Abstract
Background Exposure to microgravity induces cardiovascular deconditioning, manifested by orthostatic intolerance (OI). We assessed the renal, cardioendocrine, and cardiovascular responses of women and men to simulated microgravity to examine the impact of gender on OI.
Methods Fifteen healthy female and 14 healthy male subjects were given a constant diet for 3 to 5 days, after which they underwent a tilt-stand test (pre-TST) and began 14 to 16 days of head-down tilt bed rest (HDTB), followed by a repeat tilt-stand test (post-TST). Female subjects began HDTB so that the post-TST was at the same time in their menstrual cycle as their pre-TST. Twenty-four-hour urine collections (daily), hormonal measurements, plethysmography, and cardiovascular system identification were performed.
Results The times to presyncope were significantly different for men and women before (p = .005) and after HDTB (p = .001), with all of the women but only 50% of the men experiencing presyncope during the pre-TST (p = .002) and all of the women but only 64% of the men experiencing presyncope during the post-TST. At baseline, the following differences between women and men were observed: women had higher serum aldosterone levels (p = .02), higher parasympathetic responsiveness (p = .01), lower sympathetic responsiveness (p = .05), and lower venous compliance (p = .05). Several parameters changed with HDTB in both men and women. In a double-blinded randomized trial, midodrine (5 mg orally) or placebo given to female subjects 1 hour before post-TST was ineffective in preventing OI.
Conclusion In conclusion, the frequency of OI is higher in women than in men and is not modified by midodrine at the dose used. This increased susceptibility is likely secondary to intrinsic basal differences in the activity of volume-mediated parasympathetic and adrenergic systems and in venous tone. Thus, approaches to reduce OI in women are likely to differ from those effective in men.
Postspaceflight orthostatic intolerance (OI) is a problem known to affect both male and female astronauts.1Several reports have suggested that women are less tolerant than men of orthostatic stress at baseline,2-9after simulated microgravity,10and after spaceflight,11,12although some investigators reported no difference to orthostatic challenge or lower-body negative pressure (LBNP).13,14
A few reports have explored the possible etiology of gender differences in the response to orthostatic stress. They suggested as possible culprits decreased catecholamine responsiveness,2,12,13lower plasma volume,2,12greater pooling of blood in the pelvic region,15impaired vasoconstriction,10decreased cardiac filling,5greater thoracic impedance,16greater parasympathetic dominance,10,17lower heart rate (HR) response to baroreflex stimulation,2and lower mean arterial pressure (MAP) response18in women. Others also reported that women tend to have a greater increase in HR during orthostatic challenge.7However, leg mass and leg venous compliance are not thought to be involved.7,19,20Overall, these findings suggest that several systems may be implicated in a poorer orthostatic tolerance in women.
In an effort to better understand the impact of gender on orthostatic tolerance and the responses to simulated microgravity, we performed identical studies in men and women in the controlled environment of a general clinical research center using standard simulated microgravity; providing a controlled diet; and, in women, taking account of the time of the menstrual cycle when measuring renal, endocrine, and cardiovascular responses to a standard tilt-stand test (TST). Our goals were to study (1) gender differences in orthostatic stress at baseline and after simulated microgravity; (2) the impact of gender on the cardiovascular, renal, and cardioendocrine responses to simulated microgravity; and (3) the efficacy of midodrine as a countermeasure for OI in female subjects after simulated microgravity, the efficiency of which has been demonstrated in the male population.21Related to those aims, we hypothesized that (1) tolerance to orthostatic stress after simulated microgravity would be lower in women than in men, (2) women and men would experience similar changes in physiologic variables with simulated microgravity, and (3) midodrine would be as effective in women as in men as a countermeasure for OI after simulated microgravity.
METHODS
Subjects
Fifteen healthy female subjects (age 29 ± 2 years; weight 61 ± 2 kg) and 14 healthy male subjects (age 38 ± 3 years; weight 79 ± 3 kg) were recruited for the study. Screening procedures included a history and physical examination, 12-lead electrocardiogram, complete blood count with differential, chemistry profile, thyroid function tests, urinalysis, toxicology screen, β-human chorionic gonadotropin (in females), and psychological evaluation. Subjects were nonsmokers and receiving no medication before enrolment in the study. The exclusion criteria included a history or evidence of hypertension, coronary artery disease, diabetes, renal insufficiency, thyroid disease, hepatitis, anemia, current pregnancy, psychiatric disorder, and alcohol or drug abuse. Additional exclusion criteria included known sleep disorders, shift work, and transmeridian travel within the 6 months prior to the study. None of the subjects had a history of syncopal disorder. Female subjects were required to have been off oral or injected contraceptive agents for 6 months before the beginning of the experiment. None of the female subjects were pregnant during conduction of the studies.
PROTOCOL
The female and male subjects were studied on two similar protocols, each consisting of two phases (Figure 1). Phase I took place before head-down tilt bed rest (pre-HDTB) and consisted of an equilibration period during which subjects were admitted to the General Clinical Research Center at Brigham and Women's Hospital and maintained on an isocaloric diet containing 200 mEq of sodium, 100 mEq of potassium, 1,000 mg of calcium, and 2,500 mL of fluid. At the end of phase I, different physiologic measurements were made, including the tilt-stand test (pre-TST). In women, the last day of phase I corresponded to day 22 of the menstrual cycle. The male subjects immediately entered phase II, a 14- to 16-day period of 4° HDTB. Bed rest was initiated at 3:00 pm on the last day of pre-HDTB after the tilt-stand test (pre-TST) and ended on day 14 or 16 at 10:00 am with the post-HDTB tilt-stand test (post-TST). Conversely, the female subjects went home and returned on the following menstrual cycle for the 14- to 16-day period of HDTB, which also ended on day 22 of the menstrual cycle with repeat TST (post-TST). In women, HDTB was preceded by 3 days of reequilibration on the constant diet, with bed rest initiated at 3:00 pm on the third day after admission and ending on day 16 (corresponding to day 22 of the menstrual cycle) at 10:00 am with the post-HDTB tilt-stand test (post-TST). Sleep-wake cycles remained constant throughout the study, with 8 hours of sleep each day between 10:00 pm and 6:00 am. Room temperature was maintained between 21 and 22°C. Subjects were confined to bed for the entire HDTB period. They were allowed to lie on their sides, back, or front. They voided and defecated in the supine position. They ate their meals while lying on their sides, propped up on one elbow. No medications, smoking, alcohol, or caffeine was allowed during the study. The study protocol was approved in advance by the Institutional Review Board of the Brigham and Women's Hospital. Each subject provided written informed consent before participating in the study.
RANDOMIZED CONTROLLED TRIAL: MIDODRINE
Midodrine, an α1-agonist, was studied as part of this investigation to assess its role as a countermeasure for OI in female subjects after simulated microgravity. Midodrine is known to increase arteriolar and venous tone through its active metabolite, desglymidodrine. Midodrine was given in a double-blinded, randomized, controlled trial versus placebo in female subjects 1 hour before post-TST. The results were compared with those of the previously published study in males that used an identical protocol.21
Tilt-Stand Tests
Pre-TST was performed at 10:00 am in both groups on the last day of pre-HDTB (phase I) and at the end of HDTB during post-TST (phase II) with a motorized tilt table (model 9607, American Echo, Kansas City, MO). Subjects were tilted to the upright position with 10-minute stops at 30°, 60°, and 90°, during which hemodynamic, hormonal, and autonomic measurements were taken (see the following section). The period on the tilt table was followed by an active period of standing for 120 minutes. Nontolerance to TST was defined as clinical signs of OI (diaphoresis, nausea, lightheadedness, or dizziness) accompanied by a decrease in systolic blood pressure (SBP) > 20 mm Hg below baseline or an increase in HR > 20 beats per minute above baseline. If subjects showed signs of nontolerance, they were returned to the supine position.
Measurements
Cardiovascular System Identification
Before TST and at 30°, 60°, and 90° of tilt, data were recorded for cardiovascular system identification (CSI) analysis. Subjects were instrumented for continuous noninvasive monitoring of arterial blood pressure (ABP) (Portapres, TNO, Amsterdam, The Netherlands, or Finapres, Ohmeda, Englewood, CO), instantaneous lung volume (ILV; Respitrace System, Ambulatory Monitoring Systems, Ardsley, NY), and HR (surface electrocardiogram). During data collection, the subjects were instructed to breathe in response to auditory tones spaced at random intervals ranging from 1 to 15 seconds, with a mean of 5 seconds. They controlled their own tidal volume to maintain normal ventilation. This random breathing protocol excites a broad range of frequencies, thereby facilitating system identification.22Previous work indicates that random-interval breathing does not have a measurable effect on autonomic function.22Data on ABP, ILV, and HR collected while the subjects were in supine and upright postures were saved for later CSI analysis (Appendix).23,24
Plethysmography
During pre-HDTB and at the end of HDTB on the days before the orthostatic testing, venous occlusion plethysmography with multiple proximal occlusion pressures was used to obtain calf-compliance measurements.25A strain gauge (EC5R Plethysmograph, Hokanson, Bellevue, WA) was placed around the calf at its maximal circumference. External pressure was applied on the thigh through an occlusion cuff, which was attached to an electronically controlled air pump. Pressure levels of 30, 40, and 50 mm Hg were delivered consecutively after having reached a steady state at the previous level. Venous compliance corresponds to the ratio of the change in calf volume over the change in external pressure.
Hemodynamic, Renal, and Cardioendocrine Measurements
SBP, diastolic blood pressure (DBP), MAP, and HR were recorded by an indirect sphygmomanometer at 6:00 am, 2:00 pm, and 10:00 pm on all study days. Body weight was determined every morning at 6:00 am following a morning void (subjects remained supine during HDTB). The 24-hour urine samples were collected by voluntary micturition for measurements of daily urine volume, sodium, potassium, aldosterone, cortisol, chloride, and creatinine excretion. Blood samples were collected at 6:00 am from a peripheral venous catheter after the subject had remained supine overnight on the last day of the pre-HDTB ambulatory baseline period and at the completion of HDTB for measurement of plasma renin activity (PRA), aldosterone, creatinine, sodium, potassium, cortisol, epinephrine, norepinephrine, and estradiol and progesterone for female subjects.
Laboratory Analysis
Blood samples were collected on ice, and the serum or plasma was frozen until assayed. Sodium and potassium levels in serum and urine were measured with the AVL 987-S Electrolyte Analyzer (AVL Scientific Corporation, Roswell, GA). The analyzer uses flame photometry, with lithium as an internal standard. A Beckman Creatinine Analyzer 2 (Beckman Instruments, Fullerton, CA) was used to measure creatinine concentrations in serum and urine. Cortisol in plasma and urine was measured with the Beckman Access Immunoassay (Beckman Instruments, Fullerton, CA). PRA was measured with a GammaCoat Plasma Renin Activity 125I radioimmunoassay (RIA) kit (DiaSorin, Stillwater, MN). The method used for measuring aldosterone was the DPC Coat-A-Count RIA procedure (Diagnostic Products, Los Angeles, CA). Estradiol was measured by an RIA double antibody (DPC Diagnostic Products, Los Angeles, CA) and luteinizing hormone (LH) and follicle-stimulating hormone (FSH), by chemiluminescence (Beckman, Chaska, MN).
Statistical Analysis
The raw data were examined for outliers and validity. Means and standard errors were used to describe the data at baseline and at the end of HDTB. The main analytic tools were the paired t-test for within-gender comparisons and the independent sample t-test for between-gender comparisons because normality was not rejected. Because the sample sizes were relatively small, the comparisons were repeated with rank methods without contradictions. The log-rank test was used to compare groups in terms of time to event, the exact McNemar test was used for within-subjects comparisons of OI, and the Wilcoxon signed rank test was used for within-subjects comparisons of time until OI. In addition, the rate of change during orthostatic challenge was reported as the linear regression coefficient using data through 20 minutes. The rates of change were summarized using the median and the interquartile range, and the groups were compared by the Wilcoxon rank sum test.
RESULTS
General Characteristics
In this study, female subjects were younger than male subjects (29 ± 2 vs 38 ± 3 years; p = .01). Both women and men experienced a significant decrease in weight with HDTB (females: δ = −0.9 ± 0.2 kg; p = .003; males: δ = −0.9 ± 0.2; p = .001). As expected, weights were different with regard to sex at baseline (p < .0001) and after HDTB (p < .0001).
Gender and Orthostatic Tolerance
None of the female subjects successfully completed the TST pre-HDTB (Figure 2), a result significantly different from that of male subjects, 50% of whom experienced OI at baseline (pre-TST) (p = .002). After HDTB, all female subjects also experienced OI. The time to presyncope was shorter after HDTB relative to baseline by an average of 6.5 minutes (p = .02) for females who did not receive midodrine. The times to presyncope were significantly different for men and women before (p = .005) and after HDTB (p = .001).
Gender and Electrolytes and Volume Regulation
Sodium
There was no significant difference in serum sodium levels between genders at baseline. Serum sodium levels did not change significantly with HDTB in females and males (Figure 3A).
Urinary sodium excretion was not significantly different between genders at baseline. Both women (p = .006) and men (p = .002) experienced a significant increase in sodium excretion on the first day of HDTB (Figure 3B). After this initial peak, sodium excretion returned to baseline values in both groups.
Urine volume was not significantly different between genders at baseline. Men experienced a significant increase in urinary volume excretion at the beginning of HDTB (358 ± 166 mL; p = .05), which was not seen in women (−168 ± 112; p = .16), a response that differed between genders (p = .03). Toward the end of HDTB, men still had a higher volume excretion compared with that at baseline (368 ± 125; p = .01), a difference not seen in women (−22 ± 122; p = .86).
Potassium
There was a trend for lower serum potassium levels at baseline in women (p = .11) (Figure 4A). Serum potassium levels significantly decreased with HDTB in women (p = .03) but not in men (p = .66) and were significantly lower after HDTB in women than in men (p = .002) (see Figure 4A).
Urinary potassium excretion was not significantly different at baseline between genders (Figure 4B). A significant increase in potassium excretion on the first day of HDTB was seen in both women (p = .04) and men (p = .01). This increase in potassium excretion was still seen at the end of HDTB in both men and women (women: p = .002; men: p = .002). The two groups did not differ in the responses to HDTB.
Renin-Angiotensin-Aldosterone System and Other Hormonal Systems
PRA was not different between genders at baseline (Figure 5A). Both women (p = .02) and men (p = .009) experienced a significant increase in PRA with HDTB. PRA was not significantly different between genders after HDTB.
Aldosterone was significantly greater in women than in men at baseline (p = .02) (Figure 5B). There was a trend for aldosterone to increase with HDTB in women (p = .08) but not in men (p = .22). After HDTB, serum aldosterone remained higher in women than in men (p = .005) (see Figure 5B).
Urinary aldosterone secretion was not different between genders at baseline. Women experienced a trend toward an increase in urinary aldosterone excretion on the first day of HDTB (p = .08), a response not seen in men (p = .32). Furthermore, females demonstrated a continued higher urinary excretion of aldosterone compared with baseline (end vs baseline; p = .0001), a response that was different from that in men, who did not experience a change in urinary aldosterone excretion at the end of HDTB (p = .69) (Figure 5C).
The serum cortisol level was not significantly different between genders before or after HDTB and did not significantly change with HDTB in either group (Figure 6A). Urinary cortisol excretion was not significantly different between genders at baseline. Men (p = .008) but not women (p = .25) had a significant increase in urinary cortisol excretion on the first day of HDTB (Figure 6B). In both men and women, urinary cortisol excretion was not significantly different from baseline at the end of HDTB (see Figure 6B).
There were no significant changes or differences in LH, FSH, or estradiol in women pre-TST versus post-TST, suggesting that the testing was performed at the same time of the menstrual cycle.
Gender and Cardiovascular Measures
Hemodynamic Parameters
Before and after HDTB, men had higher SBP, DBP, and MAP than women, along with a trend for a lower HR at baseline (Table 1). HDTB did not significantly affect the SBP, DBP, MAP, or HR in either men or women. No significant differences were demonstrated in the rate of change of SBP, DBP, and HR with orthostatic challenge (Table 2).
Cardiovascular System Identification
At baseline, women had a lower sympathetic responsiveness in the supine position and a higher parasympathetic responsiveness in the upright position at baseline than did men (Table 3). After HDTB, they had a higher parasympathetic responsiveness in the supine and upright positions than did men (see Table 3). Women did not experience significant changes in sympathetic and parasympathetic responsiveness with HDTB, and no significant differences were seen in the way men and women responded to HDTB.
Leg Venous Compliance
Leg venous compliance was significantly lower in women than in men (Table 4). There was no significant change in leg venous compliance with HDTB in women (p = .91), although there was a trend toward an increase in venous compliance in men with HDTB (p = .07). After HDTB, leg venous compliance remained different in men and women, with women having lower venous compliance.
Testing of a Countermeasure for OI in Women: Role of Midodrine
Figure 7 demonstrates the effect of midodrine versus placebo on OI after simulated microgravity. No significant difference in time to syncope was found among female subjects who received midodrine versus those who received placebo (p = .70). No significant difference was detected in the change in time to syncope from pre-TST to post-TST between subjects who received midodrine and those who received placebo (p = 1.0). However, at 10 minutes into the post-TST, there was a trend for a delay in syncope among subjects in the midodrine group (p = .06).
DISCUSSION
In the present study, we demonstrated that (1) women's orthostatic tolerance is poorer than that of men at baseline and after simulated microgravity; (2) physiologic differences exist in the renal, cardioendocrine, and cardiovascular systems between genders, differences that may be involved in the poorer orthostatic outcomes among women; and (3) in contrast to the substantial differences in response to orthostatic tolerance testing, the overall responses to the simulated microgravity between women and men demonstrate minimal differences, except for aldosterone and potassium responses. As part of this investigation, we also conducted a randomized double-blinded trial of the use of midodrine (5 mg orally) as a countermeasure for OI. We could not demonstrate a benefit in preventing OI at this dose in the female population after a period of simulated microgravity. Thus, only one of our three prestudy hypotheses was confirmed.
Why Is Orthostatic Tolerance Lower in Women?
In the present study, women experienced a lower orthostatic tolerance before and after simulated microgravity exposure. Furthermore, all women experienced presyncopal symptoms with the TST protocol used in this study during the two testing sessions (pre- and post-HDTB). Why is this? The present studies demonstrated the presence of the following physiologic factors differentiating women and men: higher parasympathetic responsiveness, lower sympathetic responsiveness, lower venous compliance, higher serum aldosterone levels, and lower serum potassium levels. In the present study, the female subjects also were younger and weighed less than their male counterparts.
The role of autonomic function in OI cannot be ignored. Several groups reported autonomic function as an important contributor in both men11,26-31and women.2,10,12,13,17 From this study, we can state that women seem to have a lower sympathetic responsiveness in the supine position but, as important, a greater parasympathetic responsiveness in the upright position. After HDTB, women demonstrated a higher parasympathetic responsiveness in both the supine and upright positions. Other investigators have also reported a greater parasympathetic dominance in women.10,17The vasovagal syncope is known to be made up of two components: vasodilation and inappropriate bradycardia leading to hypotension and loss of consciousness.32It is generally believed that vasodilation is mediated by sympathetic withdrawal and that bradycardia is mediated by increased parasympathetic activity.32During orthostatic stress, the HR is usually higher among women than men, and MAP may be well maintained until some minutes before the onset of presyncope. Although it is recognized that not all subjects develop bradycardia at the onset of presyncope (with some subjects maintaining a high HR), findings from the present study suggest that a high parasympathetic influence with bradycardia is likely to contribute to the presyncopal pattern seen in this female group.
It is interesting that leg mass and leg venous compliance have been reported as not likely to be involved in the gender differences in OI.7,19,20However, we demonstrated a lower leg venous compliance in female subjects, a finding supported by a study by Monahan and Ray.20Hence, our proposed model,30by which a greater leg venous compliance would lead to an activation of compensatory systems (sympathetic nervous system, renin-angiotensin-aldosterone system [RAAS]) and down-regulation of the parasympathetic nervous system for daily postural challenges and hence confer protection for orthostatic stresses (and vice versa for subjects with lower venous compliance), seems to hold true for women. To reiterate, women, whose venous compliance is lower than that of men, also seem to be at higher risk of OI. Furthermore, women do not seem to demonstrate an “up-regulation of compensatory systems” and rather rely on a dominant parasympathetic and lower sympathetic responsiveness. However, one problem remains related to the proposed model: the RAAS.
The present study was carried out during the luteal phase of the menstrual cycle. In this study, lower orthostatic tolerance (women) was seen in conjunction with higher aldosterone. Two views offer themselves as to the relevance of this as a contributor to OI. A practical explanation would be a chronically lower plasma blood volume, reported by other investigators,2,12which would lead to an up-regulation of the RAAS. This is not likely to be the case because the PRA was not increased, which it should have been if the difference in plasma volume were the explanation. However, the dissociation in PRA and aldosterone is intriguing and raises the possibility that as yet an unidentified factor stimulates aldosterone in women in the present study. If this is correct, then one would observe two other changes secondary to a primary effect to aldosterone: an unchanged or decreased PRA and a lower potassium level in women compared with men. This is what was observed. One possible consequence of this could be altered vascular reactivity secondary either to increased aldosterone or lower potassium levels, which has been documented.33
Chidambaram and colleagues explored another explanation relating aldosterone and orthostatic tolerance.34They studied women's orthostatic tolerance (measured with LBNP) over the two phases of the menstrual cycle, the follicular and the luteal phases. They noted that despite higher aldosterone levels during the luteal phase, women experienced lower tolerance to LBNP at that time. It is known that angiotensin II and PRA are elevated during the luteal phase,35-37probably owing to the effect of estrogen on translational regulation of angiotensinogen expression.38In the same investigation, Chidambaram and colleagues demonstrated, by angiotensin II blockade, a “blunting” of the system response at the tissue level, despite elevations in RAAS components. However, this should produce results opposite to those observed in the present study.
Responses to Bed Rest
We previously demonstrated in healthy male subjects that simulated microgravity leads to early loss of sodium, reestablishment of sodium balance through an activation of the RAAS (but dissociation of the aldosterone response), and a continued loss of potassium.39The same findings were seen in the female population, but in women, bed rest also led to a significant reduction in serum potassium and an increased aldosterone response. The potassium and aldosterone responses are tightly linked; the lower serum potassium seen with HDTB in female subjects is most likely secondary to the elevated aldosterone. In women, aldosterone is known to increase during the luteal phase,34an increase mediated by estrogen.38With HDTB, a significant increase in the urinary excretion of aldosterone was seen in women, with a trend to an increase in serum aldosterone, both of which could explain the decrease in serum potassium. Although we found no significant changes in the impact of gender on the autonomic and leg venous compliance to simulated microgravity, these parameters did not change significantly in either group with HDTB. We believe that this is related to the smaller size of each group than in the previous study.31
Effect of Midodrine
Our group previously reported the efficacy of midodrine in preventing post-simulated microgravity OI in male subjects.21In this study, a 5 mg dose of midodrine did not prevent post-simulated microgravity OI in female subjects. In an effort to mimic the postspaceflight tests done in astronauts, we performed another analysis 10 minutes into the TST and determined that this drug might have an early positive effect in preventing or delaying the presyncopal symptoms in the early part of the orthostatic test. However, the overall failure of midodrine to prevent presyncope in this study could be related to the high prevalence of OI at baseline in our subjects and possibly the use of a dose too low for female subjects. With such a severe problem at baseline, compounded by the deconditioning effects of simulated microgravity and possibly changes in receptor sensitivity in females during simulated microgravity (as demonstrated by Chidambaram and colleagues,34this countermeasure may not be sufficient to prevent OI postspaceflight. Further studies will be needed to evaluate a higher dose of the drug, for example, 10 mg versus the 5 mg used in the present study.
Limitations
The female subjects were younger than the male subjects because of the exclusion criteria, a difference that could have important implications for orthostatic tolerance. Furthermore, no TST was performed on the screening day, which could have eliminated some subjects more at risk of presyncopal episode. It is also worthy of mention that the present study did not seek to evaluate the effect of the menstrual cycle on orthostatic tolerance but rather to study the effect of microgravity on orthostatic tolerance in women, controlling for the menstrual cycle. Hence, the question as to whether the menstrual cycle alters orthostatic function was not addressed in this investigation.
CONCLUSIONS
The present study aimed at studying the impact of gender on the renal, cardioendocrine, and cardiovascular responses to simulated microgravity, focusing on OI and testing the countermeasure midodrine for OI in female subjects. This study provided stable dietary and environmental conditions to assess the above systems and used a long-duration TST to evaluate orthostatic function. We conclude that (1) women have a poorer tolerance to orthostatic stress than do men; (2) factors most likely implicated in the increased OI in women include a higher parasympathetic responsiveness, a lower venous compliance, and higher aldosterone and lower potassium levels; and (3) in contrast to men, in women, midodrine, at a dose of 5 mg, is not an efficient countermeasure for post-simulated microgravity OI.
Appendix
CSI evaluates interactions between physiologic signals (HR, ABP, and ILV) on a second‐to‐second basis to enable dynamic assessment of physiologic mechanisms. CSI generates a closed‐loop model of cardiovascular regulation specific for the individual subject at the time of signal collection. The model characterizes the dynamic coupling between physiologic signals in terms of impulse response functions. These couplings include the HR baroreflex (the autonomically mediated baroreflex coupling between fluctuations in ABP and fluctuations in HR), respiration‐induced HR variability (ILV→HR: the autonomically mediated coupling between respiration and HR), the mechanical effects of respiration on ABP owing to the alterations in venous return and the filling of intrathoracic vessels and heart chambers associated with the changes in intrathoracic pressure (ILV→ABP), and circulatory mechanics (the relationship between cardiac contraction and the generation of the ABP waveform).23,24 The impulse response functions are obtained by solving a set of causal autoregressive moving average equations relating the noninvasively measured signals. The model orders of these equations are determined using a parameter reduction algorithm in conjunction with Rissanen's minimum description length criterion.40
Because the HR baroreflex and ILV→HR couplings are regulated by the autonomic system, the features of these impulse responses reflect the autonomic responsiveness. CSI may also be used to quantify the parasympathetic responsiveness and the sympathetic responsiveness separately based on analysis of the ILV→HR impulse response function. Xiao and colleagues validated this approach using animal and human data.31 Sympathetic and parasympathetic responsiveness are unitless.