Brain Magnetic Resonance Imaging After Versus Before Climbing to 7126 m Shows No Focal White Matter Hyperintensities and Hemosiderin Depositions in Some Climbers

Mostly, small prospective or cross-sectional studies have previously reported various morphological changes in the brain detectable by magnetic resonance imaging (MRI) after exposures between 5000 and 8848 m such as cortical atrophy, focal white matter hyperintensities independent of acute mountain sickness (AMS) or high altitude cerebral edema (HACE), and hemosiderin deposition predominantly in the corpus callosum after HACE. Kottke et al. (2015) performed brain MRI in a prospective study on 38 mountaineers attempting to climb to 7126 m. They found no white matter hyperintensities and no cortical atrophy, a minor increase of white matter volume, and hemosiderin depositions in 3 of the 15 subjects reaching altitudes above 7000 m.

The significance and cause of a mild increase in white matter volume remain unclear because potential confounders, which could contribute to such findings, were not assessed. It appears that microhemorrhages occur without HACE. Nevertheless, these subjects were more hypoxemic and it cannot be excluded that signs of mild cerebral edema during ascent might have been missed.

Smoking Is Neither a Risk Factor Nor Protective for AMS

Recently published studies investigating the association of smoking and AMS have yielded controversial results as discussed in earlier sightings of the Journal. A systematic search (Vinnikov et al., 2015) identified 21 studies involving 16,566 subjects with quantitative data on smoking status and prevalence of AMS. Meta-analysis of these data revealed that cigarette smoking neither increased the risk nor protected from AMS and there were no significant effects of occupational status, altitude, study design, or geographical location on the examined association. Thus, this meta-analysis indicates that smoking status has no relevant impact on the prevalence of AMS.

Potential Implications of Cerebrospinal Fluid Dynamics for the Pathophysiology of AMS

This review (Lawley et al., 2015) is part of a series of articles that are published in the Journal of Applied Physiology and summarizes lectures that were given at the International Hypoxia Symposium 2015 in Lake Louise. It discusses the physiology of cerebrospinal fluid (CSF) fluid dynamics and suggests that low or exhausted spatial volume compensation of CSF may increase intracranial pressure (ICP) above normal with exercise or maneuvers that impair cerebral venous outflow despite normal ICP at rest. Intermittent increase of ICP could sensitize or activate pain-sensitive structures of the brain and account for symptoms of AMS. The authors suggest that susceptibility to AMS depends on the magnitude of physiologic responses of ventilation and cerebral vasculature to hypoxia and on anatomical factors such as craniospinal compensatory capacity for CSF and cerebral venous outflow capacity.

Multiple Gene Polymorphisms Associated with HAPE After Rapid Exposure to 3658 m

Ten genes with potential significance for the pathophysiology of HAPE were examined in 103 patients with HAPE and 200 controls. All subjects were recruited from a group of 1200 healthy military recruits (18–20 years old) who were flown from Chengdu (505 m) to Lhasa (3658 m) (Wu et al., 2015). Single-nucleotide polymorphisms of six genes (angiotensin converting enzyme, NO synthase, surfactant protein A2, prolyl hydroxylase [EGLN1], heat shock protein-70 [HSP70], and plasminogen activator inhibitor-1 [PAI-1]) were significantly associated with HAPE occurrence suggesting that HAPE is a polygenic disease associated with multiple genetic polymorphisms. Phenotyping of HAPE by clinical assessment only without blood gas analysis and chest radiography may explain the unusually high incidence of HAPE of 8.6% at the moderate altitude of 3658 m and somewhat limits the interpretation of the data.

Plasma Metabolite Signature for the Diagnosis of HAPE

Guo et al. (2015) set out to identify biomarkers of HAPE by assessing plasma metabolites using high-performance liquid chromatography coupled with mass spectrometry in 35 subjects with radiographically confirmed HAPE versus a matched control group at 2780–4500 m. Fourteen metabolites were differently expressed between these groups. A metabolite signature, including three of them (C8-ceramide, sphingosines, and glutamine), showed a sensitivity of 86% and a specificity of 82% for identifying HAPE subjects in a validation set of 22 patients in each group. This elaborate approach of looking for differences in metabolism leads to a wealth of data that are difficult to untangle with regard to underlying mechanisms of HAPE. Since data were obtained during HAPE, it is not clear which of these differences in plasma proteins can be attributed to pathways contributing to the susceptibility of HAPE and which are simply a consequence of (any) pulmonary edema such as more severe hypoxemia, tissue damage, and (secondarily) inflammatory responses.

Although biomarkers of HAPE susceptibility might in the future reach scientific and practical significance, they are not necessary in a clinical setting in which history taking, clinical examination, blood gas analysis, and chest radiographs are sufficient for diagnosing HAPE.

Nitrate Supplementation Increases Endothelial Function but Has No Effect on Performance and Pulmonary Vasoconstriction in Hypoxia

Beetroot juice is rich in nitrate. Nitrate supplementation has been shown to increase endogenous nitric oxide (NO) bioavailability by conversion to nitrite and increase performance in normoxia in moderately trained athletes. Decreased NO bioavailability and decreased endothelial function have been found in HAPE and in HAPE-susceptible subjects during hypoxia. Acute beetroot juice supplementation (containing 5 mmol nitrate) abolished altitude-reduced endothelial dysfunction assessed by flow-mediated dilation in 10 trekkers at 3700 m in a double blind, placebo controlled crossover study. Despite this beneficial vascular short-term effect reported by one group (Bakker et al., 2015), another group was unable to find any clinically significant effects of oral nitrate supplementation in a different setting on pulmonary artery pressure and cycling performance (Bourdillon et al., 2015). These investigators gave roughly an equivalent dose of nitrate as above (0.1 mmol nitrate/kg/day) or placebo over 3 days before an acute exposure to normobaric hypoxia (F_IO₂ 0.11 corresponding to a P_IO₂ at 5000 m) in 22 well-trained cyclists.

Normobaric and Hypobaric Hypoxia Have Similar Effects on Hemoglobin Mass and Performance in Well-Trained Cyclists

Some physiologic responses to hypoxia such as changes in ventilation or fluid balance are (slightly) different when exposures to hypobaric and normobaric hypoxia are compared. There is an ongoing discussion, however, whether this results in differences at a whole body clinical level such as prevalence of AMS or training responses. Hauser et al. (2015) show that this is not the case with hemoglobin mass and performance after 18 days of living high and training low (LHTL). Hemoglobin mass increased similarly in 22 well-trained triathletes, when living 23 hours in hypobaric versus normobaric hypoxia corresponding to an altitude of 2250 m. The decrease of 3%–4% in 3 km running time after 18 days of LHTL was also similar between these groups. Interestingly, differences in cycling performance between the LHTL groups and a control group training and living at low altitude were rather small and not statistically significantly different.

Physiological Characteristics of Elite High-Altitude Climbers

Whether elite mountaineers have cardiorespiratory characteristics different from equally fit lowland athletes has been the subject of much study, which finds in general that climbers do not have better maximal exercise capacity and oxygen consumption and the two groups have equivalent decreases in VO₂ max with hypoxia. In a study of 11 climbers and 11 nonclimber trained control subjects, Puthon et al. (2015) found (1) no differences in VO₂ max and similar falls in VO₂ max with cycling exercise breathing 12% oxygen and (2) similar arterial and cerebral cortex oxygenation changes in hypoxia at rest and exercise. In contrast, the climbers compared to the controls had (1) lower isocapnic hypoxic and hyperoxic hypercapnic ventilatory responses by almost 40%–60%, (2) a slower and deeper pattern of breathing, and (3) better oxygenation of exercising muscles during hypoxia than the controls.

These findings suggest that climbers are able to better maintain muscle oxygenation in hypoxia, perhaps as a result of training and changes in muscle blood flow and O₂ utilization, but surprisingly do not confer any greater VO₂ max capacity. The slower deeper pattern of breathing would be expected to yield higher arterial oxygenation saturation because of greater alveolar ventilation at equal total ventilation, but this was not evident. Thus, it remains the case that standard cardiopulmonary exercise and ventilatory response testing do not reveal any easy explanations for the particular capacities of elite climbers.

AMPK Activation in Uterine and Placental Vessels with Hypoxia During Pregnancy

The stress for the mother and offspring at high altitude is delivery of sufficient oxygen to the fetus for proper growth and maturation. This requires uterine artery vasodilation to increase uteroplacental blood flow. Skeffington et al. (2015) found that AMP kinase (AMPK), a critical signaling molecule, for adaptation to hypoxia and ischemia is upregulated in uterine arteries and placental tissue of the mouse and has vasodilator effects against phenylephrine-constricted vessels. NO synthase inhibitors abrogated this vasodilator action, suggesting an NO-mediated effect through AMPK-enhanced NO synthase activity. The authors also obtained placentas from nonlaboring low-altitude and high-altitude mothers and demonstrated greater AMPK staining in the high-altitude mothers, along with increased expression of several downstream AMPK targets. Manipulation of AMPK during high-altitude pregnancies or low-altitude high-risk pregnancies appears a very reasonable strategy to enhance maternal and fetal health.

The Power and Complexities of Placebos for High-Altitude Headache

Placebo treatment arms are a fundamental aspect of clinical research, but placebos, themselves, may have a therapeutic benefit. Furthermore, the forms of placebos may have unique actions dependent upon their route of delivery or application. Placebos used for high-altitude research have included pills, masks with different inspired gas mixtures, and sham barometric pressure, to name a few. In an interesting and somewhat complicated study (Benedetti and Dogue, 2015), four groups of healthy subjects were taken by cable car to 3500 m and studied for their responses to active and placebo treatments of high-altitude headache over the next 2 days. The subjects rated their headache intensity after 1 hour of exercise (which is known to aggravate or induce headache), twice on the first day and then twice again on the second day. For the first three exposures, group 1 was treated with nothing, group 2 with inspired oxygen, group 3 with aspirin, and group 4 with oxygen. On the last session, for the four groups, the treatment was nothing, placebo oxygen, and placebo aspirin, respectively. Oxygen given to the subjects with their knowledge reduced headache scores and had the expected results of better oxygen saturation, reduced ventilation, lower arterial pH, and a reduction in salivary PGE2. With aspirin, headache intensity was reduced, although not as effectively as oxygen. Reductions in PGE2 and other prostaglandin metabolites were noted with aspirin. When the subjects on the fourth test without their knowledge were given placebo ambient air or placebo aspirin pills, headache intensity was equally improved as before. Interestingly, placebo oxygen reduced ventilation, alkalosis, and salivary PGE2, but with no change in arterial oxygenation. Placebo aspirin caused the same reductions in all prostaglandin metabolites as with aspirin. In group 4, with previous oxygen treatments, but placebo aspirin during the last session, headache was not affected and there were none of the physiological or biochemical changes. These findings reveal the power, complexity, and different routes of mechanisms by which various placebos can act. Thus, in clinical trials, the method of placebo application and selection of outcome measures may need to be very carefully considered.

Acetazolamide Improves Brain Tissue Oxygenation by Reducing Cerebral O₂ Consumption

Acetazolamide enhances acclimation to high altitude and reduces acute mountain sickness. Previous work has shown that hypoxia typically experienced by humans at high altitude increases the cerebral metabolic rate and oxygen consumption (CMRO₂). Common wisdom is that acetazolamide improves brain PO₂ by increasing ventilation, PaO₂, and oxygen saturation. Wang et al. (2015) used MRI to measure cerebral blood flow (CBF), CMRO₂, and cerebral tissue PO₂ (PtiO₂) in healthy humans exposed to 6 hours of normobaric hypoxia (12.5% O₂) to determine whether acetazolamide alters brain oxygen consumption.

On the first day, no drug was given and on the following day, the same protocol was repeated with the subjects given acetazolamide orally 125 mg 2 hours before the baseline normoxic MRI scan, and then 125 mg again 3 hours before the MRI done at the end of the 6-hour hypoxic exposure. Acetazolamide in the normoxia caused no changes in CBF, CMRO₂, and PtiO₂. During hypoxia, CBF increased by 30% and CMRO₂ increased by 15%, with a fall in PtiO₂ from 25 to 11.4 mmHg. Acetazolamide reduced the rise in CBF with hypoxia and prevented the rise in CMRO₂. Despite the expected decrease in O₂ delivery with reductions in CBF and blood O₂ content, the net effect of these changes was that PtiO₂ in hypoxia fell only to 16.5 mmHg. The authors speculate that carbonic anhydrase inhibition in the brain and brain vasculature leads to a degree of CO₂ retention that may act by decreasing the activity of phosphofructokinase activity, the rate-limiting enzyme in glycolysis.

Sleep Disordered Breathing, Pulmonary and Systemic Blood Pressures, and Patent Foramen Ovale in Chronic Mountain Sickness

Chronic mountain sickness (CMS) is associated with systemic and pulmonary hypertension, but the mechanisms underlying vascular dysfunction remain enigmatic. Because sleep disordered breathing (SDB) causes vascular dysfunction at low altitudes, Rexhaj et al. (2015) studied 23 patients with CMS living at 3600 m and compared them to a roughly age-matched group of residents without CMS.

They measured systemic and pulmonary artery blood pressures (by transthoracic echocardiography) and performed overnight sleep recordings of arterial oxygenation saturation and sleep-associated apnea–hypopnea index (AHI). In a subgroup of 15 subjects with SDB, they searched for a patent foramen ovale (PFO) by transesophageal echocardiography. In the CMS patients, SDB and nocturnal hypoxemia were more severe than in controls (SaO₂: 80% vs. 86%; AHI: 39 vs. 14 events per hour). AHI correlated with systemic and pulmonary artery pressure. The presence of a PFO was associated with more severe SDB. These findings support a significant role of sleep-related disordered breathing and hypoxemia on the systemic and pulmonary hypertension of CMS. The presence of a PFO adds to this burden.

Lung Volumes, Ethnicity, and Childhood High-Altitude Residence

Populations that have dwelled at high altitude (Tibetans and Andeans) have larger lung volumes relative to body size than lowland dwellers. While greater lung volumes have been largely considered a genetically determined feature, likely conferring an evolutionary advantage, exposure to hypoxia during growth through the teenage years may also lead to larger lung volumes. Weitz et al. (2015) studied 1063 children and adolescents (from age 6–20) and 184 adults (age range: 21–39) of both Han and Tibetan ancestry, all of whom had lived their entire lives at high altitude (3200–4300 m) in the Qinghai Province of China. The FEV₁ and FVC values of the Han, born and raised at high altitude, are slightly lower than Tibetans up through age 15–16, but the variance is explained by differences in height. However, beyond these years, lung volumes are greater in adult Tibetans than in Han adults. This suggests that there is a unique pattern of further lung growth into adulthood that may be unique to Tibetans, as part of their heritage of longer residence at high altitude as a population.

Hypoxia in Drosophila: Lessons for Humans

The study of the common fruit fly, Drosophila melanogaster, has yielded considerable understanding to genetics in general and more recently to hypoxia tolerance. In a study of the cardiac responses to hypoxia in Drosophila, Zarndt et al. (2015) found that mutations in the sima gene (a homolog of mammalian hypoxia inducible factor 1 alpha, HIF1α) yielded a range of survival in acute and chronic hypoxia of various durations (acute: 30 minutes, sustained: 18 hours, and chronic: 3 weeks) and during reoxygenation. While wild-type flies quickly recovered with reoxygenation after acute hypoxia exposures, exposures of longer duration significantly compromised heart function during reoxygenation. Flies with mutations in sima displayed exaggerated reductions in cardiac output (measured by video imaging) with hypoxia. In flies selected over many generations for hypoxia tolerance, they showed reductions in cardiac output compared to normoxic controls. Hypoxia-tolerant flies had smaller hearts, increased collagen deposition, and reductions in contractility.

These findings suggest that sima has important effects on cardiac function in hypoxia and provide a model system of considerable power to study hypoxic responses and generate quickly tested hypotheses. Extension and relevance to mammalian systems must always take into account critical differences in organ function in such systems, such as the fact that insect hearts play very little role in O₂ delivery to tissues, since that function is assigned to the tracheal-respiratory system, an extensive network of tubules throughout the body connected to the environment through spiracles on the exoskeleton.