Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes.

BACKGROUND: Although it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited. RESULTS: We report here the results of the first whole genome resequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population tests of selection, we identify regions with a significant loss of diversity, indicative of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which is significant in both of the Ethiopian subpopulations sampled. This region contains eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in hypoxia tolerance, we experimentally tested whether individual genes from the region affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3. CONCLUSIONS: Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that many of our results would likely be unattainable using data from exome sequencing or microarray studies. This highlights the importance of whole genome sequencing for investigating adaptation by natural selection.

Cardiovascular control from cardiac and pulmonary vascular receptors.

NEW FINDINGS: What is the topic of this review? The purpose of this review is to summarize present knowledge of the function of the afferent nerves arising from the heart and the coronary and pulmonary arteries. Although there is abundant evidence that atrial receptor stimulation influences heart rate and urine flow, with little or no effect elsewhere, and that ventricular receptors are strongly excited only by chemical stimuli, there is still the erroneous belief that they act as a homogeneous group causing cardiovascular depression. What advances does it highlight? Coronary receptors deserve to be recognized as a potentially important additional group of baroreceptors. Stimulation of pulmonary arterial baroreceptors at physiological pressures causes reflex vasoconstriction and could have a hitherto unacknowledged important role in cardiovascular control, for example in exercise. Although there has been a tendency to regard cardiac and pulmonary receptors as a single population of 'cardiopulmonary receptors', this cannot be justified as the various receptor types all induce their own particular pattern of responses. Stimulation of atrial receptors increases activity in sympathetic nerves to the sino-atrial node, causing tachycardia, but there is no effect on activity to the myocardium or to most blood vessels. Renal nerve activity, however, is decreased, and secretion of antidiuretic hormone is inhibited, causing diuresis. Ventricular receptors induce a powerful depressor response, but only in response to abnormal chemical stimulation and possibly to myocardial injury. Coronary arterial receptors function as baroreceptors, but have a lower threshold and a more prolonged effect than other baroreceptors. Pulmonary arterial baroreceptors induce vasoconstriction and respiratory stimulation at physiological pressures and may be of importance in mediating some of the responses to exercise, as well as in hypoxic conditions.

Reflexes from pulmonary arterial baroreceptors in dogs: interaction with carotid sinus baroreceptors.

In contrast to the reflex vasodilatation occurring in response to stimulation of baroreceptors in the aortic arch, carotid sinuses and coronary arteries, stimulation of receptors in the wall of pulmonary arteries results in reflex systemic vasoconstriction. It is rare for interventions to activate only one reflexogenic region, therefore we investigated how these two types of reflexes interact. In anaesthetized dogs connected to cardiopulmonary bypass, reflexogenic areas of the carotid sinuses, aortic arch and coronary arteries and the pulmonary artery were subjected to independently controlled pressures. Systemic perfusion pressure (SPP) measured in the descending aorta (constant flow) provided an index of systemic vascular resistance. In other experiments, sympathetic efferent neural activity was recorded in fibres dissected from the renal nerve (RSNA). Physiological increases in pulmonary arterial pressure (PAP) induced significant increases in SPP (+39.1 ± 10.4 mmHg) and RSNA (+17.6 ± 2.2 impulses s(−1)) whereas increases in carotid sinus pressure (CSP) induced significant decreases in SPP (−42.6 ± 10.8 mmHg) and RSNA (−42.8 ± 18.2 impulses s(−1)) (P < 0.05 for each comparison; paired t test). To examine possible interactions, PAP was changed at different levels of CSP in both studies. With CSP controlled at 124 ± 2 mmHg, the threshold, 'set point' and saturation pressures of the PAP­SPP relationship were higher than those with CSP at 60 ± 1 mmHg; this rightward shift was associated with a significant decrease in the reflex gain. Similarly, increasing CSP produced a rightward shift of the PAP­RSNA relationship, although the effect on reflex gain was inconsistent. Furthermore, the responses to changes in CSP were influenced by setting PAP at different levels; increasing the level of PAP from 5 ± 1 to 33 ± 3 mmHg significantly increased the set point and threshold pressures of the CSP­SPP relationship; the reflex gain was not affected. These results indicate the existence of interaction between pulmonary arterial and carotid sinus baroreceptor reflexes; physiological and pathological states that alter the stimulus to one may alter the reflex responses from the other.

Carotid baroreflex testing using the neck collar device.

A neck chamber device for stimulation of carotid sinus baroreceptors by changing carotid transmural pressure was first described in 1957 by Ernsting and Parry and, with several modifications, has been extensively used in a number of physiological and clinical studies. This article outlines the evolution of neck chamber devices and describes some of the advantages and limitations of the technique. We also describe the responses in healthy subjects and the changes observed in patients with some disorders affecting the autonomic nervous system.

Head-up sleeping improves orthostatic tolerance in patients with syncope.

OBJECTIVES: This study was designed to examine the effect of head-up sleeping as a treatment for vasovagal syncope in otherwise healthy patients. Treatment for syncope is difficult. Pharmacological treatments have potential side effects and, although other non-pharmacological treatments such as salt and fluid loading often help, in some cases they may be ineffective or unsuitable. Head-up sleeping may provide an alternative treatment. METHODS: Twelve patients had a diagnosis of vasovagal syncope based both on the history and on early pre-syncope during a test of head-up tilting and graded lower body suction. They then underwent a period of 3-4 months of sleeping with the head-end of their bed raised by 10 degrees , after which orthostatic tolerance (time to pre-syncope during tilt test) was reassessed. RESULTS: Eleven patients (92%) showed a significant improvement in orthostatic tolerance (time to pre-syncope increased by 2 minutes or more). Plasma volume was assessed in eight patients and was found to show a significant increase (P < 0.05, Wilcoxon signed-rank test). There was no significant change in either resting or tilted heart rate or blood pressure after head-up sleeping. INTERPRETATION: Head-up sleeping is a simple, non-pharmacological treatment which is effective in the majority of patients. However, it may not be tolerated by patients or bed-partners long term and whether the effects continue after cessation of treatment remains to be determined.

Adaptation and mal-adaptation to ambient hypoxia; Andean, Ethiopian and Himalayan patterns.

The study of the biology of evolution has been confined to laboratories and model organisms. However, controlled laboratory conditions are unlikely to model variations in environments that influence selection in wild populations. Thus, the study of "fitness" for survival and the genetics that influence this are best carried out in the field and in matching environments. Therefore, we studied highland populations in their native environments, to learn how they cope with ambient hypoxia. The Andeans, African highlanders and Himalayans have adapted differently to their hostile environment. Chronic mountain sickness (CMS), a loss of adaptation to altitude, is common in the Andes, occasionally found in the Himalayas; and absent from the East African altitude plateau. We compared molecular signatures (distinct patterns of gene expression) of hypoxia-related genes, in white blood cells (WBC) from Andeans with (n = 10), without CMS (n = 10) and sea-level controls from Lima (n = 20) with those obtained from CMS (n = 8) and controls (n = 5) Ladakhi subjects from the Tibetan altitude plateau. We further analyzed the expression of a subset of these genes in Ethiopian highlanders (n = 8). In all subjects, we performed the studies at their native altitude and after they were rendered normoxic. We identified a gene that predicted CMS in Andeans and Himalayans (PDP2). After achieving normoxia, WBC gene expression still distinguished Andean and Himalayan CMS subjects. Remarkably, analysis of the small subset of genes (n = 8) studied in all 3 highland populations showed normoxia induced gene expression changes in Andeans, but not in Ethiopians nor Himalayan controls. This is consistent with physiologic studies in which Ethiopians and Himalayans show a lack of responsiveness to hypoxia of the cerebral circulation and of the hypoxic ventilatory drive, and with the absence of CMS on the East African altitude plateau.

Cerebrovascular responses to hypoxia and hypocapnia in Ethiopian high altitude dwellers.

BACKGROUND AND PURPOSE: Cerebrovascular responses to hypoxia and hypocapnia in Peruvian altitude dwellers are impaired. This could contribute to the high incidence of altitude-related illness in Andeans. Ethiopian high altitude dwellers may show a different pattern of adaptation to high altitude. We aimed to examine cerebral reactivity to hypoxia and hypocapnia in healthy Ethiopian high altitude dwellers. Responses were compared with our previous data from Peruvians. METHODS: We studied 9 Ethiopian men at their permanent residence of 3622 m, and one day after descent to 794 m. We continuously recorded cerebral blood flow velocity (CBFV; transcranial Doppler). End-tidal oxygen (P(ET)o(2)) was decreased from 100 mm Hg to 50 mm Hg with end-tidal carbon dioxide (P(ET)co(2)) clamped at the subject's resting level. P(ET)co(2) was then manipulated by voluntary hyper- and hypoventilation, with P(ET)o(2) clamped at 100 mm Hg (normoxia) and 50 mm Hg (hypoxia). RESULTS: During spontaneous breathing, P(ET)co(2) increased after descent, from 38.2+/-1.0 mm Hg to 49.8+/-0.6 mm Hg (P<0.001). There was no significant response of CBFV to hypoxia at either high (-0.19+/-3.1%) or low (1.1+/-2.9%) altitudes. Cerebrovascular reactivity to normoxic hypocapnia at high and low altitudes was 3.92+/-0.5%.mm Hg(-1) and 3.09+/-0.4%.mm Hg(-1); reactivity to hypoxic hypocapnia was 4.83+/-0.7%.mm Hg(-1) and 2.82+/-0.5%.mm Hg(-1). Responses to hypoxic hypocapnia were significantly smaller at low altitude. CONCLUSIONS: The cerebral circulation of Ethiopian high altitude dwellers is insensitive to hypoxia, unlike Peruvian high altitude dwellers. Cerebrovascular responses to P(ET)co(2) were greater in Ethiopians than Peruvians, particularly at high altitude. This, coupled with their high P(ET)co(2) levels, would lead to high cerebral blood flows, and may be advantageous for altitude living.

Enhanced vascular responses to hypocapnia in neurally mediated syncope.

OBJECTIVE: The susceptibility to suffer neurally mediated syncope and loss of consciousness varies markedly. In addition to vasodilatation and bradycardia, hyperventilation precedes loss of consciousness. The resultant hypocapnia causes cerebral vasoconstriction and peripheral vasodilatation. We postulate that more pronounced cerebral and peripheral vascular responses to reductions in arterial CO(2) levels underlie greater susceptibility to neurally mediated syncope. METHODS: We compared vascular responses to CO(2) among 31 patients with histories of recurrent neurally mediated syncope and low orthostatic tolerance and 14 age- and sex-matched control subjects with no history of syncope and normal orthostatic tolerance. Vascular responses to CO(2) were calculated after all subjects had fully recovered and their blood pressures and heart rates were stable. We measured blood flow velocity in the middle cerebral artery (transcranial Doppler) and in the left brachial artery (brachial Doppler), and end-tidal CO(2) during voluntary hyperventilation and hypoventilation (end-tidal CO(2) from 21-45mm Hg), and determined the slopes of the relations. RESULTS: Hypocapnia produced a significantly greater reduction in cerebral blood flow velocity and in forearm vascular resistance in patients with neurally mediated syncope than in control subjects. Opposite changes occurred in response to hypercapnia. In all subjects, the changes in cerebral blood flow velocity and forearm vasodilatation were inversely related with orthostatic tolerance. INTERPRETATION: Susceptibility to neurally mediated syncope can be explained, at least in part, by enhanced cerebral vasoconstriction and peripheral vasodilatation in response to hypocapnia. This may have therapeutic implications.

Cardiovascular adjustments for life at high altitude.

The effects of hypobaric hypoxia in visitors depend not only on the actual elevation but also on the rate of ascent. There are increases in sympathetic activity resulting in increases in systemic vascular resistance, blood pressure and heart rate. Pulmonary vasoconstriction leads to pulmonary hypertension, particularly during exercise. The sympathetic excitation results from hypoxia, partly through chemoreceptor reflexes and partly through altered baroreceptor function. Systemic vasoconstriction may also occur as a reflex response to the high pulmonary arterial pressures. Many communities live permanently at high altitude and most dwellers show excellent adaptation although there are differences between populations in the extent of the ventilatory drive and the erythropoiesis. Despite living all their lives at altitude, some dwellers, particularly Andeans, may develop a maladaptation syndrome known as chronic mountain sickness. The most prominent characteristic of this is excessive polycythaemia, the cause of which has been attributed to peripheral chemoreceptor dysfunction. The hyperviscous blood leads to pulmonary hypertension, symptoms of cerebral hypoperfusion, and eventually right heart failure and death.

The autonomic nervous system at high altitude.

The effects of hypobaric hypoxia in visitors depend not only on the actual elevation but also on the rate of ascent. Sympathetic activity increases and there are increases in blood pressure and heart rate. Pulmonary vasoconstriction leads to pulmonary hypertension, particularly during exercise. The sympathetic excitation results from hypoxia, partly through chemoreceptor reflexes and partly through altered baroreceptor function. High pulmonary arterial pressures may also cause reflex systemic vasoconstriction. Most permanent high altitude dwellers show excellent adaptation although there are differences between populations in the extent of the ventilatory drive and the erythropoiesis. Some altitude dwellers, particularly Andeans, may develop chronic mountain sickness, the most prominent characteristic of which being excessive polycythaemia. Excessive hypoxia due to peripheral chemoreceptor dysfunction has been suggested as a cause. The hyperviscous blood leads to pulmonary hypertension, symptoms of cerebral hypoperfusion, and eventually right heart failure and death.

Daytime variability in carotid baroreflex function in healthy human subjects.

Variability of blood pressure is limited by arterial baroreceptors, yet blood pressure still shows circadian changes. This study was undertaken to examine if the responses to the carotid baroreflex also change throughout the day. Responses of cardiac interval (RR), mean arterial pressure (MAP) and vascular resistance (VR) to carotid baroreflex stimulation and inhibition using pressures and suction applied to a neck chamber, were measured in 14 healthy, normotensive subjects. Studies were carried out at three hourly intervals between 09:00 and 21:00 hours. Stimulus-response curves were defined and the first differential of the curve was calculated to establish reflex sensitivity (maximal slope) and "operating" point (estimated carotid sinus pressure at point of maximum slope, OP). The principal findings are: (1) baroreflex sensitivity for the control of VR was at its highest at 09:00 (-3.4 +/- 0.6 units) compared to 12:00 (-1.9 +/- 0.4 units), 15:00 (-2.0 +/- 0.4 units) and 18:00 (-1.9 +/- 0.3 units) (all P < 0.05); (2) baroreflex OP for the control of MAP was at its lowest at 09:00 (P < 0.01); (3) baroreflex sensitivity for control of VR was significantly correlated with prevailing mean pressure (P < 0.05) and OP for the control of MAP (P < 0.02); (4) OP for control of RR, MAP and VR are all highly correlated to prevailing MAP (P < 0.0001). Our results suggest that baroreflex function varies throughout the day and this favors higher sensitivity and lower blood pressure in the mornings. We speculate that this may be of importance in long-term blood pressure regulation.

Autonomic regulation during orthostatic stress in highlanders: comparison with sea-level residents.

This report is a comparison of orthostatic tolerance and autonomic function in three groups of high-altitude dwellers: Andeans with and without chronic mountain sickness (CMS) and healthy Ethiopians. Results are compared with those from healthy sea-level residents. The aim was to determine whether different high-altitude populations adapted differently to the prevailing hypobaric hypoxia. Orthostatic tolerance was assessed using a test involving head-up tilt (HUT) and graded lower body suction. This was performed at the subjects' resident altitude. Blood pressure (Portapres) and R-R interval (ECG) were recorded during the test, and spectral and cross-spectral analyses of heart period and systolic blood pressure time series were performed using data obtained both while supine and during HUT. The transfer function gain in the low-frequency range (LF, approximately 0.1 Hz) at the point of maximal coherence was used as a measure of cardiac baroreflex sensitivity (BRS). As previously reported, Peruvians displayed an unusually good orthostatic tolerance, while Ethiopians showed an orthostatic tolerance comparable to that of healthy sea-level residents. There were no significant differences between groups in the supine values of the spectral analysis results. Head-up tilt induced the expected changes in Ethiopians (an increase in the LF components and a decrease in the respiratory components) but not in Andeans. Cross-spectral analysis showed abnormal results from all groups of high-altitude dwellers. These results indicate that Ethiopians, but not Peruvians, behave similarly to sea-level residents in terms of orthostatic tolerance and autonomic responses to orthostatic stress, as assessed from spectral analyses, and this indicates good adaptation to their environment. However, in all the high-altitude groups the results of cross-spectral analysis were atypical, suggesting some degree of impairment in baroreflex function.

Carotid baroreflex regulation of vascular resistance in high-altitude Andean natives with and without chronic mountain sickness.

We investigated carotid baroreflex control of vascular resistance in two groups of high-altitude natives: healthy subjects (HA) and a group with chronic mountain sickness (CMS), a maladaptation condition characterized by high haematocrit values and symptoms attributable to chronic hypoxia. Eleven HA controls and 11 CMS patients underwent baroreflex testing, using the neck collar method in which the pressure distending the carotid baroreceptors was changed by applying pressures of -40 to +60 mmHg to the chamber. Responses of forearm vascular resistance were assessed from changes in the quotient of blood pressure divided by brachial artery blood velocity. Stimulus-response curves were defined at high altitude (4338 m) and within 1 day of descent to sea level. We applied a sigmoid function or third-order polynomial to the curves and determined the maximal slope (equivalent to peak gain) and the corresponding carotid pressure (equivalent to 'set point'). The results showed that the peak gains of the reflex were similar in both groups and at both locations. The 'set point' of the reflex, however, was significantly higher in the CMS patients compared to HA controls, indicating that the reflex operates over higher pressures in the patients (94.4 +/- 3.0 versus 79.6 +/- 4.1 mmHg; P < 0.01). This, however, was seen only when subjects were studied at altitude; after descent to sea level the curve reset to a lower pressure with no significant difference between HA and CMS subjects. These results indicate that carotid baroreceptor control of vascular resistance may be abnormal in CMS patients but that descent to sea level rapidly normalizes it. We speculate that this may be explained by CMS patients having greater vasoconstrictor activity at altitude owing to greater hypoxic stimulation of chemoreceptors.

Cerebral vasodilatation to exogenous NO is a measure of fitness for life at altitude.

BACKGROUND AND PURPOSE: Andean highlanders, unlike Ethiopians, develop chronic mountain sickness (CMS), a maladaptation to their native land. Ambient hypoxia induces NO-mediated vasodilatation. Fitness for life at altitude might be revealed by cerebrovascular responses to NO. METHODS: Nine altitude-native men were examined at 3622 and 794 m in Ethiopia and compared with 9 altitude-native Andean men tested at 4338 and 150 m in Peru. We assessed CMS scores, hematocrits, end-tidal pressure of carbon dioxide (P(ET)co2), oxygen saturations, and cerebral blood flow velocity (CBV). We evaluated fitness for life at altitude from the cerebrovascular response to an exogenous NO donor. RESULTS: At high altitude, CMS scores and hematocrits were higher in Andeans, and they had lower oxygen saturations. Ethiopians had higher P(ET)co2 at all study sites. At low altitude, saturations were similar in both groups. Responsiveness of the cerebral circulation to NO was minimal in Ethiopians at low altitude, whereas Andeans had a large response. In contrast, at high altitude, Ethiopians showed large responses, and Peruvians had minimal responses. CONCLUSIONS: By our measure, high altitude-native Peruvians were well-adapted lowlanders, whereas Ethiopian highlanders were well adapted to altitude life. Environmental pressures were sufficient for human adaptation to chronic hypoxia in Africa but not South America. The mechanisms underlying these differences are unknown, although studies of neurovascular diseases suggest that this may be related to a NO receptor polymorphism.

Phase of the menstrual cycle does not affect orthostatic tolerance in healthy women.

Women of child-bearing age have a lower orthostatic tolerance (OT) than older women or men, and women suffering from frequent syncopal episodes often comment that their symptoms occur at certain times of the menstrual cycle. However, it is not known whether, in asymptomatic women, OT varies at different phases of the menstrual cycle. We studied 8 healthy asymptomatic women aged 26.8 +/- 3.4 years. We determined OT using a test of combined head-up tilting and lower body suction. We continuously monitored beat-to-beat blood pressure (Finapres), heart rate (ECG), and cerebral and forearm blood flow velocities (Doppler ultrasound). On each test day we assessed carotid baroreceptor sensitivity from suction/pressure applied to a neck chamber. We also determined estradiol and progesterone levels from a venous blood sample. Tests were performed in early follicular and late luteal phases, and during ovulation. Serum concentrations of estradiol (pmol x l(-1)) and progesterone (nmol x l(-1)) were in follicular phase 464.1 +/- 63 and 6.3 +/- 2.8; ovulation 941.6 +/- 298 and 5.8 +/- 1.2; luteal phase 698 +/- 188 and 32.3 +/- 9.6. Progesterone levels were significantly higher in the luteal phase (p < 0.001). OT was not different on any test day: follicular 31.9 +/- 1.6 min, ovulation 31.3 +/- 0.7 min; luteal 31.1 +/- 2.2 min. Supine and tilted heart rates and blood pressures, the maximum heart rate, and the cerebral autoregulatory and forearm vascular resistance responses to the orthostatic stress were similar during all studies. Both cardiac and vascular resistance carotid baroreceptor sensitivities were also similar on all test days. These results suggest that there is no difference in either OT or cardiovascular control at the tested phases of the menstrual cycle in healthy women.

Water drinking improves orthostatic tolerance in patients with posturally related syncope.

Water drinking improves OT (orthostatic tolerance) in healthy volunteers; however, responses to water in patients with PRS (posturally related syncope) are unknown. Therefore the aim of the present study was to examine whether water would improve OT in patients with PRS. In a randomized controlled cross-over fashion, nine patients with PRS ingested 500 ml and 50 ml (control) of water 15 min before tilting on two separate days. OT was determined using a combined test of head-up tilting and lower body suction and expressed as the time required to induce presyncope. We measured blood pressure and heart rate (using Portapres) and middle cerebral artery velocity (using transcranial Doppler). SV (stroke volume) and TPR (total peripheral resistance) were calculated using the Modelflow method. OT was significantly (P<0.02) greater after drinking 500 ml of water than after 50 ml (25.4+/-1.5 compared with 19.8+/-2.3 min respectively). After ingestion of 500 ml of water, blood pressure during tilting was higher, the tiltinduced reduction in SV was smaller and the increase in TPR was greater (all P<0.05). The correlation coefficient of the relationship between cerebral blood flow velocity and pressure was lower after 500 ml of water (0.43+/-0.1 compared with 0.73+/-0.1; P<0.05), indicating better autoregulation. In conclusion, drinking 500 ml of water increased OT and improved cardiovascular and cerebrovascular control during orthostasis. Patients with PRS should be encouraged to drink water before situations likely to precipitate a syncopal attack.

Increased postural sway in control subjects with poor orthostatic tolerance.

OBJECTIVES: This study sought to evaluate postural sway in control subjects with good and poor orthostatic tolerance (OT). BACKGROUND: Some asymptomatic volunteers, when subjected to a progressive orthostatic stress test, show early presyncope. We hypothesized that normal subjects with poor OT do not usually faint because they adopt a strategy of increased lower limb movement, which helps maintain venous return. METHODS: In 12 asymptomatic subjects with good OT and 11 with poor OT, assessed by the combined orthostatic stress of head-up tilting and lower body suction, we determined postural sway using a force platform after 1, 5, and 10 min of motionless standing. RESULTS: The subjects with poor tolerance had greater distances and velocities of sway in the anteroposterior direction but not the mediolateral direction. There was a significant negative correlation between postural sway and orthostatic tolerance. CONCLUSIONS: We have shown that in normal subjects with poor OT during a passive orthostatic stress test, their leg movements tend to be greater when standing. These movements are likely to enhance venous return and may at least partly explain why, despite their poor test results, they do not normally faint.

Prolonged latency in the baroreflex mediated vascular resistance response in subjects with postural related syncope.

In addition to the gain, the delay of the baroreflex response plays an important role in the maintenance of cardiovascular system stability. Additionally when postural changes induce sudden drops in blood pressure, a delayed response may fail to maintain sufficient cerebral perfusion pressure. We tested the hypothesis that the delay of the carotid baroreceptor reflex is impaired in subjects with poor orthostatic tolerance. An orthostatic test with 60 degrees head-up tilt, and progressive lower-body negative pressure was performed on 27 patients with histories of unexplained syncope and 13 control subjects. The test was stopped at the onset of presyncope and time to presyncope was taken as a measure of orthostatic tolerance. Twelve patients had normal tolerance and thirteen patients had low tolerance. We measured beat-to-beat blood pressure (Finapres) and brachial artery blood flow velocity (Doppler ultrasonography). Before the test, we determined the response of forearm vascular resistance (mean arterial pressure/mean brachial artery velocity) to loading/unloading of carotid baroreceptors by the application of neck suction/pressure (-/+30 mmHg) to a chamber fitted overlying the carotid sinus. We measured the gain in the response (maximum percentage change from baseline value in vascular resistance divided by the neck collar pressure) and the latency in the response (delay of the maximum change in vascular resistance after neck-collar stimulation). Results are reported as means +/- SEM. In the three groups, there were no differences in the sensitivity of the vascular resistance response after baroreceptor loading/unloading. Following baroreceptor unloading, the latency of the response was 14.0+/-1.3 seconds in early fainters, 9.3+/-0.7 seconds in normal patients and 10.1+/-1.2 seconds in controls. The latency in blood pressure rise was 11.1+/-1.3 seconds in early fainters, 7.9+/-0.9 seconds in normal patients and 7.2+/-1.0 seconds in controls. The results following baroreceptor loading were more scattered. The early fainters still had a tendency to show prolonged latency. These results suggest that the delay in the baroreflex response plays an important role in postural related syncope.