Pathophysiology of orthostatic hypotension after bed rest: paradoxical sympathetic withdrawal

Although orthostatic hypotension is a common clinical syndrome after spaceflight and its ground-based simulation model, 6 degrees head-down bed rest (HDBR), the pathophysiology remains unclear. The authors' hypothesis that a decrease in sympathetic nerve activity is the major pathophysiology underlying orthostatic hypotension after HDBR was tested in a study involving 14-day HDBR in 22 healthy subjects who showed no orthostatic hypotension during 15-min 60 degrees head-up tilt test (HUT) at baseline. After HDBR, 10 of 22 subjects demonstrated orthostatic hypotension during 60 degrees HUT. In subjects with orthostatic hypotension, total activity of muscle sympathetic nerve activity (MSNA) increased less during the first minute of 60 degrees HUT after HDBR (314% of resting supine activity) than before HDBR (523% of resting supine activity, P < 0.05) despite HDBR-induced reduction in plasma volume (13% of plasma volume before HDBR). The postural increase in total MSNA continued during several more minutes of 60 degrees HUT while arterial pressure was maintained. Thereafter, however, total MSNA was paradoxically suppressed by 104% of the resting supine level at the last minute of HUT (P < 0.05 vs. earlier 60 degrees HUT periods). The suppression of total MSNA was accompanied by a 22 +/- 4-mmHg decrease in mean blood pressure (systolic blood pressure <80 mmHg). In contrast, orthostatic activation of total MSNA was preserved throughout 60 degrees HUT in subjects who did not develop orthostatic hypotension. These data support the hypothesis that a decrease in sympathetic nerve activity is the major pathophysiological factor underlying orthostatic hypotension after HDBR. It appears that the diminished sympathetic activity, in combination with other factors associated with HDBR (e.g., hypovolemia), may predispose some individuals to postural hypotension.     

'Neutral point titration': cardiovascular regulation during combined (LBNP/HDT vs. LBPP/HUT) stimulation

This study was undertaken to identify combinations ('neutral points', NP) of orthostatic (tilt: head-down = HDT, head-up = HUT) and pseudo-orthostatic (lower body pressure: positive = LBPP, negative = LBNP) stimuli able to compensate one another in their effect on hemodynamic variables, electrical thoracic impedance (TI), hematocrit and plasma mass density (PD), and blood hormone concentrations. We asked if NP's exist for tested variables (hypothesis 1), if NP's differ with variables (hypothesis 2), and if NP's change as a function of time (hypothesis 3). For the blood volume sensitive variables (PD, plasma total protein concentration, and hematocrit) we found a NP at > or = 30 degrees HDT at LBNP-35 and -15 degrees HUT with LBPP+35. There was no clear PD / total plasma protein concentration effect with various degrees of LBNP-15 / HDT. NP's could be derived for some hemodynamic variables: With LBNP-35, a NP for heart rate was derived at -25 degrees HDT and for MAP at -30 degrees HDT. Heart rate intersected at > or = 30 degrees HDT with LBNP-15 (extrapolated), stroke volume index (SVI) at -20 degrees HDT. With LBPP+35, SVI had its NP at 11 degrees HUT. The hormonal responses displayed a pattern where plasma renin activity (PRA) NP's were logically scattered with LBNP intensity, whereas aldosterone displayed similar NP's with both LBNP intensities.     

Hemodynamic consequences of rapid changes in posture in humans.

Tolerance to +G(z) gravitational stress is reduced when +G(z) stress is preceded by exposure to hypogravity (fraction, 0, or negative G(z)). For example, there is an exaggerated fall in eye-level arterial pressure (ELAP) early on during +G(z) stress (head-up tilt; HUT) when this stress is immediately preceded by -G(z) stress (head-down tilt; HDT). The aims of the present study were to characterize the hemodynamic consequences of brief HDT on subsequent HUT and to test the hypothesis that an elevation in leg vascular conductance induced by -G(z) stress contributes to the exaggerated fall in ELAP. Young healthy subjects (n = 3 men and 4 women) were subjected to 30 s of 30 degrees HUT from a horizontal position and to 30 s of 30 degrees HUT when HUT was immediately preceded by 20 s of -15 degrees HDT. Four bouts of HDT-HUT were alternated between five bouts of HUT in a counterbalanced designed to minimize possible time effects of repeated exposure to gravitational stress. One minute was allowed for recovery between tilts. Brief exposure to HDT elicited an exaggerated fall in ELAP during the first seconds of the subsequent HUT (-17.9 +/- 1.4 mmHg) compared with HUT alone (-12.4 +/- 1.2 mmHg, P <0.05) despite a greater rise in stroke volume (Doppler ultrasound) and cardiac output over this brief time period in the HDT-HUT trials compared with the HUT trials (thereafter stroke volume fell under both conditions). The greater fall in ELAP was associated with an exaggerated increase in leg blood flow (femoral artery Doppler ultrasound) and was therefore largely (70%) attributable to an exaggerated rise in estimated leg vascular conductance, confirming our hypotheses. Thus brief exposure to -G(z) stress leads to an exaggerated fall in ELAP during subsequent HUT, owing to an exaggerated increase in estimated leg vascular conductance.     

Effect of posture on arterial baroreflex control of heart rate in humans

Altered baroreflex function may contribute to the cardiovascular changes associated with weightlessness. Since central blood volume (CBV) increases during simulated weightlessness we have examined the possibility that acute changes in CBV may modify baroreceptor function. We used graded head-up tilt (HUT) and head-down tilt (HDT) to induce changes in CBV, and neck suction to stimulate carotid baroreceptors, in 6 subjects. The increase in pulse interval induced by a negative pressure of 8.2 kPa (62 mm Hg) imposed for 10 s while supine was compared with the increase while tilted for 8 min at +/- 15 degrees, +/- 30 degrees and +/- 45 degrees. During HDT at 15 degrees the pulse interval over the first 5 cardiac cycles following suction onset was 51 +/- (SEM) 18 ms longer (p less than 0.05), at 30 degrees it was 61 +/- 20 ms longer (p less than 0.05), and at 45 degrees it was 74 +/- 35 ms longer (p less than 0.01), compared with supine. During HUT at 15 degrees the pulse interval was 25 +/- 9 ms shorter (p less than 0.05) than when supine, but was not significantly different at 30 degrees and 45 degrees. These responses occurred independently of changes in brachial blood pressure. Attenuation was also observed after 5 min (56 +/- 17 ms; less than 0.05), and after 40 min (25 +/- 9 ms; p less than 0.05) of 60 degrees HUT compared with supine. We conclude that posture does modify arterial baroreflex control of heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular and hormonal changes with different angles of head-up tilt in men

The purpose of this study was to assess the endocrine status, thoracic impedance, blood concentration, and hemodynamic dose-responses using different angles of passive head-up tilt (HUT) ranging from 12 degrees to 70 degrees in the same subjects. Measurements were performed during 20 min supine position (pre-HUT), 30 min upright (HUT12, HUT30, HUT53, or HUT70), and 20 min supine (post-HUT); subjects 70 min in the supine position only (HUT0) served as resting controls. Norepinephrine increased above resting control values by 19, 44, 80, and 102%; epinephrine by 30, 41, 64, and 68%; aldosterone by 29, 62, 139, and 165%; plasma renin activity n. s., 41, 91, and 89%; vasopressin n.s., 27, 47, and 59%; thoracic bioimpedance n. s., 8, 13, and 16%; heart rate n. s., 5, 26, and 45%, and mean arterial pressure n. s., 5, 7, and 10%; at min 27 of HUT12, HUT30, HUT53, and HUT70, respectively. Pulse pressure decreased with HUT53 and HUT70 by 4 and 10%. Hematocrit increased by 0.2, 1.7, 6.3, and 7.2%, respectively. Blood density increased by 2.3 and 3.0 g/l, plasma density by 1.7 and 1.8 g/l with HUT53 and HUT70. After finishing HUT, heart rate fell to values which stayed below pre-HUT, and also below resting control levels for > or = 5 min ("post-orthostatic bradycardia") even after the lowest orthostatic load (HUT12). Thoracic impedance and arterial pressure remained increased after terminating HUT30, HUT53, and HUT70. In conclusion, passive orthostatic loading of different extent produces specific dose-responses of different magnitude in the endocrine system, blood composition, thoracic impedance, and hemodynamic variables. The heart rate is depressed even after HUT12, while arterial blood pressure and thoracic impedance exceed pre-stimulus levels after greater head-up tilt, indicating altered cardiovascular response after passive orthostasis.     

Effect of hydration on some orthostatic and haematological responses to head-up tilt

Experiments were undertaken to determine the effects of hydration status on a) orthostatic responses, and on b), relative changes in intravascular volume and protein content, during 70 degrees head-up tilt (HUT). Six men underwent 45 min of HUT, preceded by 45 min supine, first dehydrated, and again 105 min later after rehydration with water. Heart rate was consistently lower following rehydration (p less than 0.01), while supine diastolic pressure was higher (p less than 0.02). Systolic pressure fell during dehydrated HUT (p less than 0.01), but not during rehydrated HUT. Postural haemoconcentration, which was reduced after rehydration (p less than 0.001), was accompanied by a decrease in intravascular albumin content (p less than 0.05). Two subjects experienced severe presyncopal symptoms during dehydrated HUT, but not during rehydrated HUT. Thus, it appears that rehydration after fluid restriction improves orthostatic tolerance. Furthermore, extravascular hydration status may be more important than intravascular hydration status in determining orthostatic tolerance.     

Arterial baroreflex control of sympathetic vasoconstrictor traffic and orthostatic intolerance after head-down bed rest

The purpose of the present study is to examine the changes in the arterial baroreflex control of muscle sympathetic nerve activity (MSNA) after head-down bed rest (HDBR), in relation to orthostatic hypotension after HDBR. Therefore, we performed 60 degrees head-up tilt (HUT) tests before and after 14 days of HDBR, with monitoring MSNA, heart rate and blood pressure. We calculated the gain of the arterial baroreflex control of MSNA, and compared the gains between the subjects who did (defined as the fainters) and those who did not (defined as the nonfainters) become presyncopal in HUT tests after HDBR.     

四周尾部悬吊致大鼠立位耐力不良

目的:观察中期(4周)尾部悬吊大鼠在立位应激下的心血管反应。方法:采用本实验室改进的尾部悬吊方法,利用头高位倾斜和下体负压模拟立位应激,通过股动脉插管和心电图记录检测大鼠血压和心率改变。结果:与对照组相比,4周尾部悬吊(SUS)大鼠体重下降及后肢承重骨骼肌萎缩;其静息血压和心率与对照组(CON)相比无明显差别(P0.05);在两组大鼠中,头高位倾斜和下体负压均可导致血压降低和心率加快,但SUS大鼠平均动脉压下降幅度与CON大鼠相比显著增大(P0.05),而两组的心率增快幅度并无明显差别(P0.05)。结论:4周尾部悬吊大鼠在立位应激下维持血压稳定的能力减弱,可用于中期失重/模拟失重后立位耐力不良机理的研究。     

Gender affects sympathetic neurovascular control during postural stress

Sympathetic outflow increases during head-up tilt (HUT) to stabilize blood pressure in the presence of decreases in venous return and stroke volume (SV). Otherwise, orthostatic hypotension would develop. Gender differences in orthostatic tolerance have been noted but the mechanisms are still uncertain. More recently, Waters et al. reported in a limited sample, greater susceptibility of women to demonstrate orthostatic intolerance following space flight. Therefore, it is important to understand gender differences in reflex blood pressure regulation. Recently, we reported smaller increments in muscle sympathetic nerve activity (MSNA) in healthy women during graded HUT and a non-baroreflex cold pressor test. The purpose of this report is to examine the hypothesis that gender differences in blood pressure control during HUT are related to important variations in MSNA discharge patterns.     

Comparison of cardiovascular response to passive tilt in young and elderly men

To test the hypothesis that altered hemodynamic responses to postural changes are associated with aging, cardiovascular responses to head-up tilt (HUT) and head-down tilt (HDT) were examined in 12 healthy young (average age, 24.6 +/- 1.7 years) and 12 healthy elderly (average age, 68.6 +/- 2.2 years) men. Subjects were passively tilted from supine to 30 degrees, 60 degrees, and 90 degrees HUT and HDT. Responses to these perturbations were determined 5 min after tilting with measures of heart rate (HR), blood pressure (SBP, DBP), and echocardiographically determined left ventricular diameter in systole and diastole (LVIDs, LVIDd). In HUT there were no significant age effects. In both young and elderly, SBP decreased significantly (p less than 0.05), and DBP and HR increased significantly. Ejection fraction (EF), mean arterial blood pressure (MABP), and rate-pressure product (RPP) were unchanged in both groups. In HDT, the hemodynamic responses of the young and elderly were in opposite directions and significant age effects were found for SBP, DBP, HR, LVIDs, EF, MABP, and RPP. In HDT, the young appear to increase cardiac output primarily due to an increase in EF and end-diastolic volume (LVIDd), while HR is unchanged and SBP is decreased. MABP is unchanged, suggesting a small decrease in total peripheral resistance. The elderly may increase cardiac output slightly, owing to an increase in LVIDd with no change in EF, and a large increase in HR. Afterload increased markedly, therefore attenuating any increase in cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of cardiovascular responses between lower body negative pressure and head-up tilt.

To investigate local blood-flow regulation during orthostatic maneuvers, 10 healthy subjects were exposed to -20 and -40 mmHg lower body negative pressure (LBNP; each for 3 min) and to 60 degrees head-up tilt (HUT; for 5 min). Measurements were made of blood flow in the brachial (BF(brachial)) and femoral arteries (BF(femoral)) (both by the ultrasound Doppler method), heart rate (HR), mean arterial pressure (MAP), cardiac stroke volume (SV; by echocardiography), and left ventricular end-diastolic volume (LVEDV; by echocardiography). Comparable central cardiovascular responses (changes in LVEDV, SV, and MAP) were seen during LBNP and HUT. During -20 mmHg LBNP, -40 mmHg LBNP, and HUT, the following results were observed: 1) BF(brachial) decreased by 51, 57, and 41%, and BF(femoral) decreased by 40, 53, and 62%, respectively, 2) vascular resistance increased in the upper limb by 110, 147, and 85%, and in the lower limb by 76, 153, and 250%, respectively. The increases in vascular resistance were not different between the upper and lower limbs during LBNP. However, during HUT, the increase in the lower limb was much greater than that in the upper limb. These results suggest that, during orthostatic stimulation, the vascular responses in the limbs due to the cardiopulmonary and arterial baroreflexes can be strongly modulated by local mechanisms (presumably induced by gravitational effects).     

Heat acclimation increases skin vasodilation and sweating but not cardiac baroreflex responses in heat-stressed humans.

In the present study, to test the hypothesis that exercise-heat acclimation increases orthostatic tolerance via the improvement of cardiac baroreflex control in heated humans, we examined cardiac baroreflex and thermoregulatory responses, including cutaneous vasomotor and sudomotor responses, during whole body heating before and after a 6-day exercise-heat acclimation program [4 bouts of 20-min exercise at 50% peak rate of oxygen uptake separated by 10-min rest in the heat (36 degrees C; 50% relative humidity)]. Ten healthy young volunteers participated in the study. On the test days before and after the heat acclimation program, subjects underwent whole body heat stress produced by a hot water-perfused suit during supine rest for 45 min and 75 degrees head-up tilt (HUT) for 6 min. The sensitivity of the arterial baroreflex control of heart rate (HR) was calculated from the spontaneous changes in beat-to-beat arterial pressure and HR. The HUT induced a presyncopal sign in seven subjects in the preacclimation test and in six subjects in the postacclimation test, and the tilting time did not differ significantly between the pre- (241 +/- 33 s) and postacclimation (283 +/- 24 s) tests. Heat acclimation did not change the slope in the HR-esophageal temperature (Tes) relation and the cardiac baroreflex sensitivity during heating. Heat acclimation decreased (P < 0.05) the Tes thresholds for cutaneous vasodilation in the forearm and dorsal hand and for sweating in the forearm and chest. These findings suggest that short-term heat acclimation does not alter the spontaneous baroreflex control of HR during heat stress, although it induces adaptive change of the heat dissipation response in nonglabrous skin.     

Gender influence on vasoactive hormones at rest and during a 70 degrees head-up tilt in healthy humans.

To evaluate the influence of age and gender on the neuroendocrine control of blood pressure in normal subjects, a 13-min 70 degrees head-up tilt (HUT) was applied after 3 h of recumbency to 109 healthy men and women aged 23-50 yr (age group I) and 51-77 yr (age group II). We found that age and gender had a significant influence on plasma norepinephrine (PNE) concentration at baseline and in the upright position. PNE was significantly higher in older men compared with the younger men and women of both age groups, suggesting a divergent age-related activation of the sympathetic nervous system between genders at baseline as well as during a sustained orthostatic challenge. There was no significant influence of age or gender on plasma epinephrine at baseline or during HUT. Plasma renin activity was significantly higher at baseline as well as in the upright position during HUT in elderly men than in women. Age or gender had no influence on plasma vasopressin (PAVP), and, regardless of age, nonhypotensive HUT induced an extremely modest increase in PAVP. The syncopal subjects displayed a hormonal pattern associating increased PNE and a surge in plasma epinephrine and PAVP minutes before syncope during HUT. The orthostatic intolerance appears not to be a feature of healthy aging per se. In healthy subjects, both age and gender modulate markedly the cardiovascular and neuroendocrine responses to an orthostatic challenge and must be taken into consideration, particularly when catecholamine responses are studied.     

Effects of aging on adipose resistance artery vasoconstriction: possible implications for orthostatic blood pressure regulation.

The purpose of this investigation was to determine mean arterial pressure (MAP) and regional vascular conductance responses in young and aged Fisher-344 rats during orthostatic stress, i.e., 70 degrees head-up tilt (HUT). Both groups demonstrated directionally different changes in MAP during HUT (young, 7% increase; aged, 7% decrease). Vascular conductance during HUT in young rats decreased in most tissues but largely remained unchanged in the aged animals. Based on the higher vascular conductance of white adipose tissue from aged rats during HUT, resistance arteries from white visceral fat were isolated and studied in vitro. There was diminished maximal vasoconstriction to phenylephrine and norepinephrine (NE: young, 42 +/- 5%; old, 18 +/- 6%) in adipose resistance arteries from aged rats. These results demonstrate that aging reduces the ability to maintain MAP during orthostatic stress, and this is associated with a diminished vasoconstriction of adipose resistance arteries.     

Cardiac homeostasis is independent of calf venous compliance in subjects with paraplegia

The purpose of this study was to examine cardiac hemodynamics during acute head-up tilt (HUT) and calf venous function during acute head-down tilt (HDT) in subjects with paraplegia compared with sedentary nondisabled controls. Nineteen paraplegic males (below T6) and nine age-, height-, and weight-matched control subjects participated. Heart rate, stroke volume, and cardiac output were assessed using the noninvasive acetylene uptake method. Venous vascular function of the calf was assessed using venous occlusion plethysmography. After supine measurements were collected, the table was moved to 10 degrees HDT followed by the three levels of HUT (10, 35, and 75 degrees ) in random order. Cardiac hemodynamics were similar between the groups at all positions. Calf circumference was significantly reduced in the paraplegic group compared with the control group (P < 0.001). Venous capacitance and compliance were significantly reduced in the paraplegic compared with control group at supine and HDT. Neither venous capacitance (P = 0.37) nor compliance (P = 0.19) increased from supine with 10 degrees HDT in the paraplegic group. A significant linear relationship was established between supine venous compliance and supine cardiac output in the control group (r = 0.80, P < 0.02) but not in the paraplegic group. The findings of reduced calf circumference and similar venous capacitance at supine rest and 10 degrees HDT in the paraplegic group imply that structural changes may have limited venous dispensability in individuals with chronic paraplegia. Furthermore, the lack of a relationship between supine venous compliance and supine cardiac output suggests that cardiac homeostasis does not rely on venous compliance in subjects with paraplegia.     

Calf venous compliance measured with head-up tilt equals supine calf compliance

Elevated calf compliance may contribute to orthostatic intolerance following space flight and bed rest. Calf venous compliance is measured conventionally with venous occulusion plethysmography in supine subjects. With this well-established technique, subjects undergo inflation of a pressure cuff around the thigh just above the knee, which increases calf venous pressure. A plethysmograph simultaneously measures calf volume elevation. Compliance equals calf volume elevation per mm Hg thigh occlusion (calf venous) pressure in relaxed legs of the supine subjects. Compliance may also be measured during stepwise head-up tilt (HUT) as calf volume elevation per mm Hg gravitational venous pressure elevation produced by HUT. However, during HUT on a tilt table with a footplate, calf muscles activate to counteract gravity: this is an obvious and natural response to gravitational force. Such muscle activation conceivably could reduce calf compliance, yet relatively little calf muscle activation occurs during HUT and orthostasis (<10% of maximal voluntary levels). Also, this activation produces minimal calf volume change (<0.3%). Therefore, we hypothesized that calf compliance measured with HUT equals that measured with supine venous occlusion.     

Low-frequency oscillation of sympathetic nerve activity decreases during development of tilt-induced syncope preceding sympathetic withdrawal and bradycardia

Sympathetic activation during orthostatic stress is accompanied by a marked increase in low-frequency (LF, approximately 0.1-Hz) oscillation of sympathetic nerve activity (SNA) when arterial pressure (AP) is well maintained. However, LF oscillation of SNA during development of orthostatic neurally mediated syncope remains unknown. Ten healthy subjects who developed head-up tilt (HUT)-induced syncope and 10 age-matched nonsyncopal controls were studied. Nonstationary time-dependent changes in calf muscle SNA (MSNA, microneurography), R-R interval, and AP (finger photoplethysmography) variability during a 15-min 60 degrees HUT test were assessed using complex demodulation. In both groups, HUT during the first 5 min increased heart rate, magnitude of MSNA, LF and respiratory high-frequency (HF) amplitudes of MSNA variability, and LF and HF amplitudes of AP variability but decreased HF amplitude of R-R interval variability (index of cardiac vagal nerve activity). In the nonsyncopal group, these changes were sustained throughout HUT. In the syncopal group, systolic AP decreased from 100 to 60 s before onset of syncope; LF amplitude of MSNA variability decreased, whereas magnitude of MSNA and LF amplitude of AP variability remained elevated. From 60 s before onset of syncope, MSNA and heart rate decreased, index of cardiac vagal nerve activity increased, and AP further decreased to the level at syncope. LF oscillation of MSNA variability decreased during development of orthostatic neurally mediated syncope, preceding sympathetic withdrawal, bradycardia, and severe hypotension, to the level at syncope.     

Effect of 21 days head-down bed rest on heart rate and blood pressure variability and orthostatic tolerance in men

Healthy males were tested for orthostatic tolerance during and following 21 days head-down bed rest. ECG and blood pressure were measured. Ten out of the 15 subjects were able to complete the head-up tilt (HUT) test following bed rest, and changes in heart rate dynamics and blood pressure were observed in both finishers and non-finishers. Specific results are presented and discussed.     

Leg intravenous pressure during head-up tilt

Leg vascular resistance is calculated as the arterial-venous pressure gradient divided by blood flow. During orthostatic challenges it is assumed that the hydrostatic pressure contributes equally to leg arterial, as well as to leg venous pressure. Because of venous valves, one may question whether, during orthostatic challenges, a continuous hydrostatic column is formed and if leg venous pressure is equal to the hydrostatic pressure. The purpose of this study was, therefore, to measure intravenous pressure in the great saphenous vein of 12 healthy individuals during 30 degrees and 70 degrees head-up tilt and compare this with the calculated hydrostatic pressure. The height difference between the heart and the right medial malleolus level represented the hydrostatic column. The results demonstrate that there were no differences between the measured intravenous pressure and the calculated hydrostatic pressure during 30 degrees (47.2 +/- 1.0 and 46.9 +/- 1.5 mmHg, respectively) and 70 degrees head-up tilt (83.9 +/- 0.9 and 85.1 +/- 1.2 mmHg, respectively). Steady-state levels of intravenous pressure were reached after 95 +/- 12 s during 30 degrees and 161 +/- 15 s during 70 degrees head-up tilt. In conclusion, the measured leg venous pressure is similar to the calculated hydrostatic pressure during orthostatic challenges. Therefore, the assumption that hydrostatic pressure contributes equally to leg arterial as well as to leg venous pressure during orthostatic challenges can be made.     

Effect of acute exposure to 3660 m altitude on orthostatic responses and tolerance.

Orthostatic reflexes were examined at 375 m and after 60 min of exposure in a hypobaric chamber at 3660 m using a 20-min 70 degrees head-up tilt (HUT) test. Mean arterial blood pressure, R wave-R wave interval (RRI), and mean cerebral blood flow velocity (MFV) were examined with coarse-graining spectral analysis. Of 14 subjects, 7 at 375 m and 12 at 3660 m were presyncopal. Immediately on arrival to high altitude, breathing frequency and MFV increased, and endtidal PCO2, RRI, RRI complexity, and the parasympathetic nervous system indicator decreased. MFV was similar in HUT at both altitudes. The sympathetic nervous system indicator increased with tilt at 3660 m, whereas parasympathetic nervous system indicator decreased with tilt at both altitudes. Multiple regression analysis of supine variables from either 375 or 3660 m and the time to presyncope at 3660 m indicated that, after 1 h of exposure, increased presyncope at altitude was the result of 1). ineffective peripheral vasoconstriction, despite increased cardiac sympathetic nervous system activity with HUT, and 2). insufficient cerebral perfusion owing to cerebral vasoconstriction as the result of hypoxic hyperventilation-induced hypocapnia.