INTRODUCTION

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MOST OF THE CARDIOVASCULAR changes induced by actual or simulated weightlessness are now considered to happen within the first days and seem to lead to a new and stable hemodynamic equilibrium after some days and at least for some months. The adaptation to actual 0 g can be characterized by a decrease in the volemia (7, 11, 15, 16, 28, 31), perturbation of the baroreflex (21, 25), decrease in the peripheral arterial vasoconstriction (7, 12, 40), and modification of the lower limb vein distensibility (40). During head-down-tilt (HDT) studies, similar changes were found for the volemia (20, 26, 29, 34), baroreflex sensitivity (18), and peripheral arterial vasoconstriction (7, 22), but of weaker amplitude. In addition, the sympathetic-parasympathetic balance was changed (38), and the venous compliance in peripheral vascular areas increased (13, 19, 33, 41). Each of these modifications alone is not sufficient to induce orthostatic intolerance, and their actual role in this setting remains to be determined (10, 37).

Different countermeasures, such as lower body negative pressure (LBNP) or isotonic or isometric exercise, have been proposed to minimize the effects of microgravity on the cardiovascular system and to reduce its deconditioning after spaceflights (17, 23, 30). The LBNP, which induces a fluid shift from the cephalad part of the body toward the lower limbs, is used to simulate partially the effects of a stand test during spaceflight. Repeated LBNP has been found to reduce the development of orthostatic intolerance during HDT (7, 26, 27) and is used extensively at the end of long-term flights in preparation for the return to 1-g gravity. Exercise is mainly used for maintaining cardiopulmonary and muscle working capacities and to prevent major muscle-mass reduction and bone demineralization.

Thigh cuffs, presently named "bracelets," are a countermeasure designed for the Russian spaceflights. This passive countermeasure consists of two straps fixed to the upper part of each thigh, applying a pressure of ~30-40 mmHg. Initially this countermeasure was designed to reduce facial edema, and the cosmonauts reported improved comfort when using the bracelets during daytime. The thigh cuffs were tested in 1984 during a 232-day spaceflight on board Saliout VII but have been used as a routine countermeasure since 1990. Most of the cosmonauts used the thigh cuffs for ~10 h/day every day throughout the 6-mo flights. During the 14-day MIR-Antares flight (1992) and 21-day MIR-Altaïr flight (1993), two cosmonauts were investigated, and it was observed that the thigh cuffs reduced the jugular vein distension, reduced the decrease in vascular tone in various areas, and significantly improved the comfort of the cosmonauts (6, 8). These findings raised two questions: 1) how the thigh cuffs, applying a pressure of ~30 mmHg, changed the amplitude and the time course of the cardiac, arterial, and venous adaptation, and 2) how they could interfere with the development of the cardiovascular deconditioning.

The first objective of the present study was to evaluate the cardiac, arterial hemodynamic, and venous morphological modifications in a group of subjects in HDT for 7 days by using thigh cuffs every day during the daytime, and in a control group not using cuffs. The second objective was to check whether the use of thigh cuffs during daytime had any influence on the development of orthostatic intolerance. Orthostatic tolerance was evaluated by using a stand test with electrocardiogram and blood pressure control, which is the reference method for detecting and quantifying orthostatic intolerance. Ultrasound imaging and Doppler were used to investigate the cardiovascular system at rest and during stand tests.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Subjects

Protocol

Stand Test

Cardiac, Arterial, and Venous Parameters Without Cuffs and After 8 h With Cuffs

Cardiac parameters. The cardiac function was assessed by echocardiography B and time-motion (TM) modes. Parasternal long-axis echocardiograms were recorded with a commercially available echocardiograph by using two working modes: a 3-MHz real-time imaging mode (sector scan) and a TM mode. Such a system has previously been used for cardiovascular investigation during spaceflight and simulated weightlessness (7, 8, 15). It allows visualization of the cardiac chambers and displays the ventricular and auricular wall movements during the cardiac cycle. The subjects were lying on their left side to increase the intercostal space window through which the cardiac chambers were investigated. Echocardiographic images and TM traces were recorded during held expiration. Under such conditions, the echocardiographic data were of good quality in all subjects. The end-diastolic diameter was selected on the TM trace as the largest ventricular diameter, and the end-systolic diameter as the smallest one. Ventricular diameters and HR were both measured on the same TM trace. Ten cardiac cycles were analyzed and averaged for each data point. The left ventricular volume was estimated from the previously measured diameters by using the Teichholz formula (39). The following parameters were measured or calculated: left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke volume (SV) (calculated as LVEDV  LVESV), HR, cardiac output (CO) (calculated as the product of HR and SV), and ejection fraction (EF) [calculated as (LVEDV  LVESV)/LVEDV].

Arterial vascular resistances. Total peripheral resistances (TPR) were calculated from the MBP and CO. The vascular resistances in particular areas (brain, lower limbs, etc.) were evaluated from the Doppler spectrum of the artery supplying the area of interest.

1

1

Artery diameter (common carotid) and vein cross-sectional area (jugular, femoral, popliteal). The systolic (CCSD) and diastolic common carotid diameters (CCDD) were measured on the TM trace of the common carotid artery. The jugular vein section (A_jv) was measured on B-mode echographic transversal views of the neck at the level of the Adam's apple. The cross-sectional area of the superficial femoral vein (A_fv) was measured on a transversal echographic view of the vein 1 cm below the femoral arterial bifurcation. The cross-sectional area of the popliteal vein (A_pv) was also measured on a transversal echographic view 1 cm up from the anterior tibial artery. The artery and venous morphological investigations were performed by using a conventional 7.5-MHz ultrasound (B-mode) probe. The diameter values were expressed in millimeters, whereas the vein areas were expressed in square millimeters.

Cardiac and Arterial Parameters During the First 10 Min With Cuffs

Arterial blood flow volume changes. The determination of the absolute value of the blood flow volume (ml/min) requires the measurement of the vessel diameter, the angle between the Doppler beam and the vessel axis (on the image), and the maximal frequency integral on the Doppler spectrum. On the other hand, during dynamic tests such as orthostatic or cuff tests, we measured flow volume changes from pretest values, and most of the time the subject was his own control. In the present case, we used a Doppler sensor fixed on the skin; thus the angle between the Doppler beam and vessel axis, to be used in the calculation of blood flow volume, remained constant (1, 3). In the present study and in other similar ones, the assessment of the femoral arteries, by using conventional ultrasound imaging, did not show any significant change in diameter during cuff compression or orthostatic tests. The diameter of the middle cerebral artery (~3 mm) cannot be measured accurately by ultrasound; thus this parameter induces an important error in the evaluation of the blood flow volume. However, by considering that the diameter remains constant, we eliminated the major factor of error in the determination of the blood flow volume. In a normal subject, any increase in flow rate is related to an increase in velocity and sometimes to an increase in diameter, but never to a decrease in diameter. Blood flow volume changes were considered to be equal to the mean velocity changes and are expressed as a percentage of the pretest values. To monitor the cerebral flow changes, we used the mean blood flow velocity changes into the middle cerebral artery (ca); for the lower limb arterial flow volume, we used the mean blood flow velocity changes measured in the superficial femoral artery (fa); and for the aortic flow, we used the mean aortic flow velocity changes (aa).

Cerebral-to-femoral blood flow ratio (ca/fa). In the ca/fa, ca and fa are proportional to the middle cerebral and femoral arterial flow volume, respectively. During head-up tilt or LBNP, changes in this ratio quantify the redistribution of flow between these two areas in response to the fluid shift toward the leg. Such a fluid shift induces a significant reduction in the circulating blood volume, which triggers an increase in HR to compensate, at least partially, for the decrease in CO, and a redistribution of the remaining blood volume to maintain an acceptable blood volume flow toward the brain. In normal subjects, this ratio has been shown to increase with the amplitude of the fluid shift toward the legs (4, 6, 9), which is a consequence of the reduction in the lower limb blood flow due to an efficient vasoconstriction at this level. In this case, the cerebral flow volume is maintained. Conversely, in the case of orthostatic intolerance, the lack of vasoconstriction in the lower limb, and probably a reduction in the volemia, contributes to reducing the increase in this ratio. Most of the time such abnormal flow redistribution is observed long before any clinical symptoms of orthostatic intolerance appear (pallor, nausea, tachycardia). As the thigh cuffs may trap a significant quantity of blood into the leg veins, one can expect a reduction in volemia and a flow redistribution process toward the brain to maintain constant the cerebral flow.

Arterial vascular resistance changes. Rca and Rfa were also measured from the Doppler velocity spectrum of each corresponding artery as already described in Cardiac, Arterial, and Venous Parameters without Cuffs and After 8 h with Cuffs.

Parameters and Sessions of Measurement

View larger version (17K): [in this window] [in a new window]   Fig. 1.   Timeline of head-down-tilt (HDT) experiment and cardiovascular measurements for cuff subjects. HDT-3 and -1, 3 and 1 day before HDT experiment; HDT1-7, days 1-7 of experiment; Post+1, 1 day after experiment. Pre-HDT echographic and Doppler measurements taken on HDT-3. Echographic and Doppler measurements taken before cuffs were donned on HDT7 at 8:45 AM. Cuffs were donned at 9 AM, and continuing Doppler measurement were taken for 15 min. At 5 PM, cuffs still in place, and same echographic and Doppler measurements taken as before. Control group subject to same echographic and Doppler measurement sessions as cuff subjects.

The following parameters were measured once on HDT day 7 before the subjects donned the cuffs (8:45 AM) and after 15 min with the cuffs: aa, ca, fa, Rca, Rfa, and ca/fa. The subjects were instrumented with the Doppler sensors just before donning the cuffs, and the sensors remained in place during the first 15 min with cuffs. Changes in these parameters at 15 min with cuffs are expressed as percentages of the initial precuff values.

Data were tested for significance by using a nonparametric test based on comparison of means in the same group (Wilcoxon matched-pairs test). Statistical results were considered as significant when P < 0.05.

Ultrasound Device and Harness

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

General Clinical and Biological Data

Orthostatic Tolerance: Results of the Post-HDT Stand Tests

Cardiovascular Adaptations to 7 Days of HDT in the Control Subjects

Cardiovascular Adaptations to 7 Days of HDT in Subjects With Cuffs

Early Cardiovascular Responses After 15 Min With Cuffs at HDT Day 7

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Cardiovascular Adaptation to 7 Days of HDT (Control Subjects)

The cerebral vascular resistance increased slightly but significantly (+6%), probably in relation to the significant blood stagnation in the cephalic veins, as confirmed by the significant enlargement of the jugular vein (+49%) in the absence of cuffs. The increase in cerebral resistance may also be related to an increase in the intracranial pressure, as suggested during a 2-day HDT (24, 36).

At the leg level, the femoral vascular resistances slightly decreased (4%), as already observed during other HDT (7, 9), which is in agreement with the reduction in plasma volume, the inactivity of the legs, and an increase in vein compliance as already observed in other HDT (19, 33). Nevertheless, the TPR were increased, confirming the fact that changes in vascular resistance are not the same in all peripheral vascular areas (increased in the brain, decreased in the legs).

The femoral and the popliteal veins significantly decreased (45 and 10%, respectively) because of the gravity that empties the lower limb venous compartment (9). This is different from what was observed in microgravity during three spaceflights where the A_fv remained enlarged throughout the flight (6, 8).

In the control group, the cardiovascular parameters measured at HDT day 7 in the morning and the evening were not significantly different.

Cardiovascular Parameters Before Cuffs Were Donned After 7 Days in HDT in Subjects Using Cuffs During Daytime

On the other hand, the EF was found to have decreased more in the cuff group than in the control one, suggesting that there was a higher decrease in left ventricle contractility and ejection capacity in the cuff group. Nevertheless it is difficult to support this hypothesis because the SV was also more reduced in the cuff group, and change in this parameter may be sufficient to modify the EF. Moreover, the absence of physical activity during the whole bed-rest period, which could contribute to the reduction in cardiac performances, was similar in both groups. Such a pattern was never observed in flight, possibly because of the daily intensive physical exercise performed by the astronauts.

Finally, the cerebral resistances were found to be significantly increased at HDT day 7 in the control group, but not in the cuff group. One may suspect that the daily use of the cuffs, which reduces the cephalic vein stasis, contributed to reducing transfer of liquid into the extravascular space at the brain level.

Early Cardiovascular Response After 15 Min With Cuffs

Cardiovascular Adaptation After 8 h With Cuffs at HDT Day 7

Hemodynamic cardiac parameters were significantly increased after 8 h with the cuffs, compared with precuff values: blood pressure (+6%), SV (+15%), and EF (+4%). The significant increase in SV and blood pressure supports an increase in the plasma volume; thus the reduction in volemia induced by the HDT position was compensated, at least partially, by the cuff countermeasure. This cardiovascular adaptation some hours after the initial reduction in the plasma volume (blood pooled in the lower limb) was unexpected, because normally the response is the opposite. In fact, just after the subjects donned the cuffs, there was a reduction in plasma volume, suggesting that a second process had come into play to adapt to the reduction in volemia, including liquid transfer from the interstitial to the vascular areas in the upper part of the body over a period of several hours. At last, after 8 h with cuffs, the cardiac parameters that were initially decreased by the HDT position had largely recovered to their pre-HDT level.

The CCSD, which tended to decrease (not significantly) during HDT, was found to be significantly increased after 8 h with cuffs (+6%). One can suggest that this increase in arterial cross section may be related to the increase in left ventricle SV and blood pressure. This raises the hypothesis that volemia may interfere with carotid baroreceptor response through carotid wall distension (hypervolemia) or relaxation (hypovolemia).

Cerebral resistance was slightly decreased (5%), which is consistent with the reduction in the A_jv by 51%. Femoral resistance was significantly increased (+42%) because of the reduction in the venous return induced by the cuff pressure. With cuffs, the cerebral and femoral vascular tone recovered their initial pre-HDT level.

The largest modifications induced by the thigh cuffs occurred in the venous system. The marked decrease in the A_jv (51%) contributes to the reduction in the venous flow stagnation, which may explain the reduction in facial edema and the sensation of comfort reported by the present HDT subjects and the cosmonauts when wearing the cuffs. These results suggest that the cuffs may also reduce any cerebral edema during HDT or spaceflights.

The leg vein sections were considerably increased as soon as the cuffs were donned (femoral vein: +288%; popliteal vein: +162%). Thus the veins remained highly distended, and the venous flow slowed during the whole daytime period with cuffs. Thus one may suspect a persistent increase in the leg vein compliance, which could favor orthostatic intolerance post-HDT or the development of a thrombophlebitic process as the cuffs were applied for a long period (8 h/day for 7 days). The marked increase in leg vein size is in agreement with the significant leg volume increase measured by plethysmography in subjects in HDT (12°) during 15 min and when wearing thigh cuffs inflated at a pressure of 50 mmHg (32). In this former experiment, HR and blood pressure were also not disturbed as in our study.

Finally, thigh cuffs applied during the daytime restored most of the cardiac and arterial parameters nearly to their pre-HDT value. No significant differences were found between the values of these parameters measured at rest pre-HDT and at HDT day 7 with cuffs. Conversely the A_jv (with thigh cuffs) was significantly lower than pre-HDT, and the facial edema was reduced, whereas the leg veins were markedly enlarged compared with pre-HDT.

At HDT day 7 (morning without cuffs), most of the cardiac and vascular parameters were similarly decreased in both groups compared with the pre-HDT values. Thus it seems that, even if the cuffs were applied for 7 consecutive days, there was no memory of the hemodynamic changes induced by these cuffs during daytime. Thus no specific effect of the cuffs on the orthostatic tolerance at the end of the HDT or postflight was expected as is the case with LBNP and exercise (27). This hypothesis was confirmed by the stand-test results, which demonstrated that the orthostatic intolerance was practically the same for each subject with or without cuffs.

Conclusion

On the other hand, although repeated LBNP or maximum exercise was found to contribute to the reduction in the development of orthostatic intolerance in HDT and spaceflights, the daily use of thigh cuffs in simulated microgravity did not have any influence on the orthostatic tolerance as evaluated by the post-HDT stand test.

Finally, the main cardiovascular effects of the thigh-cuff countermeasures have probably been identified, but the appropriate level of the cuff pressure and the duration of application to optimize their beneficial effects need to be investigated in more detail. As long as the cuffs were applied, the leg veins remained significantly enlarged, but until now no venous pathology has been reported after spaceflights. Knowing that most of the cosmonauts used these cuffs during the whole duration of the 6-mo spaceflights, one can suspect that the properties of the vein wall may be affected. This aspect will require more sophisticated postflight venous investigations.

More subjects will be needed to draw a conclusion on the true incidence of the thigh cuffs on the development of cardiovascular deconditioning. It is already clear that this simple maneuver may reduce the time during which the cerebral tissue is submitted to increased venous pressure and prevent the development of brain edema during any long-term exposure to actual or simulated microgravity.