Cardiovascular Deconditioning Research Articles

Abstract 15153: Functional Cardiac Adaptation to 60 Days Strict Head-Down-Tilt Bedrest

Background: Reduced physical activity increases the risk for heart failure. Myocardial strain measurements capture subtle abnormalities in myocardial function. We tested the hypothesis that bedrest deconditioning produces cardiac dysfunction in healthy persons. Methods: In the AGBRESA study, which assessed artificial gravity through centrifugation as potential countermeasure for space travel, 24 healthy persons (8 women) were submitted to 60 days strict -6°-head-down-tilt bedrest. 8 subjects each were included in a control group or groups subjected to continuous artificial gravity training on a short-arm centrifuge [30 minutes/day] or intermittent centrifugation [6x5 min/day]. We assessed cardiac morphology, function, strain and hemodynamics by cardiac-MRI (baseline, end of bedrest, recovery) and echocardiography (baseline, end of bedrest). Before and after bedrest, we assessed orthostatic heart rate responses as measure of cardiovascular deconditioning. Results: We conducted a pooled analysis because cardiovascular responses to bedrest did not differ between groups. Supine heart rate (baseline: 64±9.6bpm; bedrest: 72.3±10.5bpm; recovery: 69.6±10.5bpm, p <0.0001) and diastolic blood-pressure (69.6±7.3mmHg; bedrest: 78.5±6.9mmHg; recovery: 70.3±6.3mmHg, p <0.0001) increased with bedrest. With head-up tilt, heart rate increased 22.8±10.5bpm before and 45.9±213bpm at the end of bedrest ( p <0.0001) consistent with cardiovascular deconditioning. Cardiac-output decreased from 6.6±0.9l/min to 6±1l/min at end of bedrest (recovery: 6.8±1.2l/min, p =0.0096). Left ventricular ejection fraction and mass-index did not change. Echocardiographic global longitudinal strain (baseline: -19.90±2.1%; bedrest: -18.1±2.1%, p <0.0001) decreased, whereas global circumferential strain in MRI tended to increase (baseline: -18.6±1.7%; bedrest: -19.1±1.6%, p =0.0843). After four days of recovery MRI measurements had returned to baseline. Conclusion: In healthy persons, cardiovascular deconditioning through 60 days head-down-tilt bedrest does not lead to cardiac atrophy or sustained reductions in cardiac performance. The transient nature of cardiac strain changes suggests functional rather than structural changes in the heart.

ECG Holter analysis to detect induced deconditioning on cardiac activity in bedridden volunteers

Abstract Introduction Prolonged bed rest (BR) is an unnatural state, often related to hospitalization, chronic diseases and ageing, inducing reduced functional capacity in multiple body systems, possibly leading to cardiovascular deconditioning. We hypothesized that measuring this decline over time could represent the first step for the formulation of appropriate countermeasures or rehabilitation programs while in the hospital. Accordingly, our aim was to assess the effects of 10-day horizontal BR on cardiac electrical activity. Methods Ten healthy male volunteers (23±5 years) were enrolled in an hospital, after ethical approval and signed consent, to participate to a 10-day strict horizontal BR campaign, preceded and followed by 2 days in the facility, respectively as acclimatization and recovery. The 12-leads 24-hours Holter ECG (1000 Hz, H12+, Mortara Instrument Inc.) was acquired 1 day before BR (PRE), the 5th (BR5) and 10th day (BR10) of bedridden immobilization. From each recording, beat-to-beat RR and QTend interval series, as well as T wave amplitude (Tamp) and upslope (Tslope) were computed. Statistical analysis was applied to test changes induced by BR (ANOVA with Tukey test, p<0.05), separately for day (7:00–23:00) and night (23:00–7:00) periods. Results Daily RR and QTend duration increased during BR, with peak changes at BR5 compared to PRE (+13.3% and +3% respectively), and were still prolonged at BR10 (+12.6% and +2.6%). During the night, while RR increased (BR5:+5.3%; BR10:+1.3%), QTend was found progressively shortened (BR5: −1.6%; BR10: −2.9%). Also, day and night Tamp (BR10: −19.5%) and Tslope (BR10 day: −17.1%; night: −7.8%) were found progressively reduced with the duration of BR. Conclusion During BR, cardiac electrical activity is affected by 10-days bedridden immobilization. Noticeably, a mismatch in RR-QTend relation was visible at night, where vagal autonomic system activity is prevailing. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Agenzia Spaziale Italiana (ASI)

Cardiovascular adaptation to simulated microgravity and countermeasure efficacy assessed by ballistocardiography and seismocardiography

Head-down bed rest (HDBR) reproduces the cardiovascular effects of microgravity. We tested the hypothesis that regular high-intensity physical exercise (JUMP) could prevent this cardiovascular deconditioning, which could be detected using seismocardiography (SCG) and ballistocardiography (BCG). 23 healthy males were exposed to 60-day HDBR: 12 in a physical exercise group (JUMP), the others in a control group (CTRL). SCG and BCG were measured during supine controlled breathing protocols. From the linear and rotational SCG/BCG signals, the integral of kinetic energy (iK) was computed on each dimension over the cardiac cycle. At the end of HDBR, BCG rotational iK and SCG transversal iK decreased similarly for all participants (− 40% and − 44%, respectively, p < 0.05), and so did orthostatic tolerance (− 58%, p < 0.01). Resting heart rate decreased in JUMP (− 10%, p < 0.01), but not in CTRL. BCG linear iK decreased in CTRL (− 50%, p < 0.05), but not in JUMP. The changes in the systolic component of BCG linear iK were correlated to those in stroke volume and VO2 max (R = 0.44 and 0.47, respectively, p < 0.05). JUMP was less affected by cardiovascular deconditioning, which could be detected by BCG in agreement with standard markers of the cardiovascular condition. This shows the potential of BCG to easily monitor cardiac deconditioning.

Mechanisms Underlying Neuroplasticity in the Nucleus Tractus Solitarii Following Hindlimb Unloading in Rats

Hindlimb unloading (HU) in rats induces cardiovascular deconditioning (CVD) analogous to that observed in individuals exposed to microgravity or bed rest. Among other physiological changes, HU rats exhibit autonomic imbalance and altered baroreflex function. Lack of change in visceral afferent activity that projects to the brainstem in HU rats suggests that neuronal plasticity within central nuclei processing cardiovascular afferents may be responsible for these changes in CVD and HU. The nucleus tractus solitarii (nTS) is a critical brainstem region for autonomic control and integration of cardiovascular reflexes. In this study, we used patch electrophysiology, live-cell calcium imaging and molecular methods to investigate the effects of HU on glutamatergic synaptic transmission and intrinsic properties of nTS neurons. HU increased the amplitude of monosynaptic excitatory postsynaptic currents and presynaptic calcium entry evoked by afferent tractus solitarii stimulus (TS-EPSC); spontaneous (s) EPSCs were unaffected. The addition of a NMDA receptor antagonist (AP5) reduced TS-EPSC amplitude and sEPSC frequency in HU but not control. Despite the increase in glutamatergic inputs, HU neurons were more hyperpolarized and exhibited intrinsic decreased excitability compared to controls. After block of ionotropic glutamatergic and GABAergic synaptic transmission (NBQX, AP5, Gabazine), HU neuronal membrane potential depolarized and neuronal excitability was comparable to controls. These data demonstrate that HU increases presynaptic release and TS-EPSC amplitude, which includes a NMDA receptor component. Furthermore, the decreased excitability and hyperpolarized membrane after HU are associated with enhanced GABAergic modulation. This functional neuroplasticity in the nTS may underly the CVD induced by HU.

Cardiovascular deconditioning during long-term spaceflight through multiscale modeling

Human spaceflight has been fascinating man for centuries, representing the intangible need to explore the unknown, challenge new frontiers, advance technology, and push scientific boundaries further. A key area of importance is cardiovascular deconditioning, that is, the collection of hemodynamic changes—from blood volume shift and reduction to altered cardiac function—induced by sustained presence in microgravity. A thorough grasp of the 0G adjustment point per se is important from a physiological viewpoint and fundamental for astronauts’ safety and physical capability on long spaceflights. However, hemodynamic details of cardiovascular deconditioning are incomplete, inconsistent, and poorly measured to date; thus a computational approach can be quite valuable. We present a validated 1D–0D multiscale model to study the cardiovascular response to long-term 0G spaceflight in comparison to the 1G supine reference condition. Cardiac work, oxygen consumption, and contractility indexes, as well as central mean and pulse pressures were reduced, augmenting the cardiac deconditioning scenario. Exercise tolerance of a spaceflight traveler was found to be comparable to an untrained person with a sedentary lifestyle. At the capillary–venous level significant waveform alterations were observed which can modify the regular perfusion and average nutrient supply at the cellular level. The present study suggests special attention should be paid to future long spaceflights which demand prompt physical capacity at the time of restoration of partial gravity (e.g., Moon/Mars landing). Since spaceflight deconditioning has features similar to accelerated aging understanding deconditioning mechanisms in microgravity are also relevant to the understanding of aging physiology on the Earth.

MNX (Medium Duration Nutrition and Resistance-Vibration Exercise) Bed-Rest: Effect of Resistance Vibration Exercise Alone or Combined With Whey Protein Supplementation on Cardiovascular System in 21-Day Head-Down Bed Rest.

Current inflight countermeasures do not completely prevent bone and cardiovascular changes induced by microgravity. High load Resistance Exercise combined with whole body Vibration (RVE) demonstrated benefits on bone and cardiovascular system during previous Head-Down Bed Rest (HDBR) studies. We examined the effectiveness of RVE alone or combined with a nutritional supplementation of Whey protein (NeX) on cardiovascular deconditioning. Eight male subjects (age 34 ± 8 years) in a crossover design completed three 21-day HDBR campaigns (Control-CON, RVE, and NeX). Pre and post HDBR Orthostatic Tolerance (OT) was evaluated by a 15-min head-up tilt test followed by increasing levels of Lower Body Negative Pressure (LBNP). Heart rate (HR), blood pressure (BP), and Sympathetic Index (ΣI) through spectral analysis were measured during OT test. Plasma Volume (PV), and Maximal Oxygen Uptake (VO2max) were measured before and after each campaign. Left ventricular mass, left ventricular end diastolic (LVEDV), end systolic (LVESV), stroke (SV) volumes, and circumferential deformation at rest and during an orthostatic stress simulated by a 30 mmHg LBNP were measured by cardiac MRI. RVE failed to prevent any change in these variables and NeX did not have any additional effect over exercise alone. In the 3 groups, (1) OT time dropped similarly (bed rest p < 0.001), (2) HR and ΣI were increased at rest at the end of HDBR and HR increased markedly during LBNP-tilt test, with inability to increase further the ΣI, (3) PV dropped (bed rest p < 0.001), along with LVEDV, LVESV and SV (p = 0.08, p < 0.001, and p = 0.045, respectively), (4) Left ventricle mass did not change significantly, (5) Deformation of the heart assessed by global circumferential strain was preserved and early diastolic circumferential strain rate was increased during orthostatic stress at the end of HDBR, illustrating preserved systolic and diastolic function respectively, without any difference between groups. Despite the drop in PV and LV volumes, RVE and NeX tended to alleviate the decrease in VO2max. In conclusion, RVE and NeX failed to prevent the cardiovascular deconditioning induced by a 21 day-HDBR.

Impacts of Microgravity Analogs to Spaceflight on Cerebral Autoregulation.

It is well known that exposure to microgravity in astronauts leads to a plethora physiological responses such as headward fluid shift, body unloading, and cardiovascular deconditioning. When astronauts return to Earth, some encounter problems related to orthostatic intolerance. An impaired cerebral autoregulation (CA), which could be compromised by the effects of microgravity, has been proposed as one of the mechanisms responsible for orthostatic intolerance. CA is a homeostatic mechanism that maintains cerebral blood flow for any variations in cerebral perfusion pressure by adapting the vascular tone and cerebral vessel diameter. The ground-based models of microgravity are useful tools for determining the gravitational impact of spaceflight on human body. The head-down tilt bed rest (HDTBR), where the subject remains in supine position at −6 degrees for periods ranging from few days to several weeks is the most commonly used ground-based model of microgravity for cardiovascular deconditioning. head-down bed rest (HDBR) is able to replicate cephalic fluid shift, immobilization, confinement, and inactivity. Dry immersion (DI) model is another approach where the subject remains immersed in thermoneutral water covered with an elastic waterproof fabric separating the subject from the water. Regarding DI, this analog imitates absence of any supporting structure for the body, centralization of body fluids, immobilization and hypokinesia observed during spaceflight. However, little is known about the impact of microgravity on CA. Here, we review the fundamental principles and the different mechanisms involved in CA. We also consider the different approaches in order to assess CA. Finally, we focus on the effects of short- and long-term spaceflight on CA and compare these findings with two specific analogs to microgravity: HDBR and DI.

Analysis of changes in cardiac circadian rhythms of RR and QT induced by a 60-day head-down bed rest with and without nutritional countermeasure.

Prolonged weightlessness exposure generates cardiovascular deconditioning, with potential implications on ECG circadian rhythms. Head-down (-6°) tilt (HDT) bed rest is a ground-based analogue model for simulating the effects of reduced motor activity and fluids redistribution occurring during spaceflight. Our aim was to evaluate the impact of 60-day HDT on the circadianity of RR and ventricular repolarization (QTend) intervals extracted from 24-h Holter ECG recordings, scheduled 9days before HDT (BDC-9), the 5th (HDT5), 21st (HDT21) and 58th (HDT58) day of HDT, the 1st (R + 0) and 8th (R + 7) day after HDT. Also, the effectiveness of a nutritional countermeasure (CM) in mitigating the HDT-related changes was tested. RR and QTend circadian rhythms were evaluated by Cosinor analysis, resulting in maximum and minimum values, MESOR (a rhythm-adjusted mean), oscillation amplitude (OA, half variation within a night-day cycle), and acrophase (φ, the time at which the fitting sinusoid's amplitude is maximal) values. RR and QTend MESOR increased at HDT5, and the OA was reduced along the HDT period, mainly due to the increase of the minima. At R + 0, QTend OA increased, particularly in the control group. The φ slightly anticipated during HDT and was delayed at R + 0. 60-Day HDT affects the characteristics of cardiac circadian rhythm by altering the physiological daily cycle of RR and QTend intervals. Scheduled day-night cycle and feeding time were maintained during the experiment, thus inferring the role of changes in the gravitational stimulus to determine these variations. The applied nutritional countermeasure did not show effectiveness in preventing such changes.

The Place of Early Rehabilitation in Intensive Care Unit for COVID-19.

To the Editor: Coronavirus disease 2019 (COVID-19) created a previously unseen pressure on public health systems. A main issue during the peak of the disease is the availability of intensive care unit (ICU) beds to manage the severe complications of COVID-19.1 Currently, the major focus is on acute care, but the surging number of people who recover from the infection is shifting medical attention to survivors discharged from ICUs. The challenge of COVID-19 requires a multidisciplinary approach. Rehabilitative intervention should be part of the treatment pathway from the early stages of the disease. There is an urgent need to build a knowledge based on the most effective nonpharmacological measures to ensure the earliest discharge and the best recovery after complicated COVID-19 infection. Multimodal rehabilitation, in every stage of the illness, must be part of a holistic medical approach, but consensus on timing and type of intervention is still missing. In light of the pressure on ICUs during the epidemic peak, we highlight the role of an often-undervalued approach to reduce the length of hospital stay and the burden on health care systems. Early physiotherapy in acute respiratory distress syndrome, beginning early in ICU, is a critical therapeutic tool to reduce complications of immobilization in critical illness, such as myopathy, neuropathy, and ventilator dependency. Benefits include improved residual respiratory, musculoskeletal, neurological, and psychological function; it prevents readmissions in the medium and long term, improves health status, and perceived quality of life after discharge.2–4 Interventions in an acute setting may also motivate active recipients’ involvement in their rehabilitation pathway, increasing the compliance with treatment after discharge. The benefits of early rehabilitative intervention in ICU for acute respiratory distress syndrome5 are clear, but if this approach is appropriate for COVID-19, co-infection is still controversial. There are suggestions that rehabilitation is not required in the acute stage of the condition6 or recommended only after weaning.7 To clarify this topical issue, authors set up an interventional, two-arm, nonrandomized trial comparing hospital length of stay in individuals receiving early physiotherapy in ICU versus those who did not (NCT04381338). Participants are enrolled in two teaching hospitals in the Veneto region (Padova and Verona, Italy), which each provides a different standard of care, with early intervention in one but not in the other. In Padova, all individuals with COVID-19 admitted to ICU with a diagnosis of acute respiratory distress syndrome are enrolled, in an early rehabilitation intervention protocol as part of the local standard of care (for details, see https://clinicaltrials.gov/ct2/show/NCT04381338?term=rehab&cond=COVID&draw=2&rank=1). At admission, a multidisciplinary assessment confirms enrolment criteria.5 Stabile cardiovascular, respiratory, and general parameters (ie, fever, thoracic radiography) are mandatory to start and continue sessions (20 mins each, 3 times daily/6 day a week). In Verona, no rehabilitative intervention takes place during ICU admissions. The program is based on the level of consciousness (Glasgow Coma Scale8), regardless of ventilation modality: unconscious individuals (Glasgow Coma Scale score ≤ 8) are offered passive mobilization and pronation, whereas conscious persons start a hierarchical, personalized protocol. The program includes endurance, functional, respiratory, and strength training. Dysphagia, which often complicates intubation, is also treated during sessions. After ICU discharge, multimodal physiotherapy treatment continues throughout the hospital stay. An individualized program is agreed for home discharge, focusing on recovering autonomous daily-living skills and counteracting muscular and cardiovascular deconditioning. An assessment on the role of individual clinical history, pre–COVID-19 performance status, preexisting drug therapy, level of ventilator support, hemodynamic and postural management during admission, and complications to correlate with the intervention and outcomes will be made. Findings will provide essential information in case of a new wave of COVID-19 infection and will be instrumental to support timely and personalized rehabilitation in these people. In view of the difficult circumstances, it is essential that this information is shared, particularly about practices that it is not yet fully cognizant to establish whether they have a role to play. Stefano Masiero, MD Department of Neuroscience Section of Rehabilitation University General Hospital of Padova Padova, Italy Laboratory of Clinical Analysis and Biomechanics of Movement NEUROMOVE-Rehab University Hospital of Padova Padova, Italy PNC Padova Neuroscience Center Padova, ItalyDavide Zampieri, MD, PhD Department of Neuroscience Section of Rehabilitation University General Hospital of Padova Padova, ItalyAlessandra Del Felice, MD, PhD Department of Neuroscience Section of Rehabilitation University General Hospital of Padova Padova, Italy Laboratory of Clinical Analysis and Biomechanics of Movement NEUROMOVE-Rehab University Hospital of Padova Padova, Italy PNC, Padova Neuroscience Center, Padova, Italy

DI-5-CUFFS: Venoconstrictive Thigh Cuffs Limit Body Fluid Changes but Not Orthostatic Intolerance Induced by a 5-Day Dry Immersion.

Venoconstrictive thigh cuffs are used by cosmonauts to ameliorate symptoms associated with cephalad fluid shift. A ground simulation of microgravity, using the dry immersion (DI) model, was performed to assess the effects of thigh cuffs on body fluid changes and dynamics, as well as on cardiovascular deconditioning. Eighteen healthy men (25–43 years), randomly divided into two groups, (1) control group or (2) group with thigh cuffs worn 10 h/day, underwent 5-day DI. Cardiovascular responses to orthostatic challenge were evaluated using the lower body negative pressure (LBNP) test; body fluid changes were assessed by bio-impedance and hormonal assay; plasma volume evolution was estimated using hemoglobin-hematocrit; subjective tolerance was assessed by questionnaires. DI induced a decrease in plasma volume of 15–20%. Reduction in total body water of 3–6% stabilized toward the third day of DI. This reduction was derived mostly from the extracellular compartment. During the acute phase of DI, thigh cuffs limited the decrease in renin and the increase in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), the loss in total body water, and tended to limit the loss in calf volume, extracellular volume and plasma volume. At the later stable phase of DI, a moderate protective effect of thigh cuffs remained evident on the body fluids. Orthostatic tolerance time dropped after DI without significant difference between groups. Thigh cuff countermeasure slowed down and limited the loss of body water and tended to limit plasma loss induced by DI. These observed physiological responses persisted during periods when thigh cuffs were removed. However, thigh cuffs did not counteract decreased tolerance to orthostatic challenge.

Cardiovascular Deconditioning Enhances Cardiovascular and Autonomic Response to Arterial Chemoreflex Stimulation

Cardiovascular deconditioning (CVD) due to bedrest, inactivity or exposure to microgravity impairs cardiovascular regulation and circulatory homeostasis. Cardiovascular changes associated with CVD, including resting tachycardia, decreased exercise capacity and autonomic impairments are reproduced in an animal model of CVD, hindlimb unloaded (HU) rats. Autonomic dysfunction, including blunted baroreflex function, in CVD is associated with mechanisms involving the central nervous system. We hypothesized that CVD augments the arterial chemoreflex. Male Sprague‐Dawley rats were subjected to 2 weeks hindlimb unloading (HU) to simulate CVD, or maintained at normal postural position (cage control, CC). Under inactin anesthesia, baseline heart rate (HR) was elevated in HU vs CC (381±8 bpm vs 334±6 bpm). To examine the chemoreflex, HU and CC rats (n=5–6 each) were given bolus NaCN (25, 50, 75ug/kg, iv) or acute hypoxia (12% O2, 45 seconds). NaCN dose dependently increased HR and mean arterial pressure (MAP) in HU but not CC. At the highest NaCN concentration, HU increased MAP (22±4 mmHg) and HR (16±3 bpm) more than CC MAP (8±1 mmHg) and HR (6±2 bpm). NaCN also increased splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA) in both groups, and responses tended to be greater in HU rats. Likewise, the peak hypoxic response of SSNA and PhrNA were greater in HU than CC rats (SSNA, HU 143 ± 26% vs CC 111 ± 9%; PhrAmp%; HU 382 ± 208 vs CC 300 ± 103). Exposure to NaCN or hypoxia did not change PhrFreq in either group. These data suggest that HU enhances cardiovascular responses to chemoreflex activation.Support or Funding InformationFunding: HL132836

Mechanisms underlining excitatory synaptic plasticity in the Nucleus Tractus Solitarii following Cardiovascular Deconditioning

The nucleus tractus solitarii (nTS) is a critical central region for autonomic control and integration of cardiovascular reflexes. Neuroplasticity in nTS contributes to several cardiovascular dysfunctions. Our previous data showed that Hindlimb‐unloading (HU), a well‐established model of cardiovascular deconditioning in rats, increases glutamatergic neurotransmission yet reduces the excitability of nTS neurons. In this study we aimed to investigate the mechanisms underlining these alterations. For this purpose, stainless wire rings were placed in the tail of male Sprague‐Dawley rats (3 weeks). After one week of recovery the rings was connected to a suspension apparatus and rats were suspended at an angle of 30–35° for two weeks with free access to food and water. Control animals were maintained in normal postural conditions. After the HU protocol, coronal brainstem slices were generated and the whole‐cell patch clamp technique was performed to evaluate the synaptic neurotransmission and electrophysiological properties of nTS neurons. Compared to control rats, HU increased the amplitude of excitatory postsynaptic currents evoked by afferent tractus solitarii stimulus (TS‐EPSC). The addition of a NMDA receptor antagonist (AP5, 10 μM) significantly reduced TS‐EPSC amplitude in HU but not controls. Despite the increase in glutamatergic inputs, the neurons of HU vs control rats are hyperpolarized and have decreased excitability. The block of both NMDA and non‐NMDA (NBQX, 10 μM) glutamatergic receptors did not affect these parameters. However, in the presence of a GABAA receptor antagonist (Gabazine, 25 μM) the resting membrane potential depolarized and excitability of HU neurons were comparable to neurons from control rats. The results indicate that HU increases TS‐EPSC amplitude via a NMDA receptor component. Furthermore, the decreased excitability and hyperpolarized membrane is associated with enhanced GABAergic modulation to these neurons. This functional neuroplasticity in the nTS may contribute to the cardiovascular deconditioning induced by HU.Support or Funding InformationHL132836 AAS lundbeck fellowship

Effects of Resistance Exercise and Nutritional Supplementation on Dynamic Cerebral Autoregulation in Head-Down Bed Rest.

Head-down bed rest (HDBR) is commonly considered as ground-based analog to spaceflight and simulates the headward fluid shift and cardiovascular deconditioning associated with spaceflight. We investigated in healthy volunteers whether HDBR, with or without countermeasures, affect cerebral autoregulation (CA). Twelve men (at selection: 34 ± 7 years; 176 ± 7 cm; 70 ± 7 kg) underwent three interventions of a 21-day HDBR: a control condition without countermeasure (CON), a condition with resistance vibration exercise (RVE) comprising of squats, single leg heel, and bilateral heel raises and a condition using also RVE associated with nutritional supplementation (NeX). Cerebral blood flow velocity was assessed using transcranial Doppler ultrasonography. CA was evaluated by transfer function analysis and by the autoregulatory index (Mxa) in order to determine the relationship between mean cerebral blood flow velocity and mean arterial blood pressure. In RVE condition, coherence was increased after HDBR. In CON condition, Mxa index was significantly reduced after HDBR. In contrast, in RVE and NeX conditions, Mxa were increased after HBDR. Our results indicate that HDBR without countermeasures may improve dynamic CA, but this adaptation may be dampened with RVE. Furthermore, nutritional supplementation did not enhance or worsen the negative effects of RVE. These findings should be carefully considered and could not be applied in spaceflight. Indeed, the subjects spent their time in supine position during bed rest, unlike the astronauts who perform normal daily activities.

Interrelationships between pulse arrival time and arterial blood pressure during postural transitions before and after spaceflight.

We tested the hypothesis that acute changes in arterial blood pressure (BP) when astronauts moved between supine and standing posture before and after spaceflight can be tracked by beat-to-beat changes in pulse arrival time (PAT). Nine male crewmembers (45 ± 7 yr of age; mean mission length: 165 ± 13 days) participated in a standardized supine-to-sit-to-stand test (5 min-30 s-3 min) before flight and 1 day following return to Earth with continuous monitoring of ECG and finger arterial BP. PAT was determined from the R-wave of the ECG to the foot of the BP waveform. On average, modest cardiovascular deconditioning was detected by ~10 beats/min increase in heart rate in supine and standing posture after spaceflight (P < 0.05). When looking across the full data collection period, the r2 values between inverse of PAT (1/PAT) and systolic (SBP) and diastolic BP (DBP) varied considerably between individuals (SBP preflight 0.142 ± 0.186, postflight 0.262 ± 0.243). Individual variability was consistent during periods of transition (SBP preflight 0.284 ± 0.324, postflight 0.297 ± 0.269); however, when SBP dropped >20 mmHg, r2 was significant in 5 of 5 preflight tests and 5 of 7 postflight tests. The standard error of the estimate based on a simple linear model during both pre- and postflight testing was 9-11 mmHg for SBP and 6-7 mmHg for DBP. Overall, the results support the hypothesis that PAT tracked dynamic changes in BP. PAT as a noninvasive, nonintrusive surrogate for changes in BP could be developed as an indicator of risk for syncope on return from spaceflight or other Earth-based applications.NEW & NOTEWORTHY Astronauts returning to Earth's gravity are at increased risk of low blood pressure on standing. Arterial pulse arrival time tracked the decrease in arterial blood pressure on moving from supine to upright posture. Nonintrusive technology providing indicators sensitive to acute changes in blood pressure could act as an early warning system to identify risk for hypotension that place astronauts, or people on Earth, at risk of impaired cognitive performance, fainting, and falls.

Medications in Space: In Search of a Pharmacologist's Guide to the Galaxy.

Medications have been used during space missions for more than half a century, yet our understanding of the effects of spaceflight on drug pharmacokinetics and pharmacodynamics is poor. The space environment induces time-dependent alterations in human physiology that include fluid shifts, cardiovascular deconditioning, bone and muscle density loss, and impaired immunity. This review presents the current knowledge on the physiological effects of spaceflight that can translate into altered drug disposition and activity and eventually to inadequate treatment. It describes findings from studies in astronauts along with mechanistic studies in animal models and in vitro systems. Future missions into deeper space and the emergence of commercial spaceflight will require a more detailed understanding of space pharmacology to optimize treatment in astronauts and space travelers.

Overexpression of Catalase in Mitochondria Mitigates the Inflammatory Effects of Simulated Microgravity and Social Isolation in Mouse Hippocampus

Space flight missions are becoming longer and more common and evidence points to the physiological toll the missions have on the human body. Aging, sedentary lifestyle, and spaceflight have similar degenerative effects on almost every part of our body; both exposure to the space environment and aging result in cardiovascular deconditioning, bone loss, muscle atrophy, brain changes, and immune response impairment. We hypothesize that exposure to the space environment generates excessive Reactive Oxygen Species (ROS), which results in neuroinflammation and aging‐like degenerative symptoms in the brain. We used the hindlimb unloading (HU) model to mimic microgravity with either paired or single housed animals (social isolation). Responses to 30d of HU were compared in wildtype or transgenic MCAT mice, in which mitochondrial ROS is quenched by over‐expression of human catalase. Expression of 4‐Hydroxynonenal (4HNE) and Park7 (redox‐sensitive chaperone and sensor of oxidative stress) were measured by ELISA, a protein array quantified from the hippocampal cytokines and 8‐hydroxy‐2’‐deoxyguanosine in serum was measured by ELISA to assess oxidative DNA damage. Preliminary analysis of cage behavior patterns from video collected at the end of the study showed that MCAT HU mice (socially housed) were more active and conducted more exploratory activities compared to NL. Our biochemical results showed simulated microgravity and/or social isolation caused changes in levels of cytokines related to immune responses. Two‐way ANOVA revealed significant interaction effects of HU and genotype in expression levels of five cytokines (out of 35) in socially‐housed animals. Elevation of these generally pro‐inflammatory cytokines by HU in WT mice was mitigated in MCAT mice, suggesting a role for mitochondrial ROS signaling in inflammatory CNS responses to microgravity. Interestingly, some of these cytokines in the hippocampus displayed strong correlations to the 4HNE levels. We also found substantive cytokine responses to social isolation in the hippocampus; housing and genotype interaction effects were significant (by 2‐Factor ANOVA) for 15 cytokines, most of which were mitigated in MCAT mice.Taken together, our results showed that both simulated microgravity and social isolation influenced cytokine levels in the hippocampus and MCAT mice were at least partially protected from these changes. These findings implicate a potentially important role for mitochondrial ROS in CNS responses to the challenges posed by long duration spaceflight.Support or Funding InformationThis work is supported by a NASA Space Biology Grant to RKG (NNH14ZTT001N). LG was supported by a Space Biology NASA Postdoctoral Fellowship AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

FUNCTIONAL CAPACITY IN ADOLESCENT IDIOPATHIC SCOLIOSIS DURING THE POSTOPERATIVE PERIOD

ABSTRACT Introduction: Patients with Adolescent Idiopathic Scoliosis (AIS) show reduced exercise capacity during the Incremental Shuttle Walk Test (ISWT). However, we not know how patients behave in the late postoperative (LPO) period. Objective: The aim of this study was to evaluate the ISWT distance (ISWTD) and physiological responses during ISWT in AIS patients during the LPO period. Methods: We included 22 patients with AIS in the LPO period (SG) and 21 adolescents in the Control Group (CG). We assessed pulmonary function (FVC and FEV1). During ISWT, a gas analyzer was used to assess peak oxygen (VO2) and submaximal relations: Oxygen Uptake Efficiency Slope (OUES) and the breathing pattern (ΔVT/ΔlnVE). Results: Significantly lower values were observed in SG: VO2 (22 ± 5 vs. 27 ± 4), ISWTD (567 ± 94 vs.604 ± 86), FVC (2.70 ± 0.47 vs. 3.33 ± 0.52) and FEV1 (2.41 ± 0.46 vs. 2.84 ± 0.52). There were significant correlations between ISWTD and VO2/Kg (r = 0.80); between OUES and ΔVT/ΔlnVE (r = 0.65); and between the main thoracic curve with VO2/Kg (r= −0.61). Conclusion: AIS patients in the LPO period have significantly reduced exercise capacity associated with reduced lung function, residual spinal curve and cardiovascular deconditioning. Level of Evidence III; Prognostic Studies - Investigation of the effect of characteristic of a patient on the outcome of the disease.

Differential Circulating microRNA Expression after Bed Rest: Potential Role in Cardiovascular Deconditioning

Bed rest, an analog of spaceflight microgravity, elicits changes in left ventricular loading conditions resulting in cardiac deconditioning that adversely effects functional outcomes and cardiopulmonary exercise performance. Given the significant and time‐dependent changes in cardiovascular function associated with bed rest, a continued evaluation of these adaptations are required, particularly in regards to their molecular regulators. MicroRNAs are noncoding RNA that regulate gene expression, with several plasma‐based ‘circulating’ microRNAs (c‐miRs) used as biomarkers of tissue‐specific physiologic adaptation. Quantification of cardiac‐c‐miRs may allow for manifestations of cardiovascular deconditioning to be identified and be used to predict cardiovascular related outcomes in response to bed rest. Therefore, the primary aim of this study was to test the hypotheses that cardiovascular‐c‐miRs are differentially expressed following bed rest and their changes associated with decreases in cardiac function and cardiopulmonary exercise capacity. Eleven participants completed 30‐days bed rest at an ambient CO2 of 0.05% (replicate CO2 levels on the International Space Station). Blood samples were obtained prior to and immediately following bed rest. 44‐targeted c‐miRs identified from published roles in cardiovascular structure/function were analyzed via RT‐qPCR. Resting stroke volume was evaluated via ultrasonography. Peak oxygen uptake (peakVO2) was determined using a grade exercise test. Ten cardiovascular‐c‐miRs were significantly increased following bed rest. The differentially expressed c‐miRs were grouped into clusters according to their expression profile. Cluster A included c‐miRs that have been identified as regulators of cardiac function and hypertrophy (c‐miR‐133), atrial fibrillation and mitochondrial function (c‐miR‐1), skeletal muscle atrophy (c‐miR‐1), vascular control (c‐miR‐155) and aerobic capacity (c‐miR‐133). Cluster B contained c‐miR identified as regulators of cardiac hypertrophy (c‐miR‐30, c‐miR‐15), fibrosis (c‐miR‐22, c‐miR‐18), mitochondrial function (c‐miR‐181), and aerobic capacity (c‐miR‐20a). Following bed rest stroke volume was decreased and correlated with changes in cmiR‐18a and c‐miR‐378a. PeakVO2 was decreased and correlated with changes in c‐miR‐133. In conclusion, we found that bed rest induced a distinct and specific cardiovascular‐c‐miR response, which was associated with changes in cardiac function and cardiopulmonary exercise capacity. Although future work is required, these results suggest the potential value of c‐miRs as biomarkers and their possible role as physiological mediators of cardiovascular deconditioning to bed rest.Support or Funding InformationNational Aeronautics and Space Administration (NASA) research grant awarded to C.J AdeThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Revisiting the Role of Exercise Countermeasure on the Regulation of Energy Balance During Space Flight.

A body mass loss has been consistently observed in astronauts. This loss is of medical concern since energy deficit can exacerbate some of the deleterious physiological changes observed during space flight including cardiovascular deconditioning, bone density, muscle mass and strength losses, impaired exercise capacity, and immune deficiency among others. These may jeopardize crew health and performance, a healthy return to Earth and mission’s overall success. In the context of planning for planetary exploration, achieving energy balance during long-term space flights becomes a research and operational priority. The regulation of energy balance and its components in current longer duration missions in space must be re-examined and fully understood. The purpose of this review is to summarize current understanding of how energy intake, energy expenditure, and hence energy balance are regulated in space compared to Earth. Data obtained in both actual and simulated microgravity thus far suggest that the obligatory exercise countermeasures program, rather than the microgravity per se, may be partly responsible for the chronic weight loss in space. Little is known of the energy intake, expenditure, and balance during the intense extravehicular activities which will become increasingly more frequent and difficult. The study of the impact of exercise on energy balance in space also provides further insights on lifestyle modalities such as intensity and frequency of exercise, metabolism, and the regulation of body weight on Earth, which is currently a topic of animated debate in the field of energy and obesity research. While not dismissing the significance of exercise as a countermeasure during space flight, data now challenge the current exercise countermeasure program promoted and adopted for many years by all the International Space Agencies. An alternative exercise approach that has a minimum impact on total energy expenditure in space, while preventing muscle mass loss and other physiological changes, is needed in order to better understand the in-flight regulation of energy balance and estimate daily energy requirements. A large body of data generated on Earth suggests that alternate approaches, such as high intensity interval training (HIIT), in combination or not with sessions of resistive exercise, might fulfill such needs.

A Comparison of Squatting Exercise on a Centrifuge and With Earth Gravity.

Purpose: Long-duration space missions require countermeasures against the muscular wasting and cardiovascular deconditioning associated with microgravity. Replacing gravitational acceleration by means of centrifugation is a promising alternative as it challenges all physiological systems at once. The aim of this study is to examine the metabolic energy costs of squatting on a centrifuge in comparison with squatting in an upright standing posture under natural gravity.Methods: 24 subjects (11 male, 13 female) performed continuous squatting exercise for 9 min with increasing cadence (10, 12, and 15 squats min-1). This was done under three conditions: Upright under natural gravity and lying supine on a centrifuge at two radii (2.5 and 3.5 m) at 1 g of centrifugal acceleration at the subject’s average center of mass during the exercise.Results: Generally, subjects did not suffer from motion sickness. Exercise under natural gravity led to a higher Δ V’O2/body mass (7.1 ± 2.0, ml min-1 kg-1, mean ± SD) compared with exercise on the centrifuge (6.1 ± 1.6, ml min-1 kg-1, mean ± SD). Exercise efficiency was also reduced under natural 1 g at 28.2 ± 1.0% compared to 40.4 ± 1.5% on the centrifuge. As expected, oxygen consumption increased with increasing cadences. The Coriolis effect had a negligible impact as there was no significant difference in V’O2 between the two radii. However, during centrifugation and upward movement the right leg was more loaded than the leg left and vice versa during downward movement (centrifuge running clockwise looking down, so to the subjects’ right).Conclusion: The lower V’O2 on the centrifuge may be attributed to the unloading of trunk muscles while subjects were lying on the sled, which in the upright condition leaning against the sled were still working to stabilize the torso. Subjects tolerated high rotational rates combined with exercise very well.