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Orthostatic Intolerance Among Female Astronauts: Future Research Priorities
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The volume indifferent point: an approach for explaining orthostatic intolerance
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Graded Compression Stockings Prevent Post-spaceflight Orthostatic Hypotension
Post-spaceflight orthostatic intolerance is characterized by hypotension and presyncope in 20-30% of returning astronauts. Previous data from our laboratory suggests that this is largely a result of decreased venous return. Currently, NASA astronauts wear an anti-gravity suit (AGS) which consists of inflatable air bladders over the calves, thighs and abdomen, which are typically pressurized from 0.5 to 1.5 PSI (~27 to 78 mmHg). ISS crew members sometimes wear Russian Kentavr suits which consist of laced compression shorts and gaiters, providing ~30 mmHg nominally. While these garments are effective during reentry, there are a number of drawbacks that make them impractical for postflight use. We studied the ability of commercially available, custom fit, graded compression stockings (Jobst, 55 mmHg at ankle to 6 mmHg at top of thigh, 25 mmHg mean compression) to prevent postflight orthostatic intolerance, hypothesizing that these garments would prevent orthostatic intolerance following short duration space flight. Crew members from a single Space Shuttle flight were tilted to 80 degrees for 10 min while wearing the stockings (n=5 males) upon arrival at the clinic (~2 hrs after landing). Hemodynamic data were compared to data from all crewmembers tilted (without countermeasures) since return to flight (n=9). Two-way, repeated measures ANOVA, using the entire tilt time curve (0-10 min) show that systolic blood pressure (SBP, group effect p=0.008), stroke volume (SV, group effect p=0.003), and cardiac output (CO, group effect p=0.004) were higher in crewmembers who wore the Jobst stockings. A one-way ANOVA comparing the last minute standing also showed that SV (p=0.001) and CO (p less than 0.001) were higher and SBP tended to be higher (p=0.06) in Jobst subjects compared to controls. Control subjects had a higher rate of presyncope than Jobst subjects (3/9 vs 0/5) during the tilt on landing day. Orthostatic hypotension continues to present following spaceflight, despite fluid loading and other countermeasures. This preliminary study shows that commercially available compression stockings may ameliorate this problem. These stockings are readily available, inexpensive, and can be worn for days following landing. We have observed similar protection against orthostatic intolerance in ground-based studies of hypovolemic test subjects. Further refinements to the design and compression of the stockings are in progress.
Water drinking as a treatment for orthostatic syndromes
PURPOSE: Water drinking increases blood pressure in a substantial proportion of patients who have severe orthostatic hypotension due to autonomic failure. We tested the hypothesis that water drinking can be used as a practical treatment for patients with orthostatic and postprandial hypotension, as well as those with orthostatic tachycardia. SUBJECTS AND METHODS: We studied the effect of drinking water on seated and standing blood pressure and heart rate in 11 patients who had severe orthostatic hypotension due to autonomic failure and in 9 patients who had orthostatic tachycardia due to idiopathic orthostatic intolerance. We also tested the effect of water drinking on postprandial hypotension in 7 patients who had autonomic failure. Patients drank 480 mL of tap water at room temperature in less than 5 minutes. RESULTS: In patients with autonomic failure, mean (+/- SD) blood pressure after 1 minute of standing was 83 +/- 6/53 +/- 3.4 mm Hg at baseline, which increased to 114 +/- 30/66 +/- 18 mm Hg (P <0.01) 35 minutes after drinking. After a meal, blood pressure decreased by 43 +/- 36/20 +/- 13 mm Hg without water drinking, compared with 22 +/- 10/12 +/- 5 mm Hg with drinking (P <0.001). In patients with idiopathic orthostatic intolerance, water drinking attenuated orthostatic tachycardia (123 +/- 23 beats per minute) at baseline to 108 +/- 21 beats per minute after water drinking ( P <0.001). CONCLUSION: Water drinking elicits a rapid pressor response in patients with autonomic failure and can be used to treat orthostatic and postprandial hypotension. Water drinking moderately reduces orthostatic tachycardia in patients with idiopathic orthostatic intolerance. Thus, water drinking may serve as an adjunctive treatment in patients with impaired orthostatic tolerance.
Cardiovascular function in space flight
Changes in orthostatic heart rate have been noted universally in Soviet and U.S. crewmembers post space flight. The magnitude of these changes appears to be influenced by mission duration, with increasing orthostatic intolerance for the first 7-10 days of flight and then a partial recovery in the orthostatic heart rate response. Fluid loading has been used as a countermeasure to this postflight orthostatic intolerance. Previous reports have documented the effectiveness of this technique, but it has also been noted that the effectiveness of volume expansion diminishes as flight duration exceeds one week. The response of carotid baroreceptor function was investigated utilizing a commercially available neck collar which could apply positive and negative pressure to effect receptor stimulation. Bedrest studies had validated the usefulness and validity of the device. In these studies it was shown that carotid baroreceptor function curves demonstrated less responsiveness to orthostatic stimulation than control individuals. Twelve Space Shuttle crewmembers were examined pre- and postflight from flights lasting from 4-5 days. Plots of baroreceptor function were constructed and plotted as change in R-R interval vs. carotid distending pressure (an orthostatic stimulus). Typical sigmoidal curves were obtained. Postflight the resting heart rate was higher (smaller R-R interval) and the range of R-R value and the slope of the carotid sigmoidal response were both depressed. These changes were not significant immediately postflight (L + O), but did become significant by the second day postflight (L + 2), and remained suppressed for several days thereafter. It is hypothesized that the early adaptation to space flight involves a central fluid shift during the initial days of flight, but subsequent alterations in neural controlling mechanisms (such as carotid baroreceptor function) contribute to orthostatic intolerance.
60 Days of Head-down Bedrest Differentially Alters Venous Function in Lower and Upper Body Between Healthy Men and Women
The incidence of orthostatic intolerance after space flight is disproportionally higher in female compared to male crewmembers (83% vs. 20%). Experimental and human data suggest that the loss of orthostatic tolerance is due, at least in part, to microgravity-induced changes in venous compliance and that these changes are specific to the lower body. It is unknown however, whether the changes in venous compliance are different between males and females after space flight, and whether this is related to the disparity in orthostatic intolerance between the sexes. Using 6deg head-down bed rest (BR) as a model of space flight, we tested the following hypotheses; 1) females, compared to males, would experience a greater increase in venous compliance in dorsal foot veins as an effect of BR and 2) no differences in venous compliance would be found in dorsal hand veins between sexes and across BR days. Using 2-D ultrasound, dorsal hand (DHV) and foot vein (DFV) responses (diameter; expressed as sq mm) to 40 mmHg of congestion pressure (compliance) and to intravenous infusion of phenylephrine (PE; 3160ng/min) were determined in 10 females and 16 males before and after 60 days of BR. The relation between changes in vein diameter (in response to pressure and PE), sex, limb, and BR days were determined using a mixed-effect linear regression. It was found that after 60 days of BR, DFV dilator response to pressure was significantly greater in females and significantly less in males compared to pre-BR. As expected, there were no differences in DHV dilator response between sexes nor was there a significant difference between pre and post measures within groups. Notably, the venoconstrictor response to infusions of PE in the DHV and DFV where similar between sexes and across BR days. In conclusion, this study demonstrates that after 60 days of BR, dorsal foot veins are more compliant in women and less compliant in men. Moreover, the changes in lower body vein compliance in females do not appear to be due to changes in vasoconstrictor tone as their response to PE was preserved and similar to that in males. Taken together these data suggest that the higher incidence of orthostatic intolerance in females after space flight is due to increased venous compliance in the lower body which could translate to lower venous filling pressures and a reduced stroke volume.
Regulation of central blood volume and cardiac filling in endurance athletes: the Frank-Starling mechanism as a determinant of orthostatic tolerance
Orthostatic intolerance may result from either an abnormally large postural decrease in central blood volume, cardiac filling pressures, and stroke volume, or inadequate neurohumoral responses to orthostasis. Endurance athletes have been reported as having a high incidence of orthostatic intolerance, which has been attributed primarily to abnormalities in baroreflex regulation of heart rate and peripheral resistance. In this review, we present evidence that athletes also have structural changes in the cardiovascular system that although beneficial during exercise, lead to an excessively large decrease in stroke volume during orthostasis and contribute to orthostatic intolerance. A unifying hypothesis based on cardiac mechanics that may explain the divergence of findings in conditions such as bed rest or spaceflight, and short- and long-term endurance training is presented.
Postural Regulation of Muscle Sympathetic Nerve Activity Before and After Simulated and Actual Microgravity Deconditioning
The etiology of orthostatic intolerance after spaceflight is multifaceted. Morphological adaptations, in particular cardiac atrophy, are likely to magnify the decrease in stroke volume that occurs with reductions in cardiac filling pressure when standing. Neural adaptations may be inferred as well, as reductions in carotid-cardiac baroreflex responsiveness have been reported following bedrest deconditioning and spaceflight. Neural control of vascular resistance has not been studied directly when orthostatic intolerance is florid in the hours following spaceflight. However, the increases in systemic vascular resistance and plasma catecholamines during orthostatic stress are inappropriately low in orthostatically intolerant subjects following spaceflight, suggesting that deficits in the regulation of vascular resistance may be associated with hypoadrenergic function. The studies described in this abstract were designed to test this hypothesis.
Correlation of Space Shuttle Landing Performance with Post-Flight Cardiovascular Dysfunction
Introduction: Microgravity induces cardiovascular adaptations resulting in orthostatic intolerance on re-exposure to normal gravity. Orthostasis could interfere with performance of complex tasks during the re-entry phase of Shuttle landings. This study correlated measures of Shuttle landing performance with post-flight indicators of orthostatic intolerance. Methods: Relevant Shuttle landing performance parameters routinely recorded at touchdown by NASA included downrange and crossrange distances, airspeed, and vertical speed. Measures of cardiovascular changes were calculated from operational stand tests performed in the immediate post-flight period on mission commanders from STS-41 to STS-66. Stand test data analyzed included maximum standing heart rate, mean increase in maximum heart rate, minimum standing systolic blood pressure, and mean decrease in standing systolic blood pressure. Pearson correlation coefficients were calculated with the null hypothesis that there was no statistically significant linear correlation between stand test results and Shuttle landing performance. A correlation coefficient? 0.5 with a p<0.05 was considered significant. Results: There were no significant linear correlations between landing performance and measures of post-flight cardiovascular dysfunction. Discussion: There was no evidence that post-flight cardiovascular stand test data correlated with Shuttle landing performance. This implies that variations in landing performance were not due to space flight-induced orthostatic intolerance.
Regulation of sympathetic nervous system function after cardiovascular deconditioning
Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.
Human Research Program Human Health Countermeasures Element Cardiovascular Risks Standing Review Panel (SRP)
The Cardiovascular Risk Standing Review Panel (SRP) evaluated several cardiovascular risks associated with space flight along with the ongoing and emerging plans to study these issues and potentially propose and/or develop countermeasures. The areas of focus included: 1) The risk of cardiac rhythm problems during prolonged space flight, and 2) Issues related to the risk of orthostatic intolerance during re-exposure to gravity. An emerging area of concern is radiation associated vascular injury. The risk of cardiac rhythm disturbances has emerged based on case reports only. No systematic study of this risk has been published. However, concerns about this risk are heightened by the age range of astronauts, the structural changes in the heart that occur during space flight, and the potential shifts in fluids and electrolytes. The current plan is to use prolonged Holter monitor EKG records made as part of the "Integrated Cardiovascular SMO" in space to determine more about the frequency and magnitude of this problem and to link this data to complementary data from the nutrition group on electrolytes. The SRP was supportive of this approach. The SRP also felt that any data related to cardiovascular risk in space should be better coordinated with the medical screening data that all astronauts undergo at regular intervals. Additionally, while there are potential privacy issues related to this suggestion, many of the current barriers to better coordination of experimental and clinical data appear to reflect longstanding cultural traditions at NASA that need rethinking. The risk of orthostatic intolerance during re-exposure to gravity was seen by the SRP as an area supported by a wealth of published physiological evidence. The SRP also felt that moving forward with the planned approach to countermeasures was reasonable and that extensive additional hypothesis testing on the physiology of orthostatic intolerance was not needed at this time. There was support for developing ground based models of limited (e.g. 1/6 th) G environments on Earth that generated a number of ideas for consideration by NASA investigators.
Genetic basis of clinical catecholamine disorders
Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.
Presyncopal/Non-Presyncopal Outcomes of Post Spaceflight Stand Tests are Consistent from Flight to Flight
The overall prevalence of orthostatic hypotension after short duration (6-18 d) spaceflight is 20% with existing countermeasures. However, it is not known if the outcomes of stand tests for orthostatic tolerance are consistent within individuals on subsequent flights, or if first time fliers are more (or less) likely to experience orthostatic hypotension and presyncope than are veteran astronauts. Fifty astronauts were studied retrospectively. Stand test data, which had been collected before and after spaceflight, were compared from at least two flights for each astronaut. For twenty-five of these astronauts, their first flight in this database was also their first time to fly into space. For the remaining 25, their first flight in this database was their second, third or fourth flight, as data were available. No subject became presyncopal during preflight testing. Of the 50 subjects, 45 (90%) had the same outcome on their first and second fligh ts of this study. Of 14 subjects on whom we had data from a third mission, 12 had the same stand test outcome on all three flights (86% same outcome across three flights). There was no correlation between flight duration and orthostatic tolerance (r = 0.39). These data support the idea that astronauts are predisposed to orthostatic tolerance/intolerance after spaceflight and that this predisposition is not altered by subsequent flights. Flight durations within this data set did not alter the likelihood of orthostatic intolerance and rookie fliers were no more likely to experience orthostatic intolerance than were veteran astronauts.
Fitness, autonomic regulation and orthostatic tolerance
Work on this grant has consisted of two major studies of cardiovascular regulation in athletes along with several smaller supporting studies. This summary will give a brief overview of two major studies, and then conclude with an analysis of what the findings from these studies mean practically, and how they can be applied to current problems with post-flight orthostatic intolerance. The first study addresses a cross-sectional analysis of orthostatic intolerance in highly aerobically trained individuals; the second addresses ventricular pressure/volume relationships in athletes.
Cardiovascular function in space flight
Postflight orthostatic intolerance and cardiac hemodynamics associated with manned space flight have been investigated on seven STS missions. Orthostatic heart rates appear to be influenced by the mission duration. The rates increase during the first 7-10 days of flight and recover partially after that. Fluid loading is used as a countermeasure to the postflight orthostatic intolerance. The carotid baroreceptor function shows only slight responsiveness to orthostatic stimulation. Plots of the baroreceptor function are presented. It is concluded that an early adaptation to the space flight conditions involves a fluid shift and that the subsequent alterations in the neutral controlling mechanisms contribute to the orthoststic intolerance.
Clinical models of cardiovascular regulation after weightlessness
After several days in microgravity, return to earth is attended by alterations in cardiovascular function. The mechanisms underlying these effects are inadequately understood. Three clinical disorders of autonomic function represent possible models of this abnormal cardiovascular function after spaceflight. They are pure autonomic failure, baroreflex failure, and orthostatic intolerance. In pure autonomic failure, virtually complete loss of sympathetic and parasympathetic function occurs along with profound and immediate orthostatic hypotension. In baroreflex failure, various degrees of debuffering of blood pressure occur. In acute and complete baroreflex failure, there is usually severe hypertension and tachycardia, while with less complete and more chronic baroreflex impairment, orthostatic abnormalities may be more apparent. In orthostatic intolerance, blood pressure fall is minor, but orthostatic symptoms are prominent and tachycardia frequently occurs. Only careful autonomic studies of human subjects in the microgravity environment will permit us to determine which of these models most closely reflects the pathophysiology brought on by a period of time in the microgravity environment.
Baroreflex Function in Rats after Simulated Microgravity
Prolonged exposure of humans to decreased gravitational forces during spaceflight results in a number of adverse cardiovascular consequences, often referred to as cardiovascular deconditioning. Prominent among these negative cardiovascular effects are orthostatic intolerance and decreased exercise capacity. Rat hindlimb unweighting is an animal model which simulates weightlessness, and results in similar cardiovascular consequences. Cardiovascular reflexes, including arterial and cardiopulmonary baroreflexes, are required for normal adjustment to both orthostatic challenges and exercise. Therefore, the orthostatic intolerance and decreased exercise capacity associated with exposure to microgravity may be due to cardiovascular reflex dysfunction. The proposed studies will test the general hypothesis that hindlimb unweighting in rats results in impaired autonomic reflex control of the sympathetic nervous system. Specifically, we hypothesize that the ability to reflexly increase sympathetic nerve activity in response to decreases in arterial pressure or blood volume will be blunted due to hindlimb unweighting. There are 3 specific aims: (1) To evaluate arterial and cardiopulmonary baroreflex control of renal and lumbar sympathetic nerve activity in conscious rats subjected to 14 days of hindlimb unweighting; (2) To examine the interaction between arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in conscious hindlimb unweighted rats; (3) to evaluate changes in afferent and/or central nervous system mechanisms in baroreflex regulation of the sympathetic nervous system. These experiments will provide information related to potential mechanisms for orthostatic and exercise intolerance due to microgravity.