STEM Today by Abhishek Sinha

STEM TODAY June 2018, No. 33

CONTENTS CV8: Can manifestations of sub足clinical or environmentally induced cardiovascular diseases during spaceflight be predicted? Limited data are available to definitively establish the individual roles of spaceflight stressors (i.e. exposure to microgravity, radiation, oxidative and mental stress, or lifestyle alterations in diet and exercise) on short足term and long足term cardiovascular health outcomes. Existing evidence suggest increased vascular stiffness and carotid intimal media thickness immediately post足flight, but it is unclear if these effects persist or resolve over time.

Editorial Editor: Mr. Abhishek Kumar Sinha Editor / Technical Advisor: Mr. Martin Cabaniss

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Disclaimer ( Non-Commercial Research and Educational Use ) STEM Today is dedicated to STEM Education and Human Spaceflight. This newsletter is designed for Teachers and Students with interests in Human Spaceflight and learning about NASA’s Human Research Roadmap. The opinion expressed in this newsletter is the opinion based on fact or knowledge gathered from various research articles. The results or information included in this newsletter are from various research articles and appropriate credits are added. The citation of articles is included in Reference Section. The newsletter is not sold for a profit or included in another media or publication that is sold for a profit. Cover Page Astronaut Drew Feustel is pictured outside of the Tranquility module iss055e071438 (May 16, 2018) — Astronaut Drew Feustel is pictured outside of the Tranquility module during a spacewalk on May 16 to swap thermal control gear. Image Credit: NASA

Back Cover The Cygnus spacecraft with its UltraFlex solar arrays iss053e317722 (Dec. 5, 2017) — The Cygnus spacecraft with its cymbal-like UltraFlex solar arrays deployed was pictured departing the space station Dec. 5, 2017 during Expedition 53. Image Credit: NASA

STEM Today , June 2018

Editorial Dear Reader All young people should be prepared to think deeply and to think well so that they have the chance to become the innovators, educators, researchers, and leaders who can solve the most pressing challenges facing our world, both today and tomorrow. But, right now, not enough of our youth have access to quality STEM learning opportunities and too few students see these disciplines as springboards for their careers. According to Marillyn Hewson, "Our children - the elementary, middle and high school students of today - make up a generation that will change our universe forever. This is the generation that will walk on Mars, explore deep space and unlock mysteries that we can’t yet imagine". "They won’t get there alone. It is our job to prepare, inspire and equip them to build the future." STEM Today will inspire and educate people about Spaceflight and effects of Spaceflight on Astronauts.

STEM Today, June 2018, No. 33

Editor Mr. Abhishek Kumar Sinha

Editorial Dear Reader The Science, Technology, Engineering and Math (STEM) program is designed to inspire the next generation of innovators, explorers, inventors and pioneers to pursue STEM careers. According to former President Barack Obama, " Science is more than a school subject, or the periodic table, or the properties of waves. It is an approach to the world, a critical way to understand and explore and engage with the world, and then have the capacity to change that world..." STEM Today addresses the inadequate number of teachers skilled to educate in Human Spaceflight. It will prepare , inspire and educate teachers about Spaceflight. STEM Today will focus on NASA’S Human Research Roadmap. It will research on long duration spaceflight and put together latest research in Human Spaceflight in its monthly newsletter. Editor / Technical Advisor Mr. Martin Cabaniss

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Human Health Countermeasures (HHC) CV8: Can manifestations of sub-clinical or environmentally induced cardiovascular diseases during space ight be predicted? Limited data are available to de nitively establish the individual roles of space ight stressors (i.e. exposure to microgravity, radiation, oxidative and mental stress, or lifestyle alterations in diet and exercise) on short-term and long-term cardiovascular health outcomes. Existing evidence suggest increased vascular sti ness and carotid intimal media thickness immediately post- ight, but it is unclear if these e ects persist or resolve over time.

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To determine the e ects of long-duration space ight on measures of arterial structure and function through R+3

BP Reg: Predicting fainting in astronauts

The Canadian science experiment Blood Pressure Regulation and Risk of Fainting on Return from Space (BP Reg) studied why some astronauts are more likely to faint or experience dizziness after their missions by observing how their bodies react to changes in blood pressure. The Canadian Space Agency (CSA) has supported three experiments: Cardio- vascular and Cerebrovascular control on return from the International Space Station (CCISS); Cardiovascular Health Consequences of Longduration Spaceflight (Vascular) and Blood Pressure Regulation and Risk of Fainting on Return from Space (BP Reg).

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Arterial baroreflex The CCISS experiments measured the arterial baroreflex before, during and after long-duration spaceflight from the sequence method that related to spontaneous changes in RR-interval with finger arterial blood pressure measured in space with the continuous blood pressure device (CBPD). Pre- and post-flight, astronauts were studied in supine and seated postures. The arterial baroreflex slope was not different inflight compared to pre-flight baseline in either the supine or seated postures. Post-flight, a significant reduction was observed only in paced breathing (10 breaths/min). Large changes in baroreflex slope were observed in individuals who did the most aerobic exercise sessions while on ISS. While this observation seems contrary to expectations, it is probable that the individuals who did the most aerobic exercise while on ISS were also the same astronauts who incorporated large quantities of aerobic exercise into their pre-flight routines. That is, they had the lowest heart rate prior to spaceflight due to high parasympathetic tone, but were unable to maintain their high aerobic fitness on ISS due to lack of loading of the treadmill device. These astronauts also reported frequent dizziness that might have been related to post-flight orthostatic hypotension. Arterial stiffness Increased arterial stiffness, normally observed with aging, has recently been observed during and after spaceflight including long-duration ISS missions as well as short-duration shuttle flights. Baevsky et al. measured the pulse wave transit time from the R-wave of the ECG to the arrival of the finger pressure wave. The observations of faster transit time from pre- to post-flight in the Vascular experiment (P = 0.07) were almost identical to previous data. However, preliminary new data from the first 6 astronauts in the Vascular study revealed reductions in carotid artery distensibility after approximately 6 months in space. Given the observations in older sedentary individuals that 3 months of walking or jogging for 40 min/day reduced carotid and peripheral artery stiffness, possibly through enhanced bioavailability of nitric oxide, authors investigated whether astronauts who maintained physical fitness would have less change in pulse wave transit time to the finger. There was no relationship between the change in pulse wave transit time and the change in heart rate at a fixed work rate (mean pre-flight heart rate approximately 145 Âą17 bpm) as shown in Fig. 2. It is established that multiple factors could contribute to increased arterial stiffness with aging including increased vasoconstrictor or reduced vasodilator factors, structural breakdown of elastin, accumulation of collagen, Vascular smooth muscle cell proliferation and increased cross-linking in the extracellular matrix. The possible roles of these factors related to the increased arterial stiffness with spaceflight have not been investigated. The animal model of hindlimb suspension, used as an analog of spaceflight, revealed cellular hypertrophy in the middle cerebral artery with a potential role for activation of Vascular wall renin-angiotensin system. Other experiments with a similar animal model suggested increased cross-linkage in the major elastic arteries. The Vascular experiment provides data to test these mechanisms. It is not clear from the cosmonaut data of Baevsky et al. whether the increased stiffness is an acute or long-term effect of spaceflight.

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Lifelong increased arterial stiffness in aging has important health consequences associated with increased systolic arterial blood pressure that can lead to target organ damage such as increased cerebrovascular resistance with a reduction in brain blood flow in otherwise healthy elderly individuals.

These data reveal that, like bone loss, cardiovascular health consequences of spaceflight require further research to establish effective countermeasures.

Microgravity induced changes in aortic stiffness and their role in orthostatic intolerance

Microgravity induced orthostatic intolerance (OI) in astronauts is characterized by a marked decrease in cardiac output (CO) in response to an orthostatic stress. Since CO is highly dependent on venous return, alterations in the resistance to venous return (RVR) may be important in contributing to OI. The RVR is directly dependent on arterial compliance (Ca), where aortic compliance (Cao) contributes up to 60% of Ca. All human astronaut data were from previously published studies [Meck et al.] . The data set consisted of supine hemodynamic measures taken from 57 astronauts usually 10 days before launch, on landing day, and 3 days after landing. Tilt tests were used todetermine whether astronauts were orthostatically intolerant before and after spaceflight.

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Detailed methods are available from Meck et al. and Fritsche-Yelle et al.; briefly, blood pressure was measured every minute using an automated arm cuff concurrently with beat-to-beat wrist cuff. Aortic crosssectional area, determined using two-dimensional echocardiography, and ascending aortic flow, sampled with pulsed Doppler, were used to determine the stroke volume.

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OT was evaluated using a 10-min tilt protocol that brought the subject to an 80◦ upright position from supine. The subjects remained in a vertical position for 10 min or until presyncopal symptoms manifested. A subject was determined to be intolerant if the tilt was prematurely ended due to the manifestation of presyncopal symptoms. Ca was estimated as the stroke volume divided by the arterial pulse pressure (systolic minus diastolic blood pressure).

Astronaut Ca. Figure 1 summarizes the Ca in astronauts preflight, on landing day, and post landing (in general, preflight measures were taken 10 days before flight, missions lasted between 5 and 18 days, and post landing measures were taken 3 days after landing). As demonstrated in Fig. 1A, and consistent with the hypothesis, there is a significant decrease in Ca in OT astronauts between preflight and landing day (2.0 ± 0.097 to 1.7 ± 0.083 ml/mmHg; P = 0.0011; n = 40). The Ca then returns toward normal 3 days following landing (2.0 ± 0.095 ml/mmHg). In marked contrast, there is no significant decrease in compliance in OI astronauts at landing day (1.9 ± 0.13 to 2.3 ± 0.39 ml/mmHg; P = 0.36; n = 17) (Fig. 1B).

In fact, although not statistically significant, there is a trend toward an increase in OI astronaut Ca between preflight and landing day. Interestingly, there is no significant difference between OI and OT Ca preflight [1.9 ± 0.13 (n = 17) and 2.0 ± 0.097 ml/mmHg (n = 40), respectively; P = 0.53]. However, on landing day, the Ca values are dramatically different [2.3 ± 0.39 (n = 17) and 1.7 ± 0.083 ml/mmHg (n = 40), respectively; P = 0.046; Fig. 1C]. The data presented are consistent with the hypothesis that exposure to actual or simulated microgravity induces a change in Ca. This is demonstrated by the fact that an estimate of Ca was seen to change in astronauts (Fig. 1). The data also support the hypothesis that a decrease in Ca (increase in stiffness) maybe an adaptive change that protects astronauts from OI by decreasing the resistance to venous return. The astronaut hemodynamic data indicates that while the OI astronauts had a slight, nonsignificant increase in Ca, the OT astronauts demonstrated a large decrease in Ca after spaceflight. This may explain why these astronauts were able to maintain adequate cardiac output and blood pressure during an orthostatic challenge. On the other hand, OI astronauts failed to decrease their Ca. Potts et al. showed that a reduction of Ca was partly responsible for minimizing a baroreflex-evoked increase

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in resistance to venous return. Additionally, Hatanaka et al. demonstrated that a decrease in Ca effectively decreases the resistance to venous return. Thus a stiffer, or less compliant, arterial bed will allow for less accumulation of blood volume in the arterial circulation and consequently shift the extra volume to the venous side, aiding in venous return. Therefore, it is reasonable to conclude that the decrease in Ca seen in the OT astronauts is, in part, responsible for maintaining OT, while failure to decrease compliance contributes to OI. The decreases in stroke volume, cardiac output, and mean arterial blood pressure are not as great as reported from OI astronauts during an upright tilt test [â&#x2C6;ź30-50% decrease for stroke volume and cardiac output and â&#x2C6;ź25% for mean arterial blood pressure].

Carotid Intima Media thickness in the astronaut corps

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Carotid Intima Media Thickness (CIMT) has been demonstrated to be predictive of future cardiovascular events. Within various populations, radiation exposure, stress, and physical confinement have all been linked to an increased CIMT. Recent research discovered CIMT was significantly increased in ten long duration astronauts from pre-flight to four days post flight. In 2010, CIMT was offered as part of the astronaut annual exam at the JSC Flight Medicine Clinic using a standardized CIMT screening protocol and professional sonographers. Between 2010 and 2016, CIMT measurements were collected on 213 NASA astronauts and payload specialists. The values used in this retrospective chart review are the mean of the CIMT from the right and left. Spaceflight exposure was categorized based on the total number of days spent in space at the time of the ground-based ultrasound (0, 1-29, 30-200, â&#x2030;Ľ200). Linear regressions with generalized estimating equations were used to estimate the association between spaceflight exposures and CIMT. Result Astronaut carotid intima media thickness measurements (n=530) were graphed by age to evaluate overall trends. A comparison of ARIC trends and Astronaut Corps trend charts developed from these measurements demonstrated that the Astronaut Corps is trending above the ARIC data at most age ranges (Figure 1). This is particularly pronounced at from ages 35 to 54 and from 70 to 74, and is observed primarily at the 25th and 50th percentiles. Mean year to year progression for all astronauts with 4+ CIMT measurements (n=43, mean age=47.14) was 0.00847mm/year, which is not increased over the typical progression rate observed in general population studies. However, naive astronauts identified (n=4, mean age=41) in the data set demonstrated a CIMT progression of 0.035mm during the year of their first flight, above the general population and average progression rate for the Corps. In Figure 2 below, astronaut carotid intimal medial thickness measurements grouped by spaceflight exposure are graphed by age. Spaceflight naive astronauts who were selected and underwent training for the astronaut corps, but never flew in space are included as a comparison population. Atherosclerotic Risk in Communities (ARIC) general population data is also included as a comparison group. Astronaut exposure groups are divided by total cumulative days in space with 1-29 days being designated light exposure (n=176), 30-199 days designated moderate exposure (n=253), and 200+ days designated high exposure (n=52). CIMT in astronauts in all spaceflight exposed groups trended above naive astronauts without spaceflight exposure. Astronauts in the light and high exposure groups both trended above ARIC general population trend data. Astronauts in the high and moderate exposure groups had significantly elevated CIMT measurements over the astronauts with no spaceflight exposure (p<0.0001 and p=0.002) after correction for age. Astronauts in low spaceflight exposure group also had significantly elevated CIMT over astronauts with no spaceflight exposure (p=0.0113). However, linear regression analysis did not demonstrate a direct correlation between cumulative spaceflight exposure time and astronaut CIMT (p=0.2733). Mission type also correlated with CIMT results. Within the spaceflight exposed group, lunar mission astronauts had significantly increased CIMT over non-lunar mission astronauts (p=0.0152).

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Carotid intimal medial thickness is strongly associated with cardiovascular disease risk burden and progresses

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with increasing age. Following this trend, the cumulative astronaut data progresses with age similar to the general population data demonstrated in the ARIC population study. However spaceflight naive astronauts, CIMT age related progression is significantly slower as demonstrated in Figure 2. Astronauts undergo an extensive medical screening process during their selection and must maintain a high level of physical fitness in comparison to the general population. It is likely that the slow age related progression of CIMT in the spaceflight naive astronauts is consistent with this population’s lower baseline cardiovascular disease risk. Despite population’s likely reduced baseline cardiovascular risk, astronaut CIMT in all spaceflight exposure groups trended significantly above spaceflight naive astronauts CIMT and astronauts in the light and high exposure groups trended above ARIC general population CIMT data. This suggests that astronauts are exposed to some factor during spaceflight that may result in increased CIMT. Radiation in space has been recognized as a potential health hazard for astronauts that may impact their cardiovascular risk burden. Ionizing radiation results in endothelial cell dysfunction and radiation induced fibrosis in sub-endothelial vascular layers, leading to atherosclerosis.

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Apollo era astronauts have been found to have an elevated cardiovascular morality rate and this has been attributed to deep space radiation exposure outside of the Earth’s protective upper atmosphere and magnetosphere [Delp,M.D.et.al.]. Apollo astronauts in this dataset had elevated CIMT significantly above both the general population and the rest of the Astronaut Corps, which is consistent with this hypothesis. Astronauts in light spaceflight exposure group, which includes the majority of Apollo astronauts, trended above astronauts with moderate spaceflight exposure. It is possible that their increased cosmic radiation exposure may have increased their CIMT over low earth orbit astronauts. This may also explain why the linear regression model did not find a significant direct correlation between days of exposure and increased CIMT.

Carotid Artery Structure during and after Long-Duration Space Flight

The purpose of this investigation is to determine whether long-duration space flight (>4 months) on the International Space Station results in structural changes in the carotid artery. Carotid artery intima-media thickness (CIMT) and diameter during systole (Ds) and diastole (Dd) were measured using standard ultrasound (VividQ, GE Healthcare) in 10 astronauts (9 M, 1 F) approximately 180 and 60 days before launch, at approximately 15 (FD15) and 60 days of flight (FD60), within two weeks before landing (R-14), and within one week after landing. Pre- and post-flight measures were obtained after the subjects had been supine for at least 20 min. Inflight measures were acquired by trained astronauts while being guided by an expert sonographer on the ground using telemedicine techniques. Carotid artery distensibility coefficient was calculated (cDC = (Ds2 -Dd2 )/(PP.Dd2 ); Gepner et al., Stroke 45: 48-53, 2014). Pre-flight data were averaged to represent baseline. Results were analyzed using one-way repeated measures ANOVA. Carotid artery diameters during systole (Ds FD15: 7.6 ± 0.4; FD60: 7.6 ± 0.4; R-14: 7.7 ± 0.4 mm; mean ± SD) and diastole (Dd FD15: 7.2 ± 0.3; FD60: 7.3 ± 0.4; R-14: 7.3 ± 0.5 mm) were significantly greater during space flight than pre- (Ds: 7.3 ± 0.4; Dd: 6.9 ± 0.4 mm) and post-flight (Ds: 7.4 ± 0.4; Dd: 7.1 ± 0.5 mm). There was a main effect of time on CIMT, but post-hoc analyses did not reveal significant difference from pre-flight (Pre: 0.58 ± 0.09 mm) at any time point (FD15: 0.58 ± 0.14; FD60: 0.54 ± 0.09; R-14: 0.54 ± 0.09; Post: 0.62 ± 0.10 mm). Although pre-flight cDC (0.0028 ± 0.0011/mmHg) was not different than in-flight (FD15: 0.0023 ± 0.0011; FD60: 0.0020 ± 0.0008; R-14: 0.0023 ± 0.0012/mmHg), post-flight cDC (0.0019 ± 0.0010/mmHg) was significantly less than pre-flight. The carotid artery was distended chronically during space flight and cDC was decreased in the week after landing, in these astronauts pathological remodeling of this vessel was not evident.

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Postflight carotid artery stiffness and inflight insulin resistance resulting from 6month spaceflight in male and female astronauts

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Little is known about structural adaptations of human arteries to spaceflight. Following 5- to 18-day spaceflights, total arterial compliance calculated from stroke volume divided by arterial pulse pressure was reduced (stiffer arteries) in some astronauts. However, total arterial compliance is a function of central and peripheral artery stiffness so this calculation could have reflected peripheral sympathetic vasoconstriction rather than changes in central arteries. The pulse wave transit time (PWTT) measured from the R-wave of the electrocardiogram to the arrival of the pulse in the fingertip was significantly reduced inflight (stiffer arteries) and at 5 days postflight.

This study measured carotid artery stiffness and the PWTT in astronauts before and after living 5-6 month on the International Space Station (ISS). Authors tested the hypotheses that arteries in the upper region of the body would be stiffer after spaceflight, and that blood biomarkers would reflect the development of insulin resistance and changes in the hormonal milieu that could affect vascular structure and function.

In addition, through the serendipitous assignment of astronauts over the period of this study we enrolled an equal number of male and female astronauts providing a unique opportunity to explore potential sex differences in vascular responses. Nine astronauts (4 female, 40-56 yr old, 174 Âą 7 cm height, 69 Âą 15 kg body wt) volunteered to participate in this study known by the operations name " Vascular." Participants were asked to avoid alcohol, blood pressure medications, and cold/allergy medications for 24 h prior to the test. Participants arrived at least 2 h postprandial/post-caffeine and at least 2 wk since their last leg biopsy. No strenuous exercise and no tilt tests/test that interfere with the blood pressure responses of daily life were performed within 24 h prior to the

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sessions. Crew were permitted, however, to follow their normal daily/weekly fitness regime.

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Results Preflight to postflight cardiovascular responses Resting supine heart rate was significantly elevated during testing ∼24h postflight compared with preflight baseline (Table 2). The significant Flight X Sex interaction effect for SBP reflected the decrease in SBP after spaceflight for women and an increase for men. There were no Flight effects observed for DBP, brachial PP, or carotid PP (Table 2).

Carotid artery stiffness was significantly increased postflight compared with preflight baseline. The carotid distensibility coefficient when calculated with the carotid artery pulse pressure [cDC(cPP)] was reduced 17.1 ± 23.5% postflight (Table 2). The carotid artery distensibility coefficient when calculated with the brachial artery pulse pressure [cDC(bPP)] was reduced 25.9 ± 14.1% (Table 2, Fig. 1). The carotid artery β-stiffness index calculated with carotid pulse pressure was increased 29.6 ± 34.0% postflight with a significant Flight X Sex interaction effect due to the greater increase in women (Table 2). The percent changes in carotid artery distensibility coefficient and the β-stiffness index were correlated [cDC-(cPP): r2 = 0.42, P = 0.08; cDC(bPP): r2 = 0.63, P = 0.018]. The percent change in β-stiffness index from pre- to postflight tended to correlate with the change in PWTT measured from R-wave to pulse pressure arrival in the ankle (r2 = 0.45, P=0.070). The PWTT measured from the R-wave of the ECG to the initial upslope of the finger blood pressure waveform was significantly faster after flight with a strong Flight X Sex interaction effect reflecting the greater reduction in PWTT in men (Table 2, Fig. 2). A similar pattern with a significant Flight X Sex interaction effect was observed for the PWTT measured from the R-wave to the arrival of the pressure pulse in the ankle (Fig. 2). The percentage changes in PWTT for finger and ankle measured for each individual comparing preflight to postflight were significantly correlated (r2 =0.546, P= 0.036). Preflight to inflight blood biomarkers Metabolic markers related to glucose metabolism were altered by spaceflight (Table 3, Fig. 3). Although there was no overall change in blood glucose concentration, there were differences between men and women and there was a significant Flight X Sex interaction effect revealing a trend for women to have lower blood glucose inflight and men to have higher blood glucose. Insulin concentration was elevated in all astronauts, and calculated HOMA insulin resistance index increased overall with a Flight X Sex interaction suggesting a greater increase in men than women (Fig. 3). Glycated albumin expressed as a percentage of total albumin tended to be elevated inflight, IGF-1 was increased inflight with a significant Flight X Sex interaction effect consistent with a greater increase in men than women, and RAGE was significantly reduced during spaceflight.

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The change from preflight to inflight for blood glucose was significantly correlated to the change in glycated albumin (Fig. 4, r2 =0.52, P = 0.04). Several of the measured fluid regulatory and blood pressure affecting hormones were also changed by spaceflight (Table 3, Fig. 5). Renin was elevated by spaceflight with a significant Flight X Sex interaction as women tended to increase more than men.

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Angiotensin II was not significantly affected by spaceflight. Aldosterone was increased overall, but a significant Flight X Sex interaction revealed a greater increase in women than in men. ProANP was reduced during spaceflight. Markers of inflammatory and oxidative stress were inconsistently affected by spaceflight (Table 3). Creactive protein was not changed from preflight to inflight. IL-1ra was elevated during spaceflight. Total antioxidants and SOD were not significantly affected by spaceflight; however, SOD had a trend for a Flight X Sex interaction as women tended to increase while men decreased.

A marker of growth and repair obtained from measurement of MMP-2 revealed a significant suppression during spaceflight (Table 3), while MMP-1 and MMP-9 were not significantly changed (n= 4, data not shown). Blood insulin was elevated and calculated index of insulin resistance was increased; the latter revealed a significant Flight X Sex interaction effect as a consequence of directionally different changes in fasting blood glucose. Significant Flight X Sex interactions were also observed for several physiological variables and blood markers including renin and aldosterone.

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Vascular adaptations to spaceflight Loss of hydrostatic gradient that normally reduces arterial pressure above the heart and increases it below the heart while in upright posture on Earth could affect arterial structure during spaceflight. In this study, authors focused on the carotid artery as a reflection of change occurring in vessels above the heart where hypertrophy would be anticipated. By displaying the individual astronaut changes with respect to the general population (Fig.1), it is apparent that the average increase in arterial stiffness indicator measured ∼ 24-h after return from 6-mo in space was the equivalent to the change seen with more than 20 years of normal aging. While some of the mechanisms for change are certainly different between spaceflight and aging, the magnitude of change is rather dramatic. In the current study, there were no significant differences in arterial blood pressure from pre- to postflight, although a significant Flight X Sex interaction term for systolic blood pressure reflected small decreases in women and increases in men. To avoid potential blood pressure confounds, we also used the βstiffness index and again observed significantly increased stiffness after spaceflight. However, the change in stiffness was more modest and equivalent to ∼10 years of normal aging compared with the Japanese population. The two indicators were significantly correlated, but there were some differences and a significant Flight X Sex interaction for the β -stiffness index with greater changes in women. Increased arterial stiffness with aging is associated with multiple factors. Hypertension can cause vascular wall hypertrophy that restores circumferential wall stress. The animal model analog of spaceflight with chronic elevation of arterial pressure during hindlimb suspension confirmed the hypertrophic response and suggested decreased carotid artery compliance . However, aging is also associated with loss of elastic tissue and increased collagen in large arteries. It is unlikely that breakdown of elastic tissue contributes to arterial stiffness with 6-mo spaceflight and it is unknown if collagen content changes. Prior to this study, the only evidence for increased arterial stiffness with spaceflight came from measurements

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of shorter PWTT from the R-wave to the arrival of the finger pulse in 8 male cosmonauts during and for up to 6 days after 6 mo on ISS [Baevsky.et.al.]. Authors found similar shortening of PWTT immediately after spaceflight, but a significant Flight X Sex interaction effect revealed relatively no change in women. PWTT to the ankle also had a significant Flight X Sex effect but no main effect of Flight. Reduction in arterial pressure below the heart might cause vascular atrophy. However, additional confounding factors related to cardiac stroke volume, cardiac ejection period, sympathetic nervous system activity or blood-borne factors might affect PWTT.

Cardiac stroke volume increased up to 35% during spaceflight with respect to the upright position on Earth. Peripheral vasodilation might occur as brachial artery pressure was reduced 8-10 mmHg during 24-h ambulatory data collection. However, other research noted no reduction in finger arterial pressure during spaceflight. A reduction in resting blood pressure might reduce, but not eliminate, the change in pressure proposed to stimulate change at the carotid artery. Blood biomarker responses to spaceflight Impaired glucose metabolism can contribute to increased arterial stiffness. Research in the 1970s suggested that blood glucose and insulin were reduced after 38 days of spaceflight. In the 1990s, Stein et al. reported insulin resistance from the first Spacelab Life Sciences mission, but on combining data from subsequent shortduration shuttle missions they stated "that no major changes were found with insulin production". Authors report here for the first time a significant increase in the calculated homeostatic model assessment of insulin resistance (HOMA-IR) with a significant Flight X Sex interaction effect that reflects the small but consistent increase in menâ&#x20AC;&#x2122;s blood glucose with no change or small reduction for women, while both sexes increased insulin. Physical inactivity and other risks in spaceflight Authors confirmed that astronauts perform aerobic exercises for only about 30 min/day within a lifestyle that has greatly reduced overall daily activity compared with preflight. Reduced activity can affect maximum oxygen uptake, skeletal muscle function, and bone loss. The overall physical inactivity during 6-mo spaceflights might contribute to development of stiffer arteries and early signs of insulin resistance. Sex differences Women have poorer orthostatic tolerance than men on return from space. Authors identified significant Flight X Sex differences for arterial stiffness indicators. However, the direction of difference was not consistent between measurements. There were no differences between men and women for the carotid distensibility coefficient, while the Î˛-stiffness index increased more in women than men. The opposite direction of change was observed for the PWTT with greater postflight reduction in transit time in men than women. The carotid artery stiffness reflects change in a large elastic artery while pulse wave transit time reflects the composite effects of central elastic and peripheral muscular arteries that might be affected by sympathetic vasoconstriction and regional differences in transmural pressures. Female sex hormones affect arterial stiffness, but contraceptive or menstrual

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cycle information was not available for the women (ages 41 - 50 yr) in the current study. There were sex differences in biomarkers that could potentially minimize the increased arterial stiffness with spaceflight such as the smaller increase in HOMA-IR or the trend to greater increase in superoxide dismutase in women; but there were also changes in biomarkers that could exaggerate the effects on women including the smaller increase in IGF-1 and the greater increase in aldosterone. Astronauts returned from 6-mo spaceflight with greater carotid arterial stiffness. The pre- to postflight changes in carotid distensibility coefficient and Î˛-stiffness index observed during long-duration spaceflight were equivalent to the increases in stiffness observed with more than 10-20 years of aging in reference populations on Earth. The change in pulse wave transit time was also indicative of increased arterial stiffness. While the overall pattern of change with spaceflight was increased arterial stiffness, there were interesting sex differences with women showing greater changes in carotid artery Î˛-stiffness index, whereas men had greater changes in pulse wave transit time. It is not clear whether this is simply a consequence of the relatively small sample sizes, or if there are real variations as a consequence of regional and sex differences.

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An increase in insulin resistance was determined from the fasting blood glucose and insulin concentrations measured in space as hypothesized. To the extent that the measured blood biomarker changes had an influence on vascular structure or function with spaceflight, women had less increase in the HOMA-IR and a trend to increased SOD which might positively benefit arterial responses, while having less increase in IGF-1 and greater increases in renin and aldosterone which might negatively affect arterial stiffness. Both men and women had reductions in MMP-2 which might reflect less repair of vascular wall extracellular matrix. COMPARISON OF ARTERIAL CHANGES INDUCED BY LONG TERM EXPOSURE TO CONFINEMENT, BED REST AND MICROGRAVITY (SPACEFLIGHT) WITH THE CARDIOVASCULAR EFFECTS OF AGING The purpose of this study was to determine how the observed changes, compare to those induced by aging in a normal population. Method: Echography was used to determine cardiovascular changes to 1.5 years confinement, 2 months of continuous head-down bed rest, and 6 months spaceflight aboard the International Space Station. Measurement was made of Left Ventricle Diastolic Volume (LVDV), Myocardium Thickness (Myoc), and Common Carotid (CC) Femoral Artery (FA) diameter and Intima media Thickness (IMT). Results were compared to published effects of normal aging on Earth. Results: With bed rest and spaceflight LVDV and Myoc were reduced (-12-15%, P<0,001). The observed CC and FA changes were similar to those seen in 30+ years of normal aging on Earth. Conclusion: Orthostatic intolerance induced by long term bed rest and spaceflight and Arterial changes observed in long term confinement, bed rest, and spaceflight, corresponded to changes similar to accelerated aging on Earth. These three environments which include reduced physical activity, change in nutritional regime and life in stressing environment may be a model to study the mechanism of aging on the vessels and to design adapted counter measures. The MARS 500 confinement study, which was designed as a ground based model for long duration manned spaceflight, found significant elevation in all subjects CIMT measurements over the course of its 520 day study. The authors speculated whether physical confinement/isolation and mental stress may have contributed to the development of increased artery intima media thickness. Studies performed in combat veterans have shown associations between increased CIMT and mental stress. Similar work has demonstrated a link between social isolation and elevated cardiovascular disease risk While there was no significant direct correlation between total spaceflight exposure and CIMT was identified, astronauts with 30-200 spaceflight days and astronauts with greater than 200 spaceflight days had significantly increased CIMT over astronauts who had never flown after adjustment for age. Astronauts with 1-29 spaceflight days and astronauts with greater than 200 spaceflight days both trended above the general population.

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Autonomic cardiovascular and respiratory control during prolonged spaceflights aboard the International Space Station Roman M. Baevsky, Victor M. Baranov, Irina I. Funtova, Andre Diedrich, Andrey V. Pashenko, Anja G. Chernikova, Jurgen Drescher, Jens Jordan, and Jens Tank Journal of Applied Physiology 2007 103:1, 156-161

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