Impact of Increasing Lower Body Negative Pressure and Its Abrupt Release on Left Ventricular Hemodynamics in Anesthetized Pigs.

Lower body negative pressure (LBNP) has been implemented as a tool to simulate systemic effects of hypovolemia, understand orthostatic challenges and study G load stress in humans. However, the exact hemodynamic mechanisms of graded LBNP followed by its abrupt release have not been characterized in detail, limiting its potential applications in humans. Here, we set out to investigate the immediate hemodynamic alterations occurring during LBNP in healthy Landrace pigs. Invasive cardiac monitoring via extensive pressure volume loop analysis was carried out during application of incremental LBNP up to life threatening levels from -15 to -45 mmHg as well as during its abrupt release. Three different sealing positions were evaluated. Incremental LBNP consistently induced a preload dependent depression of systemic hemodynamics according to the Frank-Starling mechanism. Overall, the pressure-volume loop progressively shifted leftwards and downwards with increasing LBNP intensity. The abrupt release of LBNP reverted the above-described hemodynamic changes to baseline values within only three respiratory cycles. These data provide quantitative translational insights into hemodynamic mechanisms of incremental and very high levels of LBNP, levels of seal and effect of abrupt release for future human applications, such as countermeasure development for long spaceflight.

Graded lower body negative pressure induces intraventricular negative pressures and incremental diastolic suction: a pressure-volume study in a porcine model.

Lower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively and remain unclear. We hypothesized that incremental LBNP reduces diastolic filling and thereby affects left ventricular (LV) diastolic suction (DS). Here, we investigated the impact of graded LBNP at three different levels of seal as well as during ß-adrenergic stimulation by invasive pressure-volume (PV) analysis. Eight Landrace pigs were instrumented closed-chest for PV assessment. LBNP was applied at three consecutive locations: I) cranial, 10 cm below xiphoid process; II) medial, half-way between cranial and caudal; III) caudal, at the iliac spine. Level III was repeated under dobutamine infusion. At each level, baseline measurements were followed by application of incremental LBNP of -15, -30, and -45 mmHg. LBNP induced varying degrees of preload-dependent hemodynamic changes, with cranial LBNP inducing more pronounced effects than caudal. According to the Frank-Starling mechanism, graded LBNP progressively reduced LV stroke volume (LV SV) following a decrease in LV end-diastolic volume. Negative intraventricular minimal pressures were observed during dobutamine-infusion as well as higher levels of LBNP. Of note, incremental LV negative pressures were accompanied by increasing DS volumes, derived by extrapolating the volume at zero transmural pressure, the so-called equilibrium volume (V0), related to LV SV. In conclusion, graded preload reduction via LBNP shifts the PV loop to smaller volumes and end-systolic volume below V0, which induces negative LV pressures and increases LV suction. Accordingly, LBNP-induced central hypovolemia is associated with increased DS.NEW & NOTEWORTHY This study examined the effects of incremental lower body negative pressure (LBNP) from -15 to -45 mmHg on hemodynamic regulation using invasive pressure-volume assessment in closed-chest pigs. Graded preload reduction via LBNP induces negative left ventricular (LV) pressures while increasing LV suction and thus allowing the ventricle to eject below the equilibrium volume at the end of systole. Accordingly, LBNP-induced central hypovolemia is associated with increased diastolic suction.

Fluid Shifts Induced by Physical Therapy in Lower Limb Lymphedema Patients.

Complete decongestive therapy (CDT), a physical therapy including manual lymphatic drainage (MLD) and compression bandaging, is aimed at mobilizing fluid and reducing limb volume in lymphedema patients. Details of fluid shifts occurring in response to CDT are currently not well studied. Therefore, we investigated fluid shifts before, during and after CDT. Thirteen patients (3 males and 10 females, aged 57 ± 8.0 years, 167.2 ± 8.3 cm height, 91.0 ± 23.4 kg weight) diagnosed with stage II leg lymphedema participated. Leg volume, limb and whole-body fluid composition (total body water (limbTBW/%TBW), extracellular (limbECF/%ECF) and intracellular (limbICF/%ICF fluid), as well as ECF/ICF and limbECF/limbICF ratios were determined using perometry and bioelectrical impedance spectroscopy. Plasma volume, proteins, osmolality, oncotic pressure and electrolytes were assessed. Leg volume (p < 0.001), limbECF (p = 0.041), limbICF (p = 0.005) and limbECF/limbICF decreased over CDT. Total leg volume and limbTBW were correlated (r = 0.635). %TBW (p = 0.001) and %ECF (p = 0.007) decreased over time. The maximum effects were seen within one week of CDT. LimbICF (p = 0.017), %TBW (p = 0.009) and %ICF (p = 0.003) increased post-MLD, whereas ECF/ICF decreased due to MLD. Plasma volume increased by 1.5% post-MLD, as well as albumin and the albumin-to-globulin ratio (p = 0.005 and p = 0.049, respectively). Our results indicate that physical therapy leads to fluid shifts in lymphedema patients, with the greatest effects occurring within one week of therapy. Fluid shifts due to physical therapy were also reflected in increased plasma volume and plasma protein concentrations. Perometry, in contrast to bioelectrical impedance analysis, does not seem to be sensitive enough to detect small fluid changes caused by manual lymphatic drainage.

Prolonged bedrest reduces plasma high-density lipoprotein levels linked to markedly suppressed cholesterol efflux capacity.

Recent observations strongly connect high-density lipoproteins (HDL) function and levels with coronary heart disease outcomes and risk for infections and sepsis. To date, our knowledge of factors determining this connection is still very limited. The immobility associated with prolonged bedrest is detrimental to health, affecting several systems, including the cardiovascular, pulmonary, gastrointestinal, musculoskeletal and urinary. Effects of prolonged bedrest on the composition and functional properties of HDL remain elusive. We evaluated metrics of HDL composition and function in healthy male volunteers participating in a randomized, crossover head-down bedrest study. We observed that HDL cholesterol efflux capacity was profoundly decreased during bedrest, mediated by a bedrest associated reduction in plasma levels of HDL-cholesterol and major apolipoproteins (apo) apoA-I and apoA-II. Paraoxonase activity, plasma anti-oxidative capacity and the activities of lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein were not affected. No change was observed in the content of HDL-associated serum amyloid A, a sensitive marker of inflammation. Resistive vibration exercise countermeasure during bedrest did not correct impaired cholesterol efflux capacity and only tended to increase arylesterase activity of HDL-associated paraoxonase. In conclusion, prolonged bedrest reduces plasma HDL levels linked to markedly suppressed HDL cholesterol efflux capacity. Resistive vibration exercise during bedrest did not correct HDL levels and impaired cholesterol efflux capacity.

Effect of novel short-arm human centrifugation-induced gravitational gradients upon cardiovascular responses, cerebral perfusion and g-tolerance.

KEY POINTS: The aim of this study was to determine the effect of rotational axis position (RAP and thus g-gradient) during short-arm human centrifugation (SAHC) upon cardiovascular responses, cerebral perfusion and g-tolerance. In 10 male and 10 female participants, 10 min passive SAHC runs were performed with the RAP above the head (P1), at the apex of the head (P2), or at heart level (P3), with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. We hypothesized that movement of the RAP from above the head (the conventional position) towards the heart might reduce central hypovolaemia, limit cardiovascular responses, aid cerebral perfusion, and thus promote g-tolerance. Moving the RAP footward towards the heart decreased the cerebral tissue saturation index, calf circumference and heart rate responses to SAHC, thereby promoting g-tolerance. Our results also suggest that RAP, and thus g-gradient, warrants further investigation as it may support use as a holistic spaceflight countermeasure. ABSTRACT: Artificial gravity (AG) through short-arm human centrifugation (SAHC) has been proposed as a holistic spaceflight countermeasure. Movement of the rotational axis position (RAP) from above the head towards the heart may reduce central hypovolaemia, aid cerebral perfusion, and thus promote g-tolerance. This study determined the effect of RAP upon cardiovascular responses, peripheral blood displacement (i.e. central hypovolaemia), cerebral perfusion and g-tolerance, and their inter-relationships. Twenty (10 male) healthy participants (26.2 ± 4.0 years) underwent nine (following a familiarization run) randomized 10 min passive SAHC runs with RAP set above the head (P1), at the apex of the head (P2), or at heart level (P3) with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. Cerebral tissue saturation index (cTSI, cerebral perfusion surrogate), calf circumference (CC, central hypovolaemia), heart rate (HR) and digital heart-level mean arterial blood pressure (MAP) were continuously recorded, in addition to incidence of pre-syncopal symptoms (PSS). ΔCC and ΔHR increases were attenuated from P1 to P3 (ΔCC: 5.46 ± 0.54 mm to 2.23 ± 0.42 mm; ΔHR: 50 ± 4 bpm to 8 ± 2 bpm, P < 0.05). In addition, ΔcTSI decrements were also attenuated (ΔcTSI: -2.85 ± 0.48% to -0.95 ± 0.34%, P < 0.05) and PSS incidence lower in P3 than P1 (P < 0.05). A positive linear relationship was observed between ΔCC and ΔHR with increasing +Gz, and a negative relationship between ΔCC and ΔcTSI, both independent of RAP. Our data suggest that movement of RAP towards the heart (reduced g-gradient), independent of foot-level Gz, leads to improved g-tolerance. Further investigations are required to assess the effect of differential baroreceptor feedback (i.e. aortic-carotid g-gradient).

Novel findings on ultrastructural protection of skeletal muscle fibers during hibernation of Daurian ground squirrels: Mitochondria, nuclei, cytoskeleton, glycogen.

We examined ultrastructure protective phenomena and mechanisms of slow and fast muscles in hibernating Daurian ground squirrels (Spermophilus dauricus). Some degenerative changes such as slightly decreased sarcomere length and vacuolization occurred in hibernation, but periaxonal capsular borders in intrafusal fibers remained distinct and the arrangement of extrafusal fibers and Z-lines unscathed. In soleus samples, the number of glycogenosomes more than tripled during hibernation. The expression of phosphorylated glycogen synthase remained unaltered while that of glycogen phosphorylase decreased during hibernation. The number of extensor digitorum longus glycogenosomes decreased and the expression of phosphorylated glycogen synthase decreased, while glycogen phosphorylase expression remained unaltered. The nuclei number remained unchanged. Kinesin and desmin, preventors of nuclear loss and damage, were maintained or just slightly reduced in hibernation. The single-fiber mitochondrial concentration and sub-sarcolemmal mitochondrial number increased in both muscle types. The expression of vimentin, which anchors mitochondria and maintains Z-line integrity, was increased during and after hibernation. Also, dynamin-related protein 1, mitochondrial fission factor, and adenosine triphosphate synthase were elevated in both muscle types. These findings confirm a remarkable ultrastructure preservation and show an unexpected increase in mitochondrial capacity in hibernating squirrels.

Lower Body Negative Pressure: Physiological Effects, Applications, and Implementation.

This review presents lower body negative pressure (LBNP) as a unique tool to investigate the physiology of integrated systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia in humans. An early review published in Physiological Reviews over 40 yr ago (Wolthuis et al. Physiol Rev 54: 566-595, 1974) focused on the use of LBNP as a tool to study effects of central hypovolemia, while more than a decade ago a review appeared that focused on LBNP as a model of hemorrhagic shock (Cooke et al. J Appl Physiol (1985) 96: 1249-1261, 2004). Since then there has been a great deal of new research that has applied LBNP to investigate complex physiological responses to a variety of challenges including orthostasis, hemorrhage, and other important stressors seen in humans such as microgravity encountered during spaceflight. The LBNP stimulus has provided novel insights into the physiology underlying areas such as intolerance to reduced central blood volume, sex differences concerning blood pressure regulation, autonomic dysfunctions, adaptations to exercise training, and effects of space flight. Furthermore, approaching cardiovascular assessment using prediction models for orthostatic capacity in healthy populations, derived from LBNP tolerance protocols, has provided important insights into the mechanisms of orthostatic hypotension and central hypovolemia, especially in some patient populations as well as in healthy subjects. This review also presents a concise discussion of mathematical modeling regarding compensatory responses induced by LBNP. Given the diverse applications of LBNP, it is to be expected that new and innovative applications of LBNP will be developed to explore the complex physiological mechanisms that underline health and disease.

Orthostatic Intolerance in Older Persons: Etiology and Countermeasures.

Orthostatic challenge produced by upright posture may lead to syncope if the cardiovascular system is unable to maintain adequate brain perfusion. This review outlines orthostatic intolerance related to the aging process, long-term bedrest confinement, drugs, and disease. Aging-associated illness or injury due to falls often leads to hospitalization. Older patients spend up to 83% of hospital admission lying in bed and thus the consequences of bedrest confinement such as physiological deconditioning, functional decline, and orthostatic intolerance represent a central challenge in the care of the vulnerable older population. This review examines current scientific knowledge regarding orthostatic intolerance and how it comes about and provides a framework for understanding of (patho-) physiological concepts of cardiovascular (in-) stability in ambulatory and bedrest confined senior citizens as well as in individuals with disease conditions [e.g., orthostatic intolerance in patients with diabetes mellitus, multiple sclerosis, Parkinson's, spinal cord injury (SCI)] or those on multiple medications (polypharmacy). Understanding these aspects, along with cardio-postural interactions, is particularly important as blood pressure destabilization leading to orthostatic intolerance affects 3-4% of the general population, and in 4 out of 10 cases the exact cause remains elusive. Reviewed also are countermeasures to orthostatic intolerance such as exercise, water drinking, mental arithmetic, cognitive training, and respiration training in SCI patients. We speculate that optimally applied countermeasures such as mental challenge maintain sympathetic activity, and improve venous return, stroke volume, and consequently, blood pressure during upright standing. Finally, this paper emphasizes the importance of an active life style in old age and why early re-mobilization following bedrest confinement or bedrest is crucial in preventing orthostatic intolerance, falls and falls-related injuries in older persons.

Identification of the optimal dose and calpain system regulation of tetramethylpyrazine on the prevention of skeletal muscle atrophy in hindlimb unloading rats.

Previous studies in our lab have shown that tetramethylpyrazine (TMP) could effectively attenuate disuse induced muscle atrophy. In order to screening out the optimal dose of tetramethylpyrazine (TMP) for protection against disuse induced muscle atrophy in hindlimb unloading (HLU) rats, in this study, we compared effects of 4 TMP doses on muscle wet weight (MWW), the ratios of muscle wet weight/body weight (MWW/BW) and muscle wet weight/dry weight (MWW/DW), fiber type composition, as well as cross-sectional area (CSA) in soleus (SOL) muscle. Consequently, we quantified optimal dose effects on both functional properties and protein expression (calpain-1, calpain-2, calpastatin and MuRF1) in SOL and extensor digitorum longus (EDL) muscles. Data indicated that the protective potential of TMP was dose-dependent: 60mg/kg TMP was most effective in terms of atrophy prevention. This dose reduced SOL MWW, MWW/BW and CSA muscle loss by 60, 60 and 54% (P<0.001), respectively. HLU-induced slow-to-fast fiber transition was reduced by 17% (P<0.01). 60mg/kg TMP also significantly lessened the decrease of contractile force, the increase of shorting velocity and fatigability induced by HLU. Besides, it also attenuated expressions of calpain-1 (SOL -8.6%, P<0.05; EDL -10.9%, P<0.05), calpain-2 (SOL -60%, P<0.001; EDL -32%, P<0.01) and MuRF1 expression (SOL -21%, P<0.001; EDL -10%, P<0.01), promoted the expression of calpastatin by 18% (P<0.05) in SOL muscle. Taken together, present study demonstrated that 60mg/kg body weight was the optimal dose of TMP against disuse induced muscle atrophy which effectively protected muscle function by inhibiting calpain-1, calpain-2 and MuRF1 expression, promoted calpastatin expression, especially in slow-twitch muscle.

Adrenomedullin and galanin responses to orthostasis in older persons.

BACKGROUND: Neuroendocrine responses to orthostasis may be critical in the maintenance of mean arterial pressure in healthy individuals. A greater reduction in orthostatic tolerance with age may relate to modulation of hormonal responses such as adrenomedullin and galanin. Thus, we investigated (i) whether adrenomedullin and galanin concentrations increase during orthostatic challenge in older subjects, (ii) whether adrenomedullin and galanin concentrations are higher in older females compared with older males when seated and during orthostatic challenge, and (iii) whether postural changes in plasma concentrations of galanin are correlated with levels of adrenomedullin in either older females or males. MATERIALS AND METHODS: Subjects (n = 18; 12 ♀; 55-80 years old) performed a sit-to-stand test in a 25°C sensory-minimised environment, with blood samples collected after 4 min of being seated and then when standing. Plasma adrenomedullin and galanin concentrations were determined. RESULTS: Baseline plasma concentration of adrenomedullin (5·35 ± 0·74 (n = 12, females) vs. 7·40 ± 1·06 pg/mL (n = 5, males)) and galanin (64·07 ± 9·05 vs. 98·99 ± 16·90 pg/mL, respectively) did not significantly differ between genders. Furthermore, plasma adrenomedullin and galanin concentrations were not significantly affected by adoption of the upright posture in either gender and were not correlated in females or males. CONCLUSIONS: Adrenomedullin and galanin concentrations were similar between genders and did not change following adoption of the standing posture. To further clarify the roles, these hormones play in orthostatic intolerance, adrenomedullin and galanin concentrations should be assessed in participants who show presyncopal symptoms during an orthostatic challenge.

Poststroke alterations in heart rate variability during orthostatic challenge.

Older adults following recovery from ischemic stroke have a higher incidence of orthostatic hypotension, syncope, and fall risk, which may be related to impaired autonomic responses limiting the ability to maintain cerebral blood flow. Thus, we investigated cerebrovascular and cardiovascular regulation in 23 adults ≥55 years of age, 10 diagnosed with ischemic stroke, and 13 age-matched healthy controls when sitting at rest and upon standing to compare differences of autonomic variables at ∼7 months (218 ±â€Š41 days) poststroke.Arterial blood pressure via finger plethysmography, muscle-pump baroreflex via electromyography, heart rate variability via 3-lead ECG, and cerebral blood flow velocity via transcranial Doppler were analyzed while sitting for 5 minutes and then during quiet standing for 5 minutes.From the seated to standing position, the stroke group had significantly greater decline in the low frequency component of heart rate variability (164 [79] vs 25 [162] ms; P = 0.043). All other cardiovascular parameters and assessments of autonomic function were not significantly different between the two groups.Our findings support the hypothesis of continued autonomic dysfunction after recovery from ischemic stroke, with potential attenuation of the cardiovascular response to standing. However, further investigation is required to determine the mechanisms underlying the increased risk of orthostatic hypotension, syncope, and falls poststroke.

Effect of postural changes on cardiovascular parameters across gender.

INTRODUCTION: We investigated the effect of postural changes on various cardiovascular parameters across gender. Twenty-eight healthy subjects (16 male, 12 female) were observed at rest (supine) and subjected to 3 interventions; head-down tilt (HDT), HDT with lower body negative pressure (HDT+ LBNP at -30 mm Hg), and head-up tilt (HUT), each for 10 minutes separated by a 10 minutes recovery period. METHODS: Measurements were recorded for heart rate (HR), standard deviation of the normal-to-normal intervals, root mean square of successive differences between the normal-to-normal intervals, heart rate variability-low frequency (LFRRI), heart rate variability-high frequency (HFRRI), low frequency/high frequency ratio (LFRRI/HFRRI), systolic blood pressure (SBP), mean arterial pressure (MAP), diastolic blood pressure (DBP), total peripheral resistance index (TPRI), stroke index (SI), cardiac index (CI), index of contractility (IC), left ventricular work index, and left ventricular ejection time. RESULTS: Across all cardiovascular parameters, there was a significant main effect of the intervention applied but there was no significant main effect of gender across all parameters. CONCLUSIONS: The results suggest that there are no specific gender differences in regards to the measured variables under the conditions of this study. Furthermore, these results suggest that in healthy subjects, there appears to be evidence that LBNP partially elicits similar cardiovascular responses to HUT, which supports the use of LBNP as an intervention to counteract the effects of central hypovolemia.

Effects of Exercise and Nutrition on the Coagulation System During Bedrest Immobilization.

Immobilization in hospitalized medical patients or during simulation of spaceflight induced deconditioning has been shown to be associated with loss of muscle mass and bone. Resistance vibrating exercise (RVE) and/or high protein diet are countermeasures, which are capable of mitigating the adverse effects of immobilization. We investigated the effect of these countermeasures on the coagulation system. Two groups of volunteers, each of whom performed such countermeasures, were enrolled in the study. Volunteers, who did nothing while bed rested, served as controls. The berest and the intervention protocols were carried out at Clinique d' Investigation, MEDES, Toulouse, France. Eleven healthy men volunteered for this randomized crossover study. The subjects underwent 21 day of 6° head down bed rest (HDBR) followed by a washout period of 4 months. The first group followed an exercise schedule using resistance-vibrating exercise (RVE group). The second group also used the RVE but complemented it with high-protein supplement diet (NeX group). The third group only did bed rest. The highly sensitive methods calibrated automated thrombography (CAT) and thrombelastometry (TEM) were applied to monitor hemostatic changes. In all 3 groups, the hemostatic system shifted toward hypocoagulability during bed rest. For example, peak and thrombin formation velocity (VELINDEX) reduced in this period. Interestingly, a tendency toward hypercoagulation was observed during re-ambulation. In all 3 groups, ttPeak and StartTail were reduced, and Peak and VELINDEX (except in the RVE group) were significantly higher in relation to baseline values. Influence of bed rest on the coagulation system in the 2 groups performing countermeasures (RVE and NeX group) was the same as in the control bed-rested group. Clotting does not seem to be worsened by prolonged immobilization, or by countermeasures such as RVE/exercise or high-protein supplementation during immobilization. Therefore, only hospitalized medical patients at an elevated risk for thrombosis should be treated with anticoagulants. However, clinicians have to be aware that the re-ambulation period following immobilization might be associated with an elevated risk of thrombotic events.

Effects of individualized centrifugation training on orthostatic tolerance in men and women.

AIMS: Exposure to artificial gravity (AG) at different G loads and durations on human centrifuges has been shown to improve orthostatic tolerance in men. However, the effects on women and of an individual-specific AG training protocol on tolerance are not known. METHODS: We examined the effects of 90 minutes of AG vs. 90 minutes of supine rest on the orthostatic tolerance limit (OTL), using head up tilt and lower body negative pressure until presyncope of 7 men and 5 women. Subjects were placed in the centrifuge nacelle while instrumented and after one-hour they underwent either: 1) AG exposure (90 minutes) in supine position [protocol 1, artificial gravity exposure], or 2) lay supine on the centrifuge for 90 minutes in supine position without AG exposure [protocol 2, control]. The AG training protocol was individualized, by first determining each subject's maximum tolerable G load, and then exposing them to 45 minutes of ramp training at sub-presyncopal levels. RESULTS: Both sexes had improved OTL (14 minutes vs 11 minutes, p < 0.0019) following AG exposure. When cardiovascular (CV) variables at presyncope in the control test were compared with the CV variables at the same tilt-test time (isotime) during post-centrifuge, higher blood pressure, stroke volume and cardiac output and similar heart rates and peripheral resistance were found post-centrifuge. CONCLUSIONS: These data suggest a better-maintained central circulating blood volume post-centrifugation across gender and provide an integrated insight into mechanisms of blood pressure regulation and the possible implementation of in-flight AG countermeasure profiles during spaceflights.

Academic Goal Orientation and Cardiovascular Reactivity in a Performance Situation.

The present study investigated whether students' academic goal orientation (learning goals, performance goals, work avoidance) and their individual competence beliefs (their academic self-concept) can predict motivation-related cardiovascular activation patterns in a demanding performance situation. A sample of seventy-two undergraduate students rated their academic goal orientation as well as their competence beliefs and completed a mental arithmetic task. Heart rate (HR), blood pressure, pre-ejection period (PEP) as well as cardiac output (CO) and total peripheral resistance were monitored continuously during rest and task exposure. Students scoring higher on work avoidance showed smaller increases in HR and CO, and a smaller shortening of the PEP. A lower academic self-concept was associated with attenuated CO reactivity and a smaller shortening of the PEP. Learning and performance goals were unrelated to cardiovascular activity. The attenuated cardiac activity observed for work avoidance and competence beliefs was interpreted in terms of reduced task engagement resulting from lower success importance.

Influence of bed rest on plasma galanin and adrenomedullin at presyncope.

BACKGROUND: The role of hormones in reduced orthostatic tolerance following long-term immobilization remains uncertain. We have previously shown that plasma concentrations of adrenomedullin and galanin, two peptides with vasodepressor properties, rise significantly during orthostatic challenge. We tested the hypothesis that bedrest immobilization increases the rise in adrenomedullin and galanin during orthostatic challenge leading to presyncope. MATERIALS AND METHODS: We measured baseline (supine), presyncope and recovery (10 min postpresyncope, supine) levels of adrenomedullin and galanin in 8 healthy men, before and after 21 days of -6° head-down bed rest (HDBR). Presyncope was elicited using a combined head-up tilt and graded lower body negative pressure protocol. Orthostatic tolerance was defined as the time taken from the commencement of head-up tilt to the development of presyncope. RESULTS: Orthostatic tolerance time after HDBR reduced by 8·36 ± 5·39 min (P = 0·0032). HDBR increased plasma adrenomedullin concentration to orthostatic challenge (P = 0·0367). Compared to pre-HDBR, a significant rise in post-HDBR presyncopal (P < 0·001) and recovery adrenomedullin concentration (P < 0·01) was demonstrated. In contrast, we observed no change in pre- and post-HDBR galanin levels to orthostatic challenge. CONCLUSIONS: Bedrest immobilization appears to affect adrenomedullin levels in that greater increases in adrenomedullin occur at presyncope following bedrest immobilization. Due to its peripheral vasculature hypotensive effect, the greater levels of adrenomedullin at presyncope following bedrest immobilization may have contributed to the reduced orthostatic capacity postbedrest.

Volume regulation and renal function at high altitude across gender.

AIMS: We investigated changes in volume regulating hormones and renal function at high altitudes and across gender. METHODOLOGY: Included in this study were 28 subjects (n = 20 males; n = 8 females. ages: 19 - 65 yrs), who ascended to a height of 3440m (HA1), on the 3rd day and to 5050m (HA2), on the 14th day. Plasma and urinary creatinine and urinary osmolality as well as plasma levels of plasma renin activity (PRA), Aldosterone, antidiuretic hormone (ADH), and atrial natriuretic peptide (ANP) were measured. The plasma volume loss (PVL) was estimated from plasma density and hematocrit. Glomerular filtration rate (GFR) was measured based on nocturnal (9 hour) creatinine clearance; this was compared with various methods for estimation of GFR. RESULTS: The mean 24-hour urine production increased significantly in both sexes across the expedition. But PVL reached significance only in males. No changes in Na+ in plasma, urine or its fractional excretion were seen at both altitudes. Urinary osmolality decreased upon ascent to the higher altitudes. ADH and PRA decreased significantly at both altitudes in males but only at HA2 in females. However, no changes in aldosterone were seen across the sexes and at different altitudes. ANP increased significantly only in males during the expedition. GFR, derived from 9-h creatinine clearance (CreaCl), decreased in both sexes at HA1 but remained stable at HA2. Conventional Crea[p]-based GFR estimates (eGFR) showed only poor correlation to CreaCl. CONCLUSIONS: We report details of changes in hormonal patterns across high altitude sojourn. To our knowledge we are not aware of any study that has examined these hormones in same subjects and across gender during high altitude sojourn. Our results also suggest that depending on the estimation formula used, eGFR underestimated the observed decrease in renal function measured by CreaCl, thus opening the debate regarding the use of estimated glomerular filtration rates at high altitudes.

Short-arm human centrifugation with 0.4g at eye and 0.75g at heart level provides similar cerebrovascular and cardiovascular responses to standing.

BACKGROUND AND PURPOSE: Orthostatic intolerance continues to be a problem with astronauts upon return to Earth as a result of cerebral and cardiovascular adaptations to weightlessness. We tested the hypothesis that artificial gravity from a short-arm human centrifuge (SAHC) could provide cerebral and cardiovascular stimuli similar to upright posture and thereby serve as a suitable countermeasure. METHODS: We compared cardiovascular and cerebrovascular responses before, during, and after exposure to hyper-G with that of standing in healthy young participants. The head was positioned such that the middle cerebral artery (MCA) was 0.46 m from the center of rotation. Two levels of hyper-G that provided 1g and 2g at foot level were investigated. Continuous blood pressure, heart rate, calf blood volume, MCA mean blood flow velocity (MFV) and end-tidal CO2 were measured. RESULTS: Blood pressure at the level of the MCA (BP-MCA) and MFV was reduced during stand and at 2g. The relationship between MFV and BP-MCA at 2g was different from supine and similar to standing, while 1g centrifugation was not different from supine. The cardiovascular system was also not different from supine at 1g but was similarly challenged in 2g compared to stand. CONCLUSIONS: Our data suggest that short-arm centrifugation 2g at the feet, with the head offset 0.5 m from the center, provides similar cardiovascular and cerebral responses to standing. This supports the hypothesis that passive 2g SAHC exposure at the feet could be used as a countermeasure for in-flight cardiovascular and cerebrovascular deconditioning.

Effect of computerized cognitive training with virtual spatial navigation task during bed rest immobilization and recovery on vascular function: a pilot study.

We investigated the effects of bed rest (BR) immobilization, with and without computerized cognitive training with virtual spatial navigation task (CCT), on vascular endothelium on older subjects. The effects of 14-day BR immobilization in healthy older males (n=16) of ages 53-65 years on endothelial function were studied using EndoPAT(®), a noninvasive and user-independent method. From the group of 16 older men, 8 randomly received CCT during the BR, using virtual navigation tasks in a virtual environment with joystick device. In all the cases, EndoPAT assessments were done at pre- and post-BR immobilization as well as following 28 days of ambulatory recovery. The EndoPAT index increased from 1.53±0.09 (mean ± standard error of the mean) at baseline to 1.61±0.16 following immobilization (P=0.62) in the group with CCT. The EndoPAT index decreased from 2.06±0.13 (mean ± standard error of the mean) at baseline to 1.70±0.09 at the last day of BR study, day 14 (BR14) (P=0.09) in the control group. Additionally, there were no statistically significant differences between BR14 and at 28 days of follow-up (rehabilitation program) (R28). Our results show a trend of immobilization in older persons affecting the vasoconstrictory endothelial response. As the control subjects had a greater increase in EndoPAT index after R28 (+0.018) compared to subjects who had cognitive training (+0.11) (calculated from the first day of BR study), it is possible that cognitive training during BR does not improve endothelial function but rather contributes to slowing down the impairment of endothelial function. Finally, our results also show that EndoPAT may be a useful noninvasive tool to assess the vascular reactivity.

Bed rest does not induce hypercoagulability.

BACKGROUND: Although there is no direct evidence, it is generally believed that bed rest shifts the haemostatic system towards hypercoagulability; thus, immobilized patients are commonly treated with anticoagulants. We therefore aimed to investigate whether long-term bed rest actually leads to an elevated risk for thromboembolic events. MATERIALS AND METHODS: Eleven healthy men were enrolled in our study (bed rest campaign in MEDES Clinique d'Investigation, Toulouse, France). Besides various standard laboratory methods, we used calibrated automated thrombography (CAT) and thrombelastometry (TEM). Activation of samples with minute amounts of relipidated tissue factor allowed sensitive detection of hyper- or hypocoagulable states. RESULTS: CAT and TEM values were not indicative of bed rest-induced hypercoagulability. On the contrary, several parameters were indicative of a tendency towards a hypocoagulable state. Peak and thrombin formation velocity (VELINDEX) were significantly decreased during bed rest compared to baseline. Coagulation times were significantly increased and alpha angles were significantly decreased, indicating attenuated clot formation. Moreover, F1 + 2 and thrombin/antithrombin complex (TAT) values were significantly decreased during bed rest, indicating suppressed coagulation activation. FVII plasma levels were also significantly decreased during the first week of bed rest. CONCLUSIONS: Our data indicate that the re-ambulation period is associated with a tendency towards hypercoagulability: ttPeak and StartTail were significantly shorter, Peak and VELINDEX were significantly higher compared to baseline. Moreover, plasma levels of F1 + 2, TAT, FVII and FVIII were significantly higher compared to baseline. The results from our study suggest that bed rest by itself is not associated with hypercoagulable states in healthy subjects.