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Background: Changes in blood vessel properties have been identified with confinement, spaceflight, bedrest, and dry immersion. Subsequently, it was suspected that other organs may also be affected in these extreme environments. The purposes of the current study were to determine the effects of head-down bedrest (HDT) on cardiovascular and organ measurements made using ultrasound imaging similar to that currently available on the International Space Station, and to evaluate the efficacy of two different countermeasure protocols in preventing any observed changes in the ultrasound measurements with HDT. Methods: Ultrasound measures were conducted on 24 individuals (3 groups of 8) pre HDT and on day 55 of the HDT. The control group (C°) remained in passive HDT for the 55 days, the C1 group performed aerobic exercise daily (EX), and the C2 group practiced aerobic exercise under artificial gravity conditions (EX-AG). Fifteen parameters were measured on 10 different organs and blood vessels including the right common carotid artery, abdominal aorta, right tibial artery, left ventricle, right jugular vein, portal vein, right kidney, cervical and lumbar vertebra, and the vastus intermedius muscle. Results: HDT resulted in changes for many of the parameters investigated. Observed changes in carotid IMT and distensibility, cardiac ejection fraction, portal vein diameter, and vastus intermedius muscle thickness were attenuated with EX and EX-AG, with EX-AG having a greater effect than exercise alone on measures of carotid distensibility. Conclusion: Results from this study indicate changes in many structures assessed with ultrasound imaging after 55 days of HDT bedrest with some changes being attenuated with the two investigated countermeasure protocols. [ABSTRACT FROM AUTHOR]

Introduction: With current technology, ultrasound imaging in remote conditions, such as the International Space Station, is performed with vocal guidance or using a teleoperated echograph controlled by an expert. Both methods require real-time communications between the novice operator and expert to locate the probe over the appropriate acoustic windows (AW). The current study presents the development and testing of a new augmented reality software (Echo-QR) that would allow novice operators (with no medical imaging background) to correctly locate the ultrasound probe over the AW of interest without expert assistance. Methods: On the first day of the study, the positions of the probe over the AWs were identified for each organ by an expert sonographer and saved in the Echo-QR software. On the second day, the novices independently performed the ultrasound investigation using the Echo-QR software to correctly position the probe over each organ's AW. Results: Using the Echo-QR software, novice operators found the AWin 73 (92%) of the 79 organs. The 2D images acquired by the novices "2D direct image" were acceptable for medical evaluation in 41% of the cases. However, when the "2D direct image" did not show the entire organ, a 3D capture of the volume below the probe was also performed, which allowed for the extraction of the appropriate 2D image "2D/3D image" for medical evaluation in 85% of the cases. Discussion: Therefore, in the absence of real-time communication between an isolated participant and an expert sonographer, novel software (Echo-QR) and automated 3D volume capture can be used to obtain images usable for ultrasound diagnostics. [ABSTRACT FROM AUTHOR]

Syncope from sustained orthostasis results from cerebral hypoperfusion associated with reductions in arterial pressure at the level of the brain (BPMCA) and reductions in arterial CO2 as reflected by end-tidal values (PetCO2). It was hypothesized that reductions in PetCO2 increase cerebrovascular tone before a drop in BPMCA that ultimately leads to syncope. Twelve men (21-42 yr of age) completed an orthostatic tolerance test consisting of head-up tilt and progressive lower body negative pressure to presyncope, before and after completing 5 days of continuous head-down bed rest (HDBR). Cerebral blood velocity (CBFV), BPMCA, and PetCO2 were continuously recorded throughout the test. Cerebrovascular indicators, cerebrovascular resistance, critical closing pressure (CrCP), and resistance area product (RAP), were calculated. Comparing from supine baseline to 6-10 min after the start of tilt, there were reductions in CBFV, PetCO2, BPMCA, and CrCP, an increase in RAP, and no change in cerebrovascular resistance index. Over the final 15 min before syncope in the pre-HDBR tests, CBFV and CrCP were significantly related to changes in PetCO2 (r = 0.69 ± 0.17 and r = 0.63 ± 0.20, respectively), and BPMCA, which was not reduced until the last minute of the test, was correlated with a reduction in RAP (r = 0.91 ± 0.09). Post-HDBR, tilt tolerance was markedly reduced, and changes in CBFV were dominated by a greater reduction in BPMCA with no relationships to PetCO2. Therefore, pre-HDBR, changes in PetCO2 with orthostasis contributed to increases in cerebrovascular tone and reductions in CBFV during the progression toward syncope, whereas, after 5 days of HDBR, orthostatic responses were dominated by changes in BPMCA. [ABSTRACT FROM AUTHOR]

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired CO2. Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day (n = 4) or the morning 1 (n = 2) or 2 days (n = 1) after return to Earth. Arterial blood pressure at the level of the middle cerebral artery (BPMCA) and expired CO2 were monitored along with transcranial Doppler ultrasound assessment of middle cerebral artery (MCA) blood flow velocity (CBFV). Cerebrovascular resistance index was calculated as (CVRi = BPMCA/CBFV). Cerebrovascular autoregulation and CO2 reactivity were assessed in a supine position from an autoregressive moving average (ARMA) model of data obtained during a test where two breaths of 10% CO2 were given four times during a 5-min period. CBFV and Doppler pulsatility index were reduced during -20 mmHg lower body negative pressure, with no differences pre- to postflight. The postflight indicator of dynamic autoregulation from the ARMA model revealed reduced gain for the CVRi response to BPMCA (P = 0.017). The postflight responses to CO2 were reduced for CBFV (P = 0.056) and CVRi (P = 0.047). These results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular CO2 reactivity. [ABSTRACT FROM AUTHOR]

Background: Analysis of ultrasound radio frequency (RF) signals allows for the determination of the index of reflectivity (IR), which is a new measure that is dependent on tissue properties. Previous work has shown differences in the IR of the carotid artery wall with long-duration spaceflight; therefore, it was hypothesized that liver tissue would also show differences in this measure with spaceflight., Methods: The RF signal of a liver tissue region of interest (ROI) was displayed and processed along six different lines covering a surface of approximately 2 cm × 2 cm. The IR was calculated as the energy backscattered by the liver ROI divided by the total energy returned to the ultrasound probe., Results: Seven astronauts were investigated preflight, inflight on day 150, and postflight 4 days and 6 months after rerunning to Earth. Compared to preflight (63% ± 18%), the liver tissue ROI IR was significantly lower on flight day 150 (46% ± 14%; p = 0.027) and 4 days postflight (46% ± 19%; p = 0.025). At 6 months postflight, the IR returned to preflight values (59% ± 13%; p = 0.919)., Conclusion: The significant decrease in the coefficient of reflectivity inflight and 4 days postflight indicates an alteration in the liver tissue that reduces the reflection of ultrasound waves. This change in tissue properties could either be due to the addition of particles that do not reflect ultrasound waves or structural or cellular changes that alter the reflectivity of the tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Arbeille, Zuj and Guillon.)

Most astronauts experience back pain after spaceflight, primarily located in the lumbar region. Intervertebral disc herniations have been observed after real and simulated microgravity. Spinal deconditioning after exposure to microgravity has been described, but the underlying mechanisms are not well understood. The dry immersion (DI) model of microgravity was used with eighteen male volunteers. Half of the participants wore thigh cuffs as a potential countermeasure. The spinal changes and intervertebral disc (IVD) content changes were investigated using magnetic resonance imaging (MRI) analyses with T1-T2 mapping sequences. IVD water content was estimated by the apparent diffusion coefficient (ADC), with proteoglycan content measured using MRI T1-mapping sequences centered in the nucleus pulposus. The use of thigh cuffs had no effect on any of the spinal variables measured. There was significant spinal lengthening for all of the subjects. The ADC and IVD proteoglycan content both increased significantly with DI (7.34 ± 2.23% and 10.09 ± 1.39%, respectively; mean ± standard deviation), p < 0.05). The ADC changes suggest dynamic and rapid water diffusion inside IVDs, linked to gravitational unloading. Further investigation is needed to determine whether similar changes occur in the cervical IVDs. A better understanding of the mechanisms involved in spinal deconditioning with spaceflight would assist in the development of alternative countermeasures to prevent IVD herniation., Competing Interests: The authors declare no conflict of interest.

Echography is the most appropriate imaging modality for investigating astronauts. Unfortunately, it requires a great deal of training to perform ultrasound examinations, which can be difficult and time consuming, especially if the astronaut does not have a medical background. We designed a new echography system with motorized probes that allows for the majority of exam functions to be controlled by a ground-based sonographer. Using tele-operation, the sonographer controls the orientation of the transducer (tilt, rotation) and echograph settings (gain, depth, freeze) and triggers ultrasound functions (pulsed wave color Doppler, 3-D capture, radiofrequency data collection, elastography). With this system, astronauts are required to hold the motorized probe only at the locations indicated, with the remainder of the exam being conducted by the ground-based sonographer. During spaceflight, ultrasound imaging of the carotid artery, jugular vein, thyroid, liver, gallbladder, biliary tract and portal vein (2-D, 3-D, color, pulsed wave, radiofrequency) were successfully performed., (Copyright © 2018 World Federation for Ultrasound in Medicine 8 Biology. Published by Elsevier Inc. All rights reserved.)

Introduction: This study aimed to assess changes in common carotid (CA) and superficial femoral (FA) arterial stiffness during long-duration spaceflight., Methods: Ultrasound imaging was used to investigate the CA and FA of 10 astronauts preflight (PRE), on flight day 15 (FD15), after 4-5 mo (FD4-5m), and 4 d after return to Earth (R+4). Arterial wall properties were assessed through the calculation of strain, stiffness (β), pressure-strain elastic modulus (Ep), and distensibility (DI). Stiffness indices were assessed for potential correlations to measurements of intima-media thickness (IMT)., Results: Significant effects of spaceflight were found for all CA stiffness indices, indicating an increase in arterial stiffness. CA strain was reduced by 34 ± 31% on FD15 and 50 ± 16% on FD4-5m and remained reduced by 42 ± 14% on R+4 with respect to PRE values. On FD4-5m, with respect to PRE values, DI was reduced by 46 ± 25% and β and Ep were increased by 124 ± 95% and 118 ± 92%, respectively. FA arterial stiffness indices appeared to show similar changes; however, a main effect of spaceflight was only found for strain. Correlation analysis showed weak but significant relationships between measurements of CA IMT and arterial stiffness indices, but no relationships were found for FA measurements., Discussion: The observed change in CA and FA stiffness indices suggest that spaceflight results in an increase in arterial stiffness. That these changes were not strongly related to measurements of IMT suggests the possibility of different mechanisms contributing to the observed results.Arbeille P, Provost R, Zuj K. Carotid and femoral arterial wall distensibility during long-duration spaceflight. Aerosp Med Hum Perform. 2017; 88(10):924-930.

Aims: Venous adaptation to microgravity, associated with cardiovascular deconditioning, may contribute to orthostatic intolerance following spaceflight. The aim of this study was to analyze the main parameters of venous hemodynamics with long-duration spaceflight. Methods: Venous plethysmography was performed on 24 cosmonauts before, during, and after spaceflights aboard the International Space Station. Venous plethysmography assessed venous filling and emptying functions as well as microvascular filtration, in response to different levels of venous occlusion pressure. Calf volume was assessed using calf circumference measurements. Results: Calf volume decreased during spaceflight from 2.3 ± 0.3 to 1.7 ± 0.2 L ( p < 0.001), and recovered after it (2.3 ± 0.3 L). Venous compliance, determined as the relationship between occlusion pressure and the change in venous volume, increased during spaceflight from 0.090 ± 0.005 to 0.120 ± 0.007 ( p < 0.01) and recovered 8 days after landing (0.071 ± 0.005, arbitrary units). The index of venous emptying rate decreased during spaceflight from -0.004 ± 0.022 to -0.212 ± 0.033 ( p < 0.001, arbitrary units). The index of vascular microfiltration increased during spaceflight from 6.1 ± 1.8 to 10.6 ± 7.9 ( p < 0.05, arbitrary units). Conclusion: This study demonstrated that overall venous function is changed during spaceflight. In future, venous function should be considered when developing countermeasures to prevent cardiovascular deconditioning and orthostatic intolerance with long-duration spaceflight.

Background: The objective was to determine if short term exposure to dry immersion (DI) results in a cephalic fluid shift similar to what has been observed with spaceflight., Methods: Data were collected from 10 individuals at rest and during the first 2 h of dry immersion. Jugular vein (JV), portal vein (PV), and thyroid volume were measured using 3D echography. Middle cerebral vein velocity (MCVv) was determined using transcranial Doppler ultrasound. The cochlear response to audio stimulation was used to derive an estimate of intracranial pressure (dICP)., Results: After 2 h of DI, there was a significant increase (mean ± SD) in JV (2.21 ± 1.10 mL), PV (1.05 ± 0.48 mL), and thyroid (0.428 ± 0.313 mL) volume. MCVv was also significantly increased with DI (3.90 ± 5.03 cm · s-1). There was no change in dICP with DI in part due to large individual variability. The range of dICP changes appeared to be related to MCVv, with participants with the largest increase in MCVv also showing increased dICP., Discussion: The results suggest that DI induces a significant cephalic fluid shift similar to what is observed with spaceflight. The increased thyroid volume suggests that cerebral tissue may also be subjected to similar fluid filtration, with implications for changes in intracranial pressure. However, despite all participants having an increase in JV and thyroid volume, only half showed an increase in dICP, suggesting that increased venous pooling alone is not sufficient to cause increased intracranial pressure.Arbeille P, Avan P, Treffel L, Zuj K, Normand H, Denise P. Jugular and portal vein volume, middle cerebral vein velocity, and intracranial pressure in dry immersion. Aerosp Med Hum Perform. 2017; 88(5):457-462.

Purpose: The objective of this study was to design and validate a "Tele-Operated UltRasound System" ("TOURS") to perform ultrasound examinations on patients located in isolated areas., Materials and Methods: A commercially available portable echograph was modified to allow functions (Doppler, two-dimensional, three-dimensional, elastography, etc.) and settings (gain, depth, freeze, record, etc.) to be teleoperated through an Internet connection. Specialized probes were developed that contained motorized transducers that could be teleoperated to change the transducer orientation. The system was installed and tested in four medical centers 50 km, 60 km, 1,800 km, and 7,000 km away from the university hospital., Results: Using the teleoperated system, 100 examinations were performed on the abdomen and pelvis (36%), vascular structures (42%), and small parts (thyroid and muscle, 22%), and 15 were performed on fetuses. During these examinations the expert sonographer was able to teleoperate the echograph and motorized probe to obtain images of sufficient quality for diagnoses in 97% of the cases. The average time for one examination was 17 ± 4 min. This new system (dimensions of 400 cm(3) and weighing 430 g) was found to be more ergonomic that a robotic arm previously developed by us for tele-echography (dimensions of 35 × 40 × 40 cm(3) and weighing 3-4 kg). In addition, the teleoperation of the echograph settings and functions allowed for greater ease in acquiring images, resulting in faster examinations with improved quality images., Conclusions: The results of this study demonstrate that the teleoperated echograph and probe system developed by our research group can be successfully used for ultrasound examinations in areas isolated from trained sonographers.

Objective: To evaluate the performance of three tele-echography systems for routine use in isolated medical centers., Methods: Three systems were used for deep (abdomen, pelvis, fetal) and superficial (muscle, thyroid, carotid artery) examinations: (a) a robotic arm (RA) holding an echographic probe; (b) an echograph with a motorized probe (MP); and (c) remote guidance (RG) where the patient site operator performed the examination assisted by an expert via videoconference. All systems were tested in the same medical center located 60 km away from the university hospital., Results: A total of 340 remote echography examinations were performed (41% RA and MP, 59% RG). MP and RA allowed full control of the probe orientation by the expert, and provided diagnoses in 97% of cases. The use of RG was sufficient for superficial vessel examinations and provided diagnoses in 98% of cases but was not suited for deep or superficial organs. Assessment of superficial organs was best accomplished using the MP., Discussion: Both teleoperated systems provided control of the probe orientation by the expert necessary for obtaining appropriate views of deep organs but the MP was much more ergonomic and easier to use than the RA. RG was appropriate for superficial vessels while the MP was better for superficial volumic organs.

Introduction: The objective was to determine the effects of 6 mo of microgravity exposure on conduit artery diameter and wall thickness., Methods: Diagnostic images of the common carotid artery (CC) and superficial femoral artery (FA) were obtained using echography which astronauts performed on themselves after receiving minimal training in the use of ultrasound imaging. Echographic video was recorded using a volume capture method directed by a trained sonographer on the ground through videoconferencing. Vessel properties were later assessed by processing the downlinked video. Data were collected from 10 astronauts who performed the echographic video capture at the beginning of the spaceflight (day 15) and near the end of the spaceflight (day 115 to 165). In-flight and postflight measurements were compared to preflight assessments., Results: No significant changes with spaceflight were found for CC and FA diameter. Intima-media thickness (IMT) of the CC was found to be significantly increased (12% ± 4) in all astronauts during the spaceflight (early and late flight) and remained elevated 4 d after returning to Earth. Similarly, FA IMT was increased during the flight but returned to preflight levels 4 d postflight., Conclusion: The experiment demonstrated that, using the volume capture method of echography, untrained astronauts were able to capture enough echographic data to display vessel images of good quality for analysis. The increase in both CC and FA IMT during the flight suggest an adaptation to microgravity and to the confined environment of spaceflight which deserves further investigation.

The objective was to design and validate a method of tele-operated echocardiography. The method was tested in a hospital facility with an expert sonographer located in a room 10 m away from the patient. An ultrasound probe, fixed to a motorized probe holder, was located on the patient by a non-sonographer and was remotely controlled by the expert sonographer via an Internet connection. Scans were performed on 41 cardiac patients. The quality of the cardiac views obtained using tele-echocardiography was lower than that of reference echocardiography, but generated similar measurements in 93%-100% of the cases. Bland-Altman plots and statistical comparison of tele- and reference echocardiography measures revealed no differences (p > 0.05). Of the 71 valve leaks or aortic stenoses present, 61 (86%) were detected using tele-echocardiography. These results indicate that tele-echocardiography provided reliable diagnoses and acceptable measurements in 86% and 93% of cases, respectively, with no false-positive diagnoses being reported., (Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

The objective of the study was to identify and quantify the potential improvement of left ventricular contractility after percutaneous transluminal coronary angioplasty (PTCA) using 4-dimensional (4D) speckle tracking echocardiography (4D STE). We investigated 41 patients with coronary disease by 4D STE pre- and 24 hours postcoronarography with (n = 18) or without (n = 23) PTCA. The 4D STE visualizes in real time the myocardium strain on 2- and 4-chamber apical views and on 3 transverse views of the left ventricle. Average and total strain of the left ventricle were measured. Of the 18 PTCA patients, 15 showed significant increase in left ventricle mean (+15 ± 6) and total strain (240 ± 100), which corresponded to an increase of 93% ± 55% from precoronarography, whereas the remainder showed no change. The total strain corresponded to 33% ± 10% (before PTCA) and 59% ± 11% (post PTCA) of the estimated normal strain for each patient. Strain improved in 70% of the segment downstream from the stent, and there was a negative correlation between the amplitude of the mean and total strain improvements after 24 hours and the mean and total strain values before PTCA. In the non-PTCA group, 21 of the 23 patients showed no changes in strain, whereas 2 showed improvement. The 4D STE showed significant improvements in left ventricular contractility in more than 70% of the areas downstream from the PTCA segment. This corresponded to an increase in the initial contractility by approximately 93% ± 55%; however, the myocardium contractility remained approximately 59% of normal level. No changes were seen in patients without PTCA., (Copyright © 2013. Published by Elsevier Inc.)

Objective: In a study to identify an early hemodynamic predictor of syncope, 12 men (25-40 yr) underwent 30 min of 80 degrees head-up tilt, followed by progressive lower body negative pressure (LBNP) until presyncope., Methods: Temporal (supplying extracranial tissues: TEMP), middle cerebral (MCA), and superficial femoral (FEM) arterial flow velocity (V) and vascular resistance indices (VR) were evaluated continuously using Doppler ultrasound. Ratios of the Doppler V(MEAN) (V(MCA)/V(FEM) or V(MCA)/ V(TEMP)) were used to assess flow redistribution between these areas., Results: The progression of the testing protocol showed increases in vascular resistance in all territories. At presyncope, both MCA(VR) and FEM(VR) were reduced while there was a large increase in TEMP(VR). Vasoconstriction of the vascular bed supplied by the temporal artery occurred early during central hypovolemia resulting in the appearance of negative velocity deflections, which could be used for the early detection of impending syncope. Analysis of the velocity ratios showed little change until the onset of presyncope where there was an increase in V(MCA)/V(TEMP) which confirmed that vasoconstriction of the vascular bed supplied by the TEMP artery contributed to cardiac output redistribution in favor of the brain, and a reduction in V(MCA)/V(FEM) suggesting a redistribution of cardiac output toward the legs., Discussion: In 67% of the tests, the appearance of the negative component of V(TEMP) was an early sign of increasing TEMP(VR) that occurred before visually detectable changes in VE(FEM) or V(MCA) and within 5 min before presyncope. Such easily identifiable in real time Doppler signs allowed experimenters to anticipate test termination.

During the WISE-2005 study of 24 women, we observed a reduction (21.6 +/- 0.89%, mean +/- SEM) in cerebral blood flow velocity (CBV) measured by transcranial Doppler ultrasound, following 0.3 mg sublingual nitroglycerin (NG). In parallel, we observed quantitative reductions in leg blood flow (47.3 +/- 7.0%) and corresponding reductions in calculated conductance (Conductance = Femoral Flow / Mean Arterial Pressure; 45.7 +/- 7.2%). To determine if the reduction in CBV was the result of reduced cerebral blood flow or dilation of the middle cerebral artery (MCA), the change in CBV in the MCA was compared with changes in quantitative flow measured in the common carotid artery (CCA). The relationship between CBV and CCA blood flow was tested in five men and four women using hyper- and hypo-ventilation to manipulate arterial PCO2. Changes in CCA blood flow were positively correlated with changes in CBV (p<0.001). We then investigated the CBV and CCA flow responses to sublingual NG in an additional two men and six women. Concurrent with the reduction in CBV there was no change in blood flow through the CCA (p>0.05). These results indicate that the decrease in CBV observed in response to NG was probably the result of dilation of the MCA and that total cerebral blood flow was similar after administration of NG. These results suggest regional differences in the vascular responses to NG during the WISE bed rest. Conduit vessels of both the peripheral and cerebral vasculature dilated; however, the resistance vessels in skeletal muscle constricted causing a reduction in blood flow, while the resistance vessels of the brain appeared to be unaffected by NG so that cerebral blood flow remained constant. These results highlight the need to obtain quantitative measures of cerebral blood flow if there is reason to suspect that the diameter of the MCA might not remain constant.

WISE-2005 studied 24 women during a 60-day head down bed rest (HDBR) who look part in an exercise countermeasure (LBNP-treadmill plus flywheel, EX) and no-exercise (No-EX). We conducted a series of experiments to explore changes in cardiovascular function and the ability of EX to prevent these changes. Resting arterial diameter in the arm was not affected but the leg arteries (femoral and popliteal) were significantly reduced in Np-EX, but was increased in EX. In this study we report on drug stimulated responses with sublingual nitroglycerin and infused isoproterenol. Heart rate increased in response to nitroglycerin with larger increases in No-EX after HDBR. Likewise during isoproterenol infusion the HR increase was greater after HDBR in the No-EX group. In all cases, the higher HR was associated with lower stroke volume in No-EX while stroke volume was protected in EX. These data do not support a change in sensitivity of beta-adrenergic receptors after HDBR. The leg vascular resistance decreased in response to isoproterenol and it decreased to a greater extent in No-EX than EX. These data were consistent with observations of lower leg vascular resistance during orthostatic challenge tests after HDBR. We conclude that consistent changes in cardiovascular function in the No-EX were detected by different methods that point to mechanisms contributing to orthostatic intolerance after HDBR.