Moderate hypoxia suppresses exercise-induced procoagulant changes

Hypoxia has been implicated as a stimulant of coagulation. As exertion is known to affect haemostasis, we sought to control for this by using a standardized protocol. Subjects were exercised both at room air and at 12% oxygen. Exercise produced an increase in procoagulant factors, which was reduced with hypoxic exercise. Room air exercise increased fibrinolytic markers. Hypoxic exercise did not affect the increase in tissue plasminogen activator, but decreased the increase in plasminogen activator inhibitor-1 expression. Thus, it appears that hypoxia may exert an antithrombotic effect by both damping exercise-induced procoagulant changes and stimulating fibrinolysis.     

Cardiac Arrhythmias Triggered by Sudden and Dynamic Efforts

Background: Some arrhythmias are triggered only during exercise. The aim of this study is to describe the frequency and type of arrhythmia induced by a standardized protocol of sudden and dynamic exercise, which tends to reflect routine situations of efforts (e.g., climbing stairs), and compare with those found on maximal cardiopulmonary exercise test (CPET). Methods: A total of 2329 subjects (1594 men) aged 9–91 years (mean 52 years, SD ± 16) were submitted to a standardized protocol of sudden and dynamic exercise (4‐second exercise test [4sET]) prior to a CPET. A continuous digital electrocardiogram (ECG) was recorded during 4sET and CPET, and later reviewed and interpreted by the same physician (who supervised all the procedures). Results: A total of 1125 subjects (43%) had cardiac arrhythmias during one or both procedures. About 57% of the arrhythmias were supraventricular, but 47 subjects (2% of all subjects) presented more complex arrhythmias including 43 cases of nonsustained supraventricular tachycardia and four nonsustained ventricular tachycardia. While arrhythmias were more often exposed by the CPET (P < 0.01), in 221 cases (10% of the total sample) of arrhythmias they were only induced by 4sET; these included four cases of nonsustained supraventricular tachycardia. Conclusion: 4sET‐induced arrhythmias tend to be simple and were always short‐lasting. In some cases, ECG recording during 4sET showed arrhythmias that would not be induced by a progressive maximal exercise test. Different situations of exercise, sudden and short versus maximal and progressive, tend to generate different arrhythmic responses and possibly complementary clinical implications. Ann Noninvasive Electrocardiol 2010;15(2):151–156     

Potential goals for the dimensions of the pulmonary arteries and aorta with stenting after the Fontan operation.

The purpose of this study was to clarify desired stent sizes for stenotic lesions in the post-Fontan circulation. Using angiograms from 22 patients before and at late follow-up (> or = 15 years) after the Fontan operation, we measured the maximum diameters of the proximal pulmonary arteries (PA) and the descending aorta. The diameters of the PA ipsilateral to the inferior vena cava, contralateral to the inferior vena cava, and descending aorta after the Fontan were 10.6-22.6 (15.8 +/- 3.3), 8.0-19.1 (12.9 +/- 3.1), and 12.1-18.9 (15.8 +/- 2.0) mm, respectively, while the percent of normal predicted diameters (% N) were 55%-104% (70% +/- 14%), 38%-99% (66% +/- 17%), and 46%-74% (60% +/- 7%), respectively. Despite somatic growth, the % N of all vessel diameters decreased significantly after the Fontan operation. In conclusion, smaller-sized stents should be acceptable for both the pulmonary artery and descending aorta in the Fontan circulation.     

急进高原卫生应急人员血氧饱和度及心率与高原反应症状发生关系研究

暴露于高原严苛的环境条件时,心血管系统会产生一系列适应性改变以更好的完成氧气输送、能量代谢等,从而抵抗高原带来的不利影响、满足机体需求。本文通过对高原心血管系统的病理生理学变化、高原心肌适应的分子机制、合并心血管疾病患者的高原建议三个方面进行综述,拟为高原心血管疾病的干预及治疗提供理论依据,进而有助于提高高原健康水平和作业能力。

     

Oxygen saturation in adult cystic fibrosis patients during exercise at high altitude.

The objective of this study was to determine the frequency and severity of decreased arterial oxy-hemoglobin saturation during exercise in adults with cystic fibrosis at 1,500 m above sea level. A convenience sample of 50 adults with cystic fibrosis who did not have hypoxemia (oxygen saturation, < 90%) at rest were evaluated. Spirometry was performed according to American Thoracic Society standards, and maximal exercise tests were performed on an electronically braked cycle ergometer using a ramp protocol individualized for each patient. Pulse oximetry was measured every 2 min. When exercising at high altitude, 45 of 50 patients had a decrease in arterial oxy-hemoglobin saturation from baseline to some degree. In 29 patients, oxy-hemoglobin saturation fell below 90%; in 14 patients, it fell below 85%; and in 4 patients, it fell below 80%. Oxy-hemoglobin saturation decreased to < 90% in 12 of 14 patients with severe pulmonary disease (FEV(1) < 40% predicted), in 15 of 26 patients with moderate disease (40% less than or equal to FEV(1) < 70% predicted), in 2 of 6 patients with mild disease (70% less than or equal to FEV(1) < 90% predicted), and in 0 of 4 with normal pulmonary function (FEV(1) greater than or equal to 90%). Percent predicted FEV(1) (r = 0.57; P < 0.0001) and FEV(1)/FVC ratio (r = 0.52; P < 0.0001) most highly correlated with arterial oxy-hemoglobin saturation at peak exercise. We conclude that at 1,500 m above sea level, adult CF patients with obstructive airways disease are at significant risk for decreased arterial oxy-hemoglobin saturation during exercise. A supervised exercise test should be considered prior to recommending an exercise program for such patients.     

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca²⁺, and PKCε; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1⁺ and AQP4⁺, we show that transfected CRFR1⁺ contributes to edema via transfected AQP4⁺. In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.Approximately 140 million people around the world live at altitudes of >2,500 m, including >8 million who live on the Qinghai–Tibet plateau of China at an average elevation of >4,000 m. Living at these altitudes requires physiological adaptations to compensate for the lower partial pressure of oxygen (1). In travelers who ascend to altitudes too high or too quickly (2–4) or in people with fatigue and infection or psychological stress (3, 4), hypoxia can induce acute mountain sickness (AMS) that can develop into high-altitude cerebral edema (HACE), a serious and often fatal condition (2–6). Today’s ability to travel rapidly to high altitudes means that, every year, millions of people are exposed to the risk of AMS and HACE (7).In human volunteers exposed for 32 h to hypobaric hypoxia (corresponding to 4,572 m altitude), brain volume increases by 2.77% (8), whereas normobaric hypoxia (12% O₂, corresponding to a simulated altitude of 4,500 m) for 16 h produces 50% AMS, headache, a mild increase in brain volume, and cytotoxic cerebral edema (9). A recent study reported that seven of nine male students exposed to isobaric hypoxia (inhaled room air enriched with N₂ for 6 h to obtain arterial saturation values of 75–80%) developed AMS; the mean apparent diffusion coefficient (ADC) increased by 2.12% in these subjects, indicating mild extracellular (vasogenic) cerebral edema. The ADC changes were negatively correlated with AMS scores, suggesting that severe AMS is associated with intracellular (cytotoxic) cerebral edema in addition to vasogenic edema (10).In parallel with the increasing brain water content, hypoxia acutely activates the hypothalamic–pituitary–adrenal axis in rats (11–13), increasing corticotropin-releasing factor (CRF) and endothelin-1 (ET-1) expression in the paraventricular nucleus of the hypothalamus (14). We previously showed that these effects are mediated by CRF receptor 1 (CRFR1) (12, 14). These observations led us to speculate that other CRF systems in the brain (15, 16) might also be involved in the response to hypoxia.Aquaporin-4 (AQP4), a water channel protein, is expressed in astrocytes, especially in the foot processes (17), and is a primary influx route for water during brain edema in pathologies such as brain injury, stroke, and brain tumors. Because both CRF and its receptor are widely distributed in the central and peripheral nervous systems (18–21), including in astrocytes, microglia, and neurons of the cortex (22), we hypothesized that cortical astrocytes that express both CRFR1 and AQP4 might be involved in hypoxia-induced brain edema.In this study, we addressed the hypothesis that, during high-altitude hypoxia, CRF mediates cerebral edema through CRFR1 signaling and AQP4 activation in cortical astrocytes.     

Acute mountain sickness is associated with sleep desaturation at high altitude

OBJECTIVE: This study was intended to demonstrate a biologically important association between acute mountain sickness (AMS) and sleep disordered breathing. METHODOLOGY: A total of 14 subjects (eight males, six females aged 36 +/- 10 years) were studied at six different altitudes from sea level to 5050 m over 12 days on a trekking route in the Nepal Himalaya. AMS was quantified by Lake Louise (LL) score. At each altitude, sleep was studied by 13 channel polysomnography (PSG). Resting arterial blood gases (ABG) and exercise SaO2 were measured. Ventilatory responses (VR) were measured at sea level. Individual data were analysed for association at several altitudes and mean data were analysed for association over all altitudes. RESULTS: ABG showed partial acclimatization. For the mean data, there were strong positive correlations between LL score and altitude, and periodic breathing, as expected. Strong negative correlations existed between LL score and PaO2, PaCO2, sleep SaO2 and exercise SaO2, but there was no correlation with sea level VR. There were equally tight correlations between LLs/PaO2 and LL score/sleep SaO2. The individual data showed no significant correlations with LL score at any altitude, probably reflecting the non-steady state nature of the experiment. In addition, mean SaO2 during sleep was similar to minimum exercise SaO2 at each altitude and minimum sleep SaO2 was lower, suggesting that the hypoxic insult during sleep was equivalent to or greater than walking at high altitude. CONCLUSIONS: It is concluded that desaturation during sleep has a biologically important association with AMS, and it is speculated that under similar conditions (trekking) it is an important cause of AMS.     

小剂量替罗非班治疗高原非ST段抬高型急性冠脉综合征的临床观察

目的:观察小剂量替罗非班治疗高原非ST段抬高型急性冠脉综合征(NSTE-ACS)患者的疗效及安全性。方法: 将75例NSTE-ACS患者随机分为对照组(n=37)和观察组(n=38)。两组均常规使用阿司匹林、氯吡格雷、低分子肝素等药物治疗,观察组加用小剂量替罗非班［负荷量0.3 μg/（kg·min）×30 min,维持量0.05 μg/（kg·min）×72 h］微量泵静脉泵入。检测治疗前后血小板计数和血小板聚集率;观察30 d内心血管事件和出血事件的发生率。结果: 对照组30 d内心血管事件的发生率为22%,观察组为5%,两组间有显著差异(P<0.05);对照组30 d内出血事件的发生率为5%,观察组为8%,两组间无显著差异;对照组血小板聚集率治疗前后无显著变化,观察组治疗后血小板聚集率显著降低(P<0.05)。两组患者中均未观察到血小板减少的发生。结论: 小剂量替罗非班联合阿司匹林、氯吡格雷和低分子肝素治疗高原NSTE-ACS是安全和有效的。     

Evaluation of Regional Myocardial Function by Doppler Tissue Imaging in Univentricular Heart after Successful Fontan Repair

Background: The univentricular heart (UVH) corrected by Fontan repair is characterized by a single dilated pumping chamber, which is both hypertrophic and hypocontractile. The complex geometrical distortion and asynchronous contraction of this organ prevents assessment of systolic and diastolic function by traditional echocardiographic procedures. Methods: Sixteen children (10 males, 6 females) aged 12–31 years, who had undergone UVH Fontan repair were enrolled in the study. A transthoracic echocardiography was performed. Twelve different myocardial wall segments from single ventricles were studied by Doppler tissue imaging to measure peak systolic velocity (S), isovolumetric relaxation time (IRT), isovolumetric contraction time (ICT), and E′/A′ ratio. Results: S and E′/A′ ratio were significantly lower in the UVH group than in controls (P < 0.01 and P < 0.05, respectively). IRT and ICT were significantly longer in UVH than in controls (P < 0.001 and P < 0.005, respectively). In the UVH, both systolic and diastolic deficits were generally registered in the apical segments and also randomly distributed between the basal and middle segments of the single ventricle. Conclusions: It is an acknowledged fact that compared to normal children ventricular function is impaired in patients with UVH. Tissue Doppler imaging at multiple points of the single ventricle provides a complete, accurate assessment of systolic and diastolic function after Fontan repair, overcoming problems posed by geometrical distortion and limitations of conventional echocardiographic methods. (Echocardiography 2010;27:702‐708)     

Does high altitude increase risks of the elderly patients with coronary artery disease？

Objective To assess the effect of altitude hypoxia on the elderly patients with coronary artery disease （CAD）. Methods Three subject groups were surveyed during their train trip on the highest railroad the Qinghai-Tibet Railway： 22 elderly individuals with documented CAD, 20 healthy elderly controls, and 20 healthy young controls, all of whom from Beijing near the sea level （76 m）, Survey questions addressed clinical features of their healthy conditions and aspects of their coronary disease. The baseline study was performed at Xining at an altitude of 2261m, and then during acute exposure to altitudes of 2808 m, 4768m, 5072 m and 4257 m by train for 24 hours. Resting pulse rate, blood pressure, oxygen saturation, electrocardiograph （ECG）, and cardiac work estimated by the heart rateblood pressure double product were obtained five times in each subject at different altitudes. Results On arrival to altitudes between 4768 m and 5072 m, the older passengers, especially those with preexisting coronary disease, had higher HR, higher BP, and lower SaO2, as well as more frequent abnormalities on ECG, as compared to the younger healthy subjects. As compared with the healthy elderly controls, incomplete right bundle branch block, left ventricular hypertrophy, and ST segment depression were more frequently seen in the elderly coronary patients （P〈0.01）. Cardiac work in group 1 was increased by 13% 12 hours after arrival to altitudes between 2808 m and 5072 m. Oxygen saturation decreased significantly with the altitude increasing by train ascent but improved after inhalation of oxygen. Most of the older subjects tolerated their sojourn at high altitude well except one who developed angina repeatedly with a significant ST segment depression. Conclusions Coronary events and ECG signs of myocardial ischemia are rare in elderly individuals with CAD who travel from sea level to moderate altitudes of 1500m to 2800 m. Patients with CAD who are well compensated at sea level generally tolerate this moderate altitude well. However, it would be prudent for patients with CAD going to altitude above 3000 m. The patients should consult their physician before undertaking a trip to such altitude （J Geriatr Cardio12009; 6：137-141）.     

From the Cover: Contribution of a mutational hot spot to hemoglobin adaptation in high-altitude Andean house wrens

A key question in evolutionary genetics is why certain mutations or certain types of mutation make disproportionate contributions to adaptive phenotypic evolution. In principle, the preferential fixation of particular mutations could stem directly from variation in the underlying rate of mutation to function-altering alleles. However, the influence of mutation bias on the genetic architecture of phenotypic evolution is difficult to evaluate because data on rates of mutation to function-altering alleles are seldom available. Here, we report the discovery that a single point mutation at a highly mutable site in the β^A-globin gene has contributed to an evolutionary change in hemoglobin (Hb) function in high-altitude Andean house wrens (Troglodytes aedon). Results of experiments on native Hb variants and engineered, recombinant Hb mutants demonstrate that a nonsynonymous mutation at a CpG dinucleotide in the β^A-globin gene is responsible for an evolved difference in Hb–O₂ affinity between high- and low-altitude house wren populations. Moreover, patterns of genomic differentiation between high- and low-altitude populations suggest that altitudinal differentiation in allele frequencies at the causal amino acid polymorphism reflects a history of spatially varying selection. The experimental results highlight the influence of mutation rate on the genetic basis of phenotypic evolution by demonstrating that a large-effect allele at a highly mutable CpG site has promoted physiological differentiation in blood O₂ transport capacity between house wren populations that are native to different elevations.An important question in evolutionary genetics is whether certain mutations or certain types of mutation make disproportionate contributions to phenotypic evolution (1–6). Within a given gene, the mutations that contribute to evolutionary changes in phenotype may represent a biased, nonrandom subset of all possible mutations that are capable of producing the same functional effect. The preferential fixation of particular mutations (substitution bias) could have several causes. Most theoretical and empirical attention has focused on causes of fixation bias, i.e., mutations have different probabilities of being fixed once they arise, due to differences in dominance coefficients or the magnitude of deleterious pleiotropy (1, 2, 4, 7–9). In principle, substitution bias can also stem directly from mutation bias (some sites have higher rates of mutation to alleles that produce the change in phenotype) (4, 9–11). However, empirical evidence for the importance of mutation bias is scarce for an obvious reason: even in rare cases where it is possible to document the contributions of individual point mutations to evolutionary changes in phenotype, data on rates of mutation to function-altering alleles are typically lacking. Rare exceptions include cases where loss-of-function deletion mutations can be traced to hot spots of chromosomal instability or highly mutable changes in the copy number of repetitive elements (12). Documenting cases where genetic changes at highly mutable loci contribute to phenotypic divergence is therefore important for elucidating the evolutionary significance of mutation bias. This is especially true for cases where mutations cause fine-tuned modifications of protein activity rather than simple losses of function.Here, we report the discovery that a single amino acid replacement at a mutational hot spot in the avian β^A-globin gene has contributed to an evolutionary change in hemoglobin (Hb) function that has likely adaptive significance. By conducting experiments on native Hb variants and engineered recombinant Hb mutants, we demonstrate that a nonsynonymous mutation at a CpG dinucleotide in the β^A-globin gene of Andean house wrens (Troglodytes aedon) has contributed to an evolved difference in Hb–O₂ affinity between high- and low-altitude populations. In mammalian genomes, point mutations at CpG sites occur at a rate that is over an order of magnitude higher than the average for all other nucleotide sites (13, 14), and available data suggest a similar discrepancy in avian genomes (15, 16).Andean house wrens are compelling subjects for studies of Hb function because this passerine bird species has an exceptionally broad and continuous elevational distribution, ranging from sea level to elevations >4,500 m (17). At 4,500-m elevation, the standard barometric pressure is ∼450 torr, so O₂ partial pressure (PO₂) is <60% that at sea level (∼96 torr compared to ∼160 torr). Under such conditions, enhancements of pulmonary O₂ uptake and blood O₂ transport capacity are required to sustain O₂ flux to the tissue mitochondria in support of aerobic ATP synthesis (18). To complement changes in the cardiorespiratory system and microcirculation, changes in the O₂-binding affinity and cooperativity of Hb can enhance the O₂ capacitance of the blood (the total amount of O₂ unloaded for a given arteriovenous difference in O₂ tension). Because the optimal Hb–O₂ affinity is expected to vary according to the ambient PO₂, genetic variation in oxygenation properties of Hb may be subject to spatially varying selection between populations that inhabit different elevations. House wrens colonized South America in the late Pliocene or early Pleistocene via the newly formed Panamanian land bridge (19, 20), so the species may have been resident in the Andean highlands for up to ∼3 million years.The Hb tetramer is composed of two semirigid α₁β₁ and α₂β₂ dimers that undergo a mutual rotation during the oxygenation-linked transition in quaternary structure between the deoxy (low-affinity “T”) conformation and the oxy (high-affinity “R”) conformation (21). This oxygenation-linked structural transition between the T and R states is the basis for cooperative O₂ binding, and is central to the allosteric function of Hb as an O₂ transport molecule. Our analysis of house wren Hb highlights the influence of mutation rate on the genetic basis of phenotypic divergence by demonstrating that mutation at a CpG dinucleotide produced a large-effect amino acid replacement at an α₁β₁ intradimer contact (β55Val→Ile)—a replacement that produced a significant increase in Hb–O₂ affinity.     

Asthma in Patients Climbing to High and Extreme Altitudes in the Tibetan Everest Region

Objectives: The aim of this study was to investigate the behavior of asthma in patients traveling to high and extreme altitudes. Methods: Twenty-four Dutch patients with mild asthma did a trekking at high and extreme altitudes (up to 6410 m = 21030 ft) in the Tibetan Everest region. Asthma symptoms, use of asthma medication, symptoms of acute mountain sickness, spirometry, peripheral oxygen saturation, and heart rate were measured at 1300 m (baseline), and at 3875, 4310, 5175, and 6410 m. Asthma symptoms were assessed by means of a modified version of the Asthma Control Test. Symptoms of acute mountain sickness were scored by the Lake Louise self-report questionnaire. The expedition staff, consisting of seven healthy persons, acted as a control group. Results: In both asthmatics and controls, forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) decreased with increasing altitude, whereas FEV1 as percent of FVC (FEV1%FVC) did not change. In both groups, peak expiratory flow (PEF) increased with increasing altitude. In general, differences in spirometric values between asthmatics and controls were not significant. Asthma symptoms did not change with increasing altitude. During ascent, less than half of the asthma patients increased their medication use. According to the Lake Louise score, no acute mountain sickness occurred, except for in the asthma group at 6410 m, which showed mild acute mountain sickness at that altitude. As expected, peripheral oxygen saturation decreased with increasing altitude in asthmatics and controls, differences between the two groups not being significant. In general, heart rate (at rest) did not change with altitude, except for an increase in asthmatics at 6410 m. Conclusions: These results suggest that traveling to high and extreme altitudes is safe for patients with mild asthma.