Why is orthostatic tolerance lower in women than in men? Renal and cardiovascular responses to simulated microgravity and the role of midodrine.

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 01. 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.

Bed rest effects on human calf hemodynamics and orthostatic intolerance: a model-based analysis.

INTRODUCTION: Microgravity-induced orthostatic intolerance continues to be a primary problem after space missions. Its etiology remains uncertain despite significant research efforts over the past years. We hypothesized that calf hemodynamic parameters (compliance and resistance) are significantly affected by 14 to 16-d head-down bed rest (simulated microgravity), and their alterations play a role in the pathogenesis of orthostatic intolerance (OI) following bed rest. METHODS: To estimate these parameters, we developed a model-based approach to quantitatively simulate calf vascular response to venous occlusion, which only necessitates measurement of plethysmography data. In this study, plethysmography data were obtained from 29 subjects before and after 14-16 d of head-down bed rest. The subjects also underwent a tilt/stand test before and after bed rest. RESULTS: Statistical analyses demonstrated an increase in calf compliance (1.87 +/- 0.08, mean +/- SE, pre-bed rest; 2.16 +/- 0.10, end-bed rest) but no significant change in vascular resistance following bed rest. Compared with the tilt-intolerant subjects, those who were tilt-tolerant before bed rest had significantly higher calf compliance [2.00 +/- 0.09 (tolerant); 1.58 +/- 0.09 (intolerant)] and higher vascular resistance [7.79 +/- 0.18 (tolerant); 6.91 +/- 0.40 (intolerant)]. After bed rest, no such difference was detected. DISCUSSION: Based on these results, we validated the hypothesis that, instead of causing orthostatic intolerance, higher calf compliance before bed rest leads to recruitment of compensatory mechanisms (validated by the enhanced vascular resistance during venous occlusion) for a better toleration of orthostatic stress. With the absence of orthostatic challenge during bed rest, the difference in calf hemodynamic parameters is attenuated between the tilt-tolerant and tilt-intolerant groups.

Simulated microgravity induces microvolt T wave alternans.

BACKGROUND: There are numerous anecdotal reports of ventricular arrhythmias during spaceflight; however, it is not known whether spaceflight or microgravity systematically increases the risk of cardiac dysrhythmias. Microvolt T wave alternans (MTWA) testing compares favorably with other noninvasive risk stratifiers and invasive electrophysiological testing in patients as a predictor of sudden cardiac death, ventricular tachycardia, and ventricular fibrillation. We hypothesized that simulated microgravity leads to an increase in MTWA. METHODS: Twenty-four healthy male subjects underwent 9 to 16 days of head-down tilt bed rest (HDTB). MTWA was measured before and after the bed rest period during bicycle exercise stress. For the purposes of this study, we defined MTWA outcome to be positive if sustained MTWA was present with an onset heart rate

Readaptation from simulated microgravity as a stimulus for improved orthostatic tolerance: role of the renal, cardioendocrine, and cardiovascular systems.

BACKGROUND: Microgravity and simulated microgravity (SM) lead to important changes in orthostatic tolerance (OT), the autonomic nervous system (ANS), and the volume-regulating systems. After one is exposed to microgravity or SM, a period of readaptation to gravity is known to take place, but it is not certain if orthostatic function returns to baseline within the initial recovery and what mechanisms are involved. We hypothesized that after a period of recovery, OT, ANS, and volume-regulating systems would return to pre-SM levels. METHODS: To test this hypothesis, 24 healthy men were placed on a constant diet for 3 to 5 days, after which a tilt-stand test (pre-TST) was performed. The TST was repeated after 14 to 16 days of head-down tilt bed rest (HDTB) (post-TST) and a 3-day period of recovery (rec-TST), at which times measurements of renal, cardioendocrine, and cardiovascular systems were conducted. RESULTS: Presyncope occurred in 46% of subjects pre-TST, in 72% post-TST, and in 23% during rec-TST. OT was significantly better during the recovery period than at baseline (p = .03). There was a significant decrease in urinary sodium and potassium excretion, along with a decrease in plasma renin activity and serum and urine aldosterone compared with baseline. Serum norepinephrine and sympathetic responsiveness remained below baseline values. CONCLUSION: In summary, OT improved compared with baseline after a period of readaptation. Retention of electrolytes (sodium, potassium) could be involved. These findings indicate that recovery after SM is not simply a gradual return to baseline values but is instead a dynamic process reflecting interaction of multiple regulatory systems.

Sleep restriction does not affect orthostatic tolerance in the simulated microgravity environment.

Orthostatic intolerance (OI) is a major problem following spaceflight, and, during flight, astronauts also experience sleep restriction. We hypothesized that sleep restriction will compound the risk and severity of OI following simulated microgravity and exaggerate the renal, cardioendocrine, and cardiovascular adaptive responses to it. Nineteen healthy men were equilibrated on a constant diet, after which they underwent a tilt-stand test. They then completed 14-16 days of simulated microgravity [head-down tilt bed rest (HDTB)], followed by repeat tilt-stand test. During HDTB, 11 subjects were assigned to an 8-h sleep protocol (non-sleep restricted), and 8 were assigned to a sleep-restricted protocol with 6 h of sleep per night. During various phases, the following were performed: 24-h urine collections, hormonal measurements, and cardiovascular system identification. Development of presyncope or syncope defined OI. There was a significant decrease in time free of OI (P = 0.02) and an increase in OI occurrence (P = 0.06) after HDTB among all subjects. However, the increase in OI occurrence did not differ significantly between the two groups (P = 0.60). The two groups also experienced similar physiological changes with HDTB (initial increase in sodium excretion; increased excretion of potassium at the end of HDTB; increase in plasma renin activity secretion without a change in serum or urine aldosterone). No significant change in autonomic function or catecholamines was noted. Simulated microgravity leads to increased OI, and sleep restriction does not additively worsen OI in simulated microgravity. Furthermore, conditions of sleep restriction and nonsleep restriction are similar with respect to renal, cardioendocrine, and cardiovascular responses to simulated microgravity.

Renal, endocrine, and cardiovascular responses to bed rest in male subjects on a constant diet.

BACKGROUND: Exposure to actual and simulated microgravity induces cardiovascular deconditioning through a variety of factors. Although the mechanisms involved remain uncertain, one involves alterations in volume-regulating systems--the hypothesis being tested in this study. To maximize our ability to detect subtle changes in the volume-regulating systems, subjects were studied on a high-average salt intake to maximally suppress these systems basally. METHODS: Fourteen healthy male subjects underwent 14-day head-down tilt bed rest (HDTB) during which a constant 200 mEq sodium, 100 mEq potassium diet was maintained. Daily 24-hour urine collection was performed; plasma renin activity, serum aldosterone, plethysmography, and cardiovascular system identification were performed during a control period (pre-HDTB) and at the end of HDTB (end HDTB). RESULTS: Sodium excretion increased initially (pre-HDTB = 182.8 +/- 10.4 mEq/total volume; early HDTB = 236.4 +/- 13.0; p = .002) and then returned to baseline values. Potassium excretion increased 4 days after the initiation of HDTB and remained elevated thereafter (pre-HDTB = 82.2 +/- 2.4/total volume; mid- to late HDTB = 89.4 +/- 2.1; p = .02). Plasma renin activity increased significantly with HDTB (pre-HDTB = 1.28 +/- 0.21 ng/mL/h; end HDTB = 1.69 +/- 0.18; p = .01), but serum aldosterone did not change. A significant decrease in autonomic responsiveness and an increase in leg compliance were observed. CONCLUSIONS: We conclude that even in the presence of a high-average salt intake diet, simulated microgravity leads to renal, cardioendocrine, and cardiovascular system alterations that likely contribute to cardiovascular deconditioning.

Effects of simulated microgravity on closed-loop cardiovascular regulation and orthostatic intolerance: analysis by means of system identification.

Microgravity-induced orthostatic intolerance (OI) continues to be a primary concern for the human space program. To test the hypothesis that exposure to simulated microgravity significantly alters autonomic nervous control and, thus, contributes to increased incidence of OI, we employed the cardiovascular system identification (CSI) technique to evaluate quantitatively parasympathetic and sympathetic regulation of heart rate (HR). The CSI method analyzes second-to-second fluctuations in noninvasively measured HR, arterial blood pressure, and instantaneous lung volume. The coupling mechanisms between these signals are characterized by using a closed-loop model. Parameters reflecting parasympathetic and sympathetic responsiveness with regard to HR regulation can be extracted from the identified coupling mechanisms. We analyzed data collected from 29 human subjects before and after 16 days of head-down-tilt bed rest (simulated microgravity). Statistical analyses showed that parasympathetic and sympathetic responsiveness was impaired by bed rest. A lower sympathetic responsiveness and a higher parasympathetic responsiveness measured before bed rest identified individuals at greater risk of OI before and after bed rest. We propose an algorithm to predict OI after bed rest from measures obtained before bed rest.