Artificial Gravity as a Countermeasure to the Cardiovascular Deconditioning of Spaceflight: Gender Perspectives.

Space flight-induced physiological deconditioning resulting from decreased gravitational input, decreased plasma volume, and disruption of regulatory mechanisms is a significant problem in returning astronauts as well as in normal aging. Here we review effects of a promising countermeasure on cardiovascular systems of healthy men and women undergoing Earth-based models of space-flight. This countermeasure is produced by a centrifuge and called artificial gravity (AG). Numerous studies have determined that AG improves orthostatic tolerance (as assessed by various protocols) of healthy ambulatory men, of men deconditioned by bed rest or by immersion (both wet and dry) and, in one case, following spaceflight. Although a few studies of healthy, ambulatory women and one study of women deconditioned by furosemide, have reported improvement of orthostatic tolerance following exposure to AG, studies of bed-rested women exposed to AG have not been conducted. However, in ambulatory, normovolemic subjects, AG training was more effective in men than women and more effective in subjects who exercised during AG than in those who passively rode the centrifuge. Acute exposure to an AG protocol, individualized to provide a common stimulus to each person, also improved orthostatic tolerance of normovolemic men and women and of furosemide-deconditioned men and women. Again, men's tolerance was more improved than women's. In both men and women, exposure to AG increased stroke volume, so greater improvement in men vs. women was due in part to their different vascular responses to AG. Following AG exposure, resting blood pressure (via decreased vascular resistance) decreased in men but not women, indicating an increase in men's vascular reserve. Finally, in addition to counteracting space flight deconditioning, improved orthostatic tolerance through AG-induced improvement of stroke volume could benefit aging men and women on Earth.

Autonomic Cardiovascular Responses to Orthostatic Stress After a Short Artificial Gravity Exposure.

BACKGROUND: Intermittent artificial gravity (AG) training over days and weeks has been shown to improve the human orthostatic tolerance limit (OTL) and improve cardiovascular regulation in response to orthostatic stress. Effects of a single AG exposure are currently unknown. METHODS: We tested cardiovascular responses to orthostatic stress in 16 hypovolemic subjects (9 men and 7 women), once following a single, short (∼90 min) bout of AG and once following a similar period of head-down bed rest (HDBR). Hypovolemia was produced by intravenous furosemide infusion (20 mg) and orthostatic stress was produced by combined 70° head-up tilt (HUT) and progressively increasing lower body negative pressure until symptoms of presyncope developed. To assess reflex-induced changes in cardiovascular regulation, heart rate and blood pressure variability were analyzed by spectral analysis and baroreflex activity was evaluated by transfer function analysis. RESULTS: Compared to HDBR, a short AG exposure increased men's low frequency (0.04-0.15 Hz) power of systolic blood pressure (SBPLF), but did not change women's SBPLF responses to orthostatic stress. In response to 70° HUT, compared to supine, low frequency phase delay (PhaseLF) between systolic blood pressure and RR intervals increased by ∼20% following HDBR, but did not change following AG, reflecting improved baroreflex activity at a milder level of orthostatic stress after AG. CONCLUSIONS: These results indicate that a short bout of AG increased both sympathetic and baroreflex responsiveness to orthostatic stress in hypovolemia-induced, cardiovascular-deconditioned men and women, which may contribute to the AG-induced improvement of OTL shown in our previous reports.Zhang Q, Evans JM, Stenger MB, Moore FB, Knapp CF. Autonomic cardiovascular responses to orthostatic stress after a short artificial gravity exposure. Aerosp Med Hum Perform. 2017; 88(9):827-833.

Body Size Predicts Cardiac and Vascular Resistance Effects on Men's and Women's Blood Pressure.

Key Points Summary We report how blood pressure, cardiac output and vascular resistance are related to height, weight, body surface area (BSA), and body mass index (BMI) in healthy young adults at supine rest and standing.Much inter-subject variability in young adult's blood pressure, currently attributed to health status, may actually result from inter-individual body size differences.Each cardiovascular variable is linearly related to height, weight and/or BSA (more than to BMI).When supine, cardiac output is positively related, while vascular resistance is negatively related, to body size. Upon standing, the change in vascular resistance is positively related to size.The height/weight relationships of cardiac output and vascular resistance to body size are responsible for blood pressure relationships to body size.These basic components of blood pressure could help distinguish normal from abnormal blood pressures in young adults by providing a more effective scaling mechanism. Introduction: Effects of body size on inter-subject blood pressure (BP) variability are not well established in adults. We hypothesized that relationships linking stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) with body size would account for a significant fraction of inter-subject BP variability. Methods: Thirty-four young, healthy adults (19 men, 15 women) participated in 38 stand tests during which brachial artery BP, heart rate, SV, CO, TPR, and indexes of body size were measured/calculated. Results: Steady state diastolic arterial BP was not significantly correlated with any index of body size when subjects were supine. However, upon standing, the more the subject weighed, or the taller s/he was, the greater the increase in diastolic pressure. Systolic pressure strongly correlated with body weight and height both supine and standing. Diastolic and systolic BP were more strongly related to height, weight and body surface area than to body mass index. When supine: lack of correlation between diastolic pressure and body size, resulted from the combination of positive SV correlation and negative TPR correlation with body size. The positive systolic pressure vs. body size relationship resulted from a positive SV vs. height relationship. In response to standing: the positive diastolic blood pressure vs. body size relationship resulted from the standing-induced, positive increase in TPR vs. body size relationship. The relationships between body weight or height with SV and TPR contribute new insight into mechanisms of BP regulation that may aid in the prediction of health in young adults by providing a more effective way to scale BP with body size.

Hypovolemic men and women regulate blood pressure differently following exposure to artificial gravity.

PURPOSE: In addition to serious bone, vestibular, and muscle deterioration, space flight leads to cardiovascular dysfunction upon return to gravity. In seeking a countermeasure to space flight-induced orthostatic intolerance, we previously determined that exposure to artificial gravity (AG) training in a centrifuge improved orthostatic tolerance of ambulatory subjects. This protocol was more effective in men than women and more effective when subjects exercised. METHODS: We now determine the orthostatic tolerance limit (OTL) of cardiovascularly deconditioned (furosemide) men and women on one day following 90 min of AG compared to a control day (90 min of head-down bed rest, HDBR). RESULTS: There were three major findings: a short bout of artificial gravity improved orthostatic tolerance of hypovolemic men (30 %) and women (22 %). Men and women demonstrated different mechanisms of cardiovascular regulation on AG and HDBR days; women maintained systolic blood pressure the same after HDBR and AG exposure while men's systolic pressure dropped (11 ± 2.9 mmHg) after AG. Third, as presyncopal symptoms developed, men's and women's cardiac output and stroke volume dropped to the same level on both days, even though the OTL test lasted significantly longer on the AG day, indicating cardiac filling as a likely variable to trigger presyncope. CONCLUSIONS: (1) Even with gender differences, AG should be considered as a space flight countermeasure to be applied to astronauts before reentry into gravity, (2) men and women regulate blood pressure during an orthostatic stress differently following exposure to artificial gravity and (3) the trigger for presyncope may be cardiac filling.

Cardiovascular and cardiorespiratory phase synchronization in normovolemic and hypovolemic humans.

We investigated whether and how cardiovascular and cardiorespiratory phase synchronization would respond to changes in hydration status and orthostatic stress. Four men and six women were tested during graded head-up tilt (HUT) in both euhydration and dehydration (DEH) conditions. Continuous R-R intervals (RRI), systolic blood pressure (SBP) and respiration were investigated in low (LF 0.04-0.15 Hz) and high (HF 0.15-0.4 Hz) frequency ranges using a phase synchronization index (λ) ranging from 0 (complete lack of interaction) to 1 (perfect interaction) and a directionality index (d), where a positive value of d reflects oscillator 1 driving oscillator 2, and a negative value reflects the opposite driving direction. Surrogate data analysis was used to exclude relationships that occurred by chance. In the LF range, respiration was not synchronized with RRI or SBP, whereas RRI and SBP were phase synchronized. In the HF range, phases among all variables were synchronized. DEH reduced λ among all variables in the HF and did not affect λ between RRI and SBP in the LF region. DEH reduced d between RRI and SBP in the LF and did not affect d among all variables in the HF region. Increasing λ and decreasing d between SBP and RRI were observed in the LF range during HUT. Decreasing λ between SBP and RRI, respiration and RRI, and decreasing d between respiration and SBP were observed in the HF range during HUT. These results show that orthostatic stress disassociated interactions among RRI, SBP and respiration, and that DEH exacerbated the disconnection.

Acute cardiovascular autonomic responses to inhaled particulates.

PURPOSE: Harmful effects of inhaled particulates have been established in epidemiologic studies of ambient air pollution. In particular, heart rate variability responses to high levels of environmental tobacco smoke (ETS), similar to responses observed during direct smoking, have been reported. We sought to determine whether such responses could be observed at lower particulate concentrations. METHODS: We monitored cardiovascular responses of non-smoking 21 women and 19 men to work-place-relevant levels of: ETS, cooking oil fumes (Coil), wood smoke (WS), and water vapor as sham control. Responses, tested on three consecutive days (random order of aerosol presentation), were averaged for each subject. RESULTS: Low frequency spectral powers of heart rate and blood pressure rose during recovery from exposure to particulate, but not to sham exposures. At breathing frequencies, spectral power of men's systolic pressure doubled, and baroreflex effectiveness increased, following ETS exposure. An index of sympathetic control of heart rate was more pronounced in men than women, in response to ETS and Coil, compared to WS and sham. CONCLUSIONS: When measured under controlled conditions, autonomic activities in non-smoking men and women exposed to low level, short term, particulate concentrations were similar to those observed during longer term, higher level exposures to ETS and to direct smoking. These increased indexes of sympathetic control of heart rate and peripheral vasomotion followed introduction of particulates by about 15 min. Finally, coupling of heart rate and systolic pressure indicated an increase in baroreflex activity in the response to breathing ETS that was less effective in men than women.

Simulations of gravitational stress on normovolemic and hypovolemic men and women.

BACKGROUND: Earth-based simulations of physiologic responses to space mission activities are needed to develop prospective countermeasures. To determine whether upright lower body positive pressure (LBPP) provides a suitable space mission simulation, we investigated the cardiovascular responses of normovolemic and hypovolemic men and women to supine and orthostatic stress induced by head-up tilt (HUT) and upright LBPP, representing standing in lunar, Martian, and Earth gravities. METHODS: Six men and six women were tested in normovolemic and hypovolemic (furosemide, intravenous, 0.5 mg x kg(-1)) conditions. Continuous electrocardiogram, blood pressure, segmental bioimpedance, and stroke volume (echocardiography) were recorded supine and at lunar, Martian, and Earth gravities (10 degrees, 20 degrees, and 80 degrees HUT vs. 20%, 40%, and 100% bodyweight upright LBPP), respectively. Cardiovascular responses were assessed from mean values, spectral powers, and spontaneous baroreflex parameters. RESULTS: Hypovolemia reduced plasma volume by approximately 10% and stroke volume by approximately 25% at supine, and increasing orthostatic stress resulted in further reductions. Upright LBPP induced more plasma volume losses at simulated lunar and Martian gravities compared with HUT, while both techniques induced comparable central hypovolemia at each stress. Cardiovascular responses to orthostatic stress were comparable between HUT and upright LBPP in both normovolemic and hypovolemic conditions; however, hypovolemic blood pressure was greater during standing at 100% bodyweight compared to 80 degree HUT due to a greater increase of total peripheral resistance. CONCLUSIONS: The comparable cardiovascular response to HUT and upright LBPP support the use of upright LBPP as a potential model to simulate activity in lunar and Martian gravities.

Cardiovascular models of simulated moon and mars gravities: head-up tilt vs. lower body unweighting.

INTRODUCTION: In this study we compare two models [head-up tilt (HUT) vs. body unweighting using lower body positive pressure (LBPP)] to simulate Moon, Mars, and Earth gravities. A literature search did not reveal any comparisons of this type performed previously. We hypothesized that segmental fluid volume shifts (thorax, abdomen, upper and lower leg), cardiac output, and blood pressure (BP), heart rate (HR), and total peripheral resistance to standing would be similar in the LBPP and HUT models. METHODS: There were 21 subjects who were studied while supine (simulation of spaceflight) and standing at 100% (Earth), 40% (Mars), and 20% (Moon) bodyweight produced by LBPP in Alter-G and while supine and tilted at 80 degrees, 20 degrees, and 10 degrees HUT (analogues of Earth, Mars, and Moon gravities, respectively). RESULTS: Compared to supine, fluid shifts from the chest to the abdomen, increases in HR, and decreases in stroke volume were greater at 100% bodyweight than at reduced weights in response to both LBPP and HUT. Differences between the two models were found for systolic BP, diastolic BP, mean arterial BP, stroke volume, total peripheral resistance, and thorax and abdomen impedances, while HR, cardiac output, and upper and lower leg impedances were similar. CONCLUSIONS: Bodyweight unloading via both LBPP and HUT resulted in cardiovascular changes similar to those anticipated in actual reduced gravity environments. The LBPP model/Alter-G has the advantage of providing an environment that allows dynamic activity at reduced bodyweight; however, the significant increase in blood pressures in the Alter-GC may favor the HUT model.

Near-infrared diffuse optical monitoring of cerebral blood flow and oxygenation for the prediction of vasovagal syncope.

Significant drops in arterial blood pressure and cerebral hemodynamics have been previously observed during vasovagal syncope (VVS). Continuous and simultaneous monitoring of these physiological variables during VVS is rare, but critical for determining which variable is the most sensitive parameter to predict VVS. The present study used a novel custom-designed diffuse correlation spectroscopy flow-oximeter and a finger plethysmograph to simultaneously monitor relative changes of cerebral blood flow (rCBF), cerebral oxygenation (i.e., oxygenated/deoxygenated/total hemoglobin concentration: r[HbO2]/r[Hb]/rTHC), and mean arterial pressure (rMAP) during 70 deg head-up tilt (HUT) in 14 healthy adults. Six subjects developed presyncope during HUT. Two-stage physiological responses during HUT were observed in the presyncopal group: slow and small changes in measured variables (i.e., Stage I), followed by rapid and dramatic decreases in rMAP, rCBF, r[HbO2], and rTHC (i.e., Stage II). Compared to other physiological variables, rCBF reached its breakpoint between the two stages earliest and had the largest decrease (76±8%) during presyncope. Our results suggest that rCBF has the best sensitivity for the assessment of VVS. Most importantly, a threshold of ∼50% rCBF decline completely separated the subjects from those without presyncope, suggesting its potential for predicting VVS.

Cardiovascular regulation during body unweighting by lower body positive pressure.

BACKGROUND: We hypothesized that human cardiovascular responses to standing in reduced gravity environments, as on the Moon or Mars, could be modeled using a lower body positive pressure (LBPP) chamber. METHODS: Heart rate, blood pressure, body segment fluid shifts, ECG, indexes of sympathetic, parasympathetic balance, and baroreflex control of the heart and periphery plus echocardiographic measures of cardiac function were recorded from seven men and seven women supine and standing at 100% (Earth), 40% (-Mars), and 20% (-Moon) bodyweights (BW). RESULTS: The fluid shifted from the chest was greater when standing at 100% BW than at 20% and 40% BW, while fluid pooled in the abdomen was similar at all BWs. Compared to moving from supine to standing at 100% BW, moving to 20% and 40% BW resulted in smaller decreases in stroke volume and pulse pressure, smaller increases in heart rate and smaller decreases in parasympathetic control of heart rate, baroreflex slope, numbers of blood pressure ramps, and much reduced indexes of sympathetic drive to the heart and periphery. However, peripheral vascular resistance, systolic pressure, and baroreflex effectiveness were elevated during 20% and 40% BW, compared to supine and standing at 100% BW. DISCUSSION: Standing at reduced bodyweight suppressed indexes of sympathetic control of heart rate and peripheral vasomotion. Regulatory responses indicated a combination of arterial and cardiopulmonary baroreflex control: mean heart rate, vasomotion, and baroreflex sensitivity appeared to be more under cardiopulmonary control while baroreflex effectiveness appeared to be driven more by the arterial baroreflex.

Artificial gravity training reduces bed rest-induced cardiovascular deconditioning.

We studied 15 men (8 treatment, 7 control) before and after 21 days of 6º head-down tilt to determine whether daily, 1-h exposures to 1.0 G(z) (at the heart) artificial gravity (AG) would prevent bed rest-induced cardiovascular deconditioning. Testing included echocardiographic analysis of cardiac function, plasma volume (PV), aerobic power (VO(2)pk) and cardiovascular and neuroendocrine responses to 80º head-up tilt (HUT). Data collected during HUT were ECG, stroke volume (SV), blood pressure (BP) and blood for catecholamines and vasoactive hormones. Heart rate (HR), cardiac output (CO), total peripheral resistance, and spectral power of BP and HR were calculated. Bed rest decreased PV, supine and HUT SV, and indices of cardiac function in both groups. Although PV was decreased in control and AG after bed rest, AG attenuated the decrease in orthostatic tolerance [pre- to post-bed rest change; control: -11.8 ± 2.0, AG: -6.0 ± 2.8 min (p = 0.012)] and VO(2)pk [pre- to post-bed rest change; control: -0.39 ± 0.11, AG: -0.17 ± 0.06 L/min (p = 0.041)]. AG prevented increases in pre-tilt levels of plasma renin activity [pre- to post-bed rest change; control: 1.53 ± 0.23, AG: -0.07 ± 0.34 ng/mL/h (p = 0.001)] and angiotensin II [pre- to post-bed rest change; control: 3.00 ± 1.04, AG: -0.63 ± 0.81 pg/mL (p = 0.009)] and increased HUT aldosterone [post-bed rest; control: 107 ± 30 pg/mL, AG: 229 ± 68 pg/mL (p = 0.045)] and norepinephrine [post-bed rest; control: 453 ± 107, AG: 732 ± 131 pg/mL (p = 0.003)]. We conclude that AG can mitigate some aspects of bed rest-induced cardiovascular deconditioning, including orthostatic intolerance and aerobic power. Mechanisms of improvement were not cardiac-mediated, but likely through improved sympathetic responsiveness to orthostatic stress.

Blood pressure regulation in diabetic patients with and without peripheral neuropathy.

Cardiac and vascular dysfunctions resulting from autonomic neuropathy (AN) are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure (BP) regulation in patients with peripheral neuropathy and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. We continuously measured electrocardiogram, arterial BP, and respiration during supine rest and 70° head-up tilt in 12 able-bodied subjects, 7 diabetics without, 7 diabetics with possible, and 8 diabetics with definite, sensory, and/or motor neuropathy (D2). During the first 3 min of tilt, systolic BP (SBP) of D2 decreased [-10.9 ± 4.5 (SE) mmHg] but increased in able-bodied (+4.8 ± 5.4 mmHg). Compared with able-bodied, D2 had smaller low-frequency (0.04-0.15 Hz) spectral power of diastolic BP, lower baroreflex effectiveness index (BEI), and more SBP ramps. Except for low-frequency power of SBP, D2 had greater SBP and smaller RR interval harmonic and nonharmonic components at rest across the 0.003- to 0.45-Hz region. In addition, our results support previous findings of smaller HF RR interval power, smaller numbers of baroreflex sequences, and lower baroreflex sensitivity in D2. We conclude that diabetic peripheral neuropathy is accompanied by diminished parasympathetic and sympathetic control of heart rate and peripheral vasomotion and diminished baroreflex regulation. A novel finding of this study lies in the sensitivity of BEI to detect AN, presumably because of its combination of parameters that measure reductions in both sympathetic control of vasomotion and parasympathetic control of heart rate.

Blood pressure regulation in neurally intact human vs. acutely injured paraplegic and tetraplegic patients during passive tilt.

We investigated autonomic control of cardiovascular function in able-bodied (AB), paraplegic (PARA), and tetraplegic (TETRA) subjects in response to head-up tilt following spinal cord injury. We evaluated spectral power of blood pressure (BP), baroreflex sensitivity (BRS), baroreflex effectiveness index (BEI), occurrence of systolic blood pressure (SBP) ramps, baroreflex sequences, and cross-correlation of SBP with heart rate (HR) in low (0.04-0.15 Hz)- and high (0.15-0.4 Hz)-frequency regions. During tilt, AB and PARA effectively regulated BP and HR, but TETRA did not. The numbers of SBP ramps and percentages of heartbeats involved in SBP ramps and baroreflex sequences increased in AB, were unchanged in PARA, and declined in TETRA. BRS was lowest in PARA and declined with tilt in all groups. BEI was greatest in AB and declined with tilt in all groups. Low-frequency power of BP and the peak of the SBP/HR cross-correlation magnitude were greatest in AB, increased during tilt in AB, remained unchanged in PARA, and declined in TETRA. The peak cross-correlation magnitude in HF decreased with tilt in all groups. Our data indicate that spinal cord injury results in decreased stimulation of arterial baroreceptors and less engagement of feedback control as demonstrated by lower 1) spectral power of BP, 2) number (and percentages) of SBP ramps and barosequences, 3) cross-correlation magnitude of SBP/HR, 4) BEI, and 5) changes in delay between SBP/HR. Diminished vasomotion and impaired baroreflex regulation may be major contributors to decreased orthostatic tolerance following injury.

Circulatory galanin levels increase severalfold with intense orthostatic challenge in healthy humans.

The purpose of this study was to test the hypothesis that plasma galanin concentration (pGal) is regularly increased in healthy humans with extensive orthostatic stress. Twenty-six test persons (14 men, 12 women) were brought to an orthostatic end point via a progressive cardiovascular stress (PCS) protocol consisting of 70 degrees head-up tilt plus increasing levels of lower body negative pressure until either hemodynamically defined presyncope or other signs of orthostatic intolerance occurred (nausea, clammy skin, excessive sweating, pallor of the skin). We further tested for possible gender, gravitational, and muscular training influences on plasma pGal responses: PCS was applied before and after 3 wk of daily vertical acceleration exposure training on a Human Powered Centrifuge. Test persons were randomly assigned to active (with bicycle work) or passive (without work) groups (seven men, six women in each group). Resting pGal was 26+/-3 pg/ml in men and 39+/-15 pg/ml in women (not significant); women had higher galanin responses (4.9-fold increase) than men (3.5-fold, P=0.017) to PCS exposure. Overall, PCS increased pGal to 186+/-5 pg/ml (P=0.0003), without significant differences between presyncope vs. orthostatic intolerance, pre- vs. postcentrifuge, or active vs. passive gravitational training. Increases in pGal were poorly related to synchronous elevations in plasma vasopressin. We conclude that galanin is regularly increased in healthy humans under conditions of presyncopal orthostatic stress, the response being independent of gravity training but larger in women than in men.

Centrifuge training increases presyncopal orthostatic tolerance in ambulatory men.

INTRODUCTION: Exposure to spaceflight or simulations of microgravity reduce human postflight orthostatic tolerance. Exercise training and volume loading can reduce associated losses of plasma volume and muscle strength, but are not successful in maintaining postflight orthostatic tolerance. A preliminary study (16) indicated that short bouts of artificial gravity (AG) training on a centrifuge could increase orthostatic tolerance in healthy, ambulatory volunteers. We tested the same AG protocol for its tolerance effect on 14 men who underwent a 3-wk exposure to Gz acceleration training on NASA-Ames' (Moffet Field, CA) human-powered centrifuge. METHODS: Subjects trained supine (head near the center of rotation) and in pairs (one subject rode passively while the other provided power to operate the 1.9-m centrifuge). The acceleration profile consisted of 7 min at 1 Gz before alternating between 1 and 2.5 Gz at 2-min intervals for 28 min. Each subject's presyncopal orthostatic tolerance limit (to a combination of 70 degrees head-up tilt and increasing lower body negative pressure) was determined before and after training. RESULTS: There were no significant differences between training groups, but presyncopal orthostatic tolerance time was improved 17 +/- 10% (p < 0.05) for the combined groups. Mechanisms associated with increased tolerance included: increased cardiac output (p < 0.04), stroke volume (p < 0.01) and low-frequency spectral power of arterial pressure (p < 0.006), and decreased arterial pressure (p < 0.05) and vascular resistance (p < 0.04). Artificial gravity training in this group of men appears to increase orthostatic tolerance through a combination of decreased vascular resistance and enhanced cardiac function.