied extensively, with most studies showing a reduction in the gain of the response.10 11 12 28 In contrast, aortic baroreflex control of heart rate appears to be enhanced,29 as is the increase in forearm vasoconstriction in response to a reduction in estimated CVP.30 The spontaneous baroreflex, observed during normal respiratory oscillations in blood pressure and involving both arterial baroreflex loops, is also reduced,31 although we have suggested that this observation may be due exclusively to plasma volume reduction.32 Recently, Ludwig and Convertino33 suggested that physical factors responsible for the fall in SV may be more important than reflex adjustments to this stress in determining individual susceptibility to orthostatic intolerance.
Despite extensive study of the reflex mechanisms of postmicrogravity orthostatic intolerance, no study has ever shown either a lower heart rate or a decreased peripheral resistance during orthostatic stress after spaceflight or bed rest compared with preexposure levels (in the absence of a sudden cardioinhibitory or vasodepressor reaction). Therefore, an abnormality in reflex control of heart rate or vascular resistance cannot by itself explain the specific clinical problem of orthostatic intolerance observed after adaptation to microgravity. Rather, in some individuals, reflex compensatory mechanisms appear to be overwhelmed by an inordinate fall in SV.5 Intriguingly, attempts to normalize orthostatic tolerance by volume loading during either spaceflight34 or bed rest35 have been only partially successful in restoring SV35 or orthostatic heart rate34 to normal. These observations suggest that a reduction in plasma volume alone may not entirely explain the reduction in SV observed after these conditions. The present study is consistent with these observations. In contrast to our original hypothesis that the reduction in plasma volume would lead simply to a shift along an unchanged Starling curve, we observed a change in the shape of the Starling curve itself, with a decreased SV for any given filling pressure (below baseline) after bed rest.
One possible explanation for such a shift in ventricular
performance is a reduction in contractility.
Although we did not measure contractility directly (ie,
by load-independent measures of contractile function) in the
present study, this alternative is effectively excluded by the
observation that the relationship between LVEDV and SV remained normal
(Fig 4
). Thus, for any given LVEDV as opposed to LVEDP, SV was the
same before and after bed rest. The logical conclusion then is that a
change in the relationship between LV pressure and volume has occurred.
In the present study, this was manifested by a leftward shift
in the LV pressure-volume relationship suggestive of decreased cardiac
distensibility.26
Despite this shift in position of the pressure-volume curve, there was no evidence for a change in overall, normalized cardiac chamber stiffness, as indicated by the similar stiffness constants k (exponential model) and S (logarithmic model) before and after bed rest. Both models were used for the following reasons. The exponential model is simple, has a long history in its application for the assessment of diastolic chamber properties,14 and has been used by our laboratory in previous studies of the relationship between cardiac stiffness and orthostatic tolerance.20 Moreover, it clearly fits the data well over the wide range of filling pressures observed in the present study. However, it has been argued that because the exponential model cannot describe the equilibrium volume of the LV (the volume at which pressure equals zero), it may not be the most accurate way to describe LV diastolic chamber properties.24 25
In the present study, as can be seen from Fig 5, both models fit
the data well over a wide range of filling pressures from 3 to 25
mm Hg. However, the extrapolation of the logarithmic model to
V0 provides the critical information that equilibrium
volume of the LV has been reduced after bed rest. Because
V0 defines the volume below which the LV must contract in
systole to take advantage of diastolic suction, we
speculate that diastolic suction may be an important
mechanism to support LV filling at high levels of
orthostatic stress. This speculation is supported by the
observation that before bed rest, V0 was significantly
greater than LVESV, confirming that diastolic suction was
operative, at least during supine rest. Under such conditions,
substantial negative pressure is generated by the recoil properties of
the myocardium, and a restoring force is produced as the
heart returns to the unstressed or equilibrium state.13
After bed rest, however, the ability to use diastolic
suction appeared compromised, because V0 had decreased to
the level of LVESV.
The lack of change in overall chamber stiffness despite a reduction in distensibility suggests that the heart remodeled during bed rest. One potential mechanism suggested by the present study for this remodeling may be cardiac atrophy with a reduction in cardiac mass, which tended to decrease by 5% on the basis of measurements made by echocardiography. Because the reduction in cardiac mass did not reach statistical significance, we cannot be certain whether the reduction in distensibility is due to a true atrophy of the myocardium with a reduction in cardiac mass or some other cardiac remodeling process (ie, interstitial). Echocardiography, the technique used in the current experiment, is limited by a relatively large variability in measurements of cardiac mass.36 We have recently obtained data in four astronauts after spaceflight demonstrating a similar order of magnitude (12%; range, 6.2% to 27.4%) of reduction in cardiac mass by MRI (C.G. Blomqvist, MD, PhD, personal communication, 1996), a method with extremely good precision in measuring cardiac mass.37 Moreover, we have been able to study an additional five subjects after 2 weeks of supine bed rest using MRI with a similar 7.4% reduction in mass (range, 3.3% to 19.0%) (R. Peshock, MD, personal communication, 1996), thus providing supportive evidence for true cardiac atrophy with real or simulated microgravity.
Cardiac mass appears to be extremely well regulated in response to changes in loading conditions.38 39 Animal studies have demonstrated that within minutes of an increase in pressure load, myosin heavy chain synthesis in the myocardium begins to increase40 in response to increased expression of immediate-early genes regulating the initiation of LV hypertrophy.41 The response to acute changes in volume load are qualitatively similar to that of pressure load.42 Volume loading of the LV is associated over time with eccentric hypertrophy and increased distensibility, whereas volume unloading is associated with eccentric atrophy and decreased chamber distensibility.43 44 Similar changes in cardiac mass and stiffness have been identified in animals after physiological changes in loading conditions, such as endurance training45 or spaceflight.46 These adaptations appear to be localized exclusively to cardiac myocytes rather than changes in the interstitium.47
We speculate that in humans undergoing bed-rest deconditioning, the
reduction in both EDV and SV due to the reduction in plasma volume as
well as the reduction in physical activity may lead to a reduction in
cardiac loading conditions and be responsible for cardiac atrophy.
Preliminary calculations support this notion. We obtained 24-hour
Holter monitor recordings of heart rate from four of our
bed-rest subjects when ambulatory and during head-down–tilt bed rest.
As expected, heart rate was higher during the ambulatory period than
during head-down–tilt bed rest, during both day and night periods. On
the basis of measured SV changes, average systolic blood
pressure recordings, and heart rate in these four subjects, we
grossly estimated the total stroke work that was accomplished over 24
hours. These calculations suggest that stroke work decreased during bed
rest by 18% compared with the ambulatory period
(1.12x109 to 0.92x109 mL ·
mm Hg-1 ·
d-1). We additionally have estimated, on the
basis of known increases in SV and blood pressure during submaximal
exercise, that it would take 90 minutes of dynamic exercise per day
at 75% of maximum heart rate to normalize stroke work between bed-rest
and ambulatory periods. Further research will be required to determine
if such an increase in cardiac work will be sufficient to prevent the
apparent cardiac atrophy observed in the present study.
The current study thus presents a unifying hypothesis for previous observations regarding the excessive fall in SV in the upright position after bed rest or spaceflight.5 9 A reduction in LV size and distensibility occurs due to an apparent physiological cardiac atrophy, as a function of the normal plasticity of the myocardium in response to changes in loading conditions. There is no evidence that this adaptation represents a pathological response of the myocardium. Coupled with a reduction in plasma volume and thereby a reduction in LVEDV, there is a shift to a more compliant portion of a less distensible pressure-volume curve, leading to a precipitous drop in LVEDV and SV via the Frank-Starling mechanism, when filling pressure is reduced during orthostasis. This prominent fall in SV then serves as the primary stimulus to cardiac and arterial baroreceptors, which may or may not be adequate to restore normal perfusion.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by NASA NSCORT No. NGW 3582 and US Public Health Service grant No. MO1-RR00633. We thank Kevin Harper, Susie McMinn, and Stacey Blaker for their excellent technical work; Russell Thurmon for data entry, construction of pressure-volume curves, and graphics; Lynda Lane and Willie Moore for their assistance with the acute head-down–tilt studies; Kay Hood for secretarial and administrative support; and the nurses and staff of the General Clinical Research Center (University of Texas Southwestern Medical Center) for their outstanding care of the subjects during bed rest. We also must thank Dr C. Gunnar Blomqvist for his continued guidance and advice.
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Footnotes |
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Dr Pawelczyk's current address is Noll Physiological Research Laboratory, Pennsylvania State University, State College, Pa.
Received October 10, 1996; revision received February 5, 1997; accepted February 11, 1997.
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References |
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