Another MRI study of the brain in normobaric hypoxia

The study by Rupp et al. (2014) investigated the brain by 3T MRI after 0.5 and 10 hours of exposure to acute normobaric hypoxia including 3×80 min of exercise at 45 % of maximum normoxic workload (152 W). The novel part of this study consisted of the early measurement after 0.5 h and of matching SaO2 during exposure at rest with the SaO₂ values measured during the exposure with exercise. This resulted in an average FIO₂ between 0.08 and 0.12 with resting in hypoxia. White matter volume increased significantly in hypoxia without difference between the exercise and non-exercise condition while total brain volume increased in hypoxia only after exercise. Cerebral blood flow measured by arterial spin labelling did not change significantly and a decrease of the apparent diffusion coefficient after 10 hours of hypoxia was comparable between exercise and rest. Neither of these changes correlated with the Lake Louise score, the acute mountain sickness (AMS)-C score or a visual analogue score for headache obtained after 11 hours of exposure. These scores were not different between the exposures with rest and with exercise. The study confirms earlier findings by the same group of moderate exercise not enhancing AMS and of brain volume changes occurring independently of AMS symptoms.

Identification of molecular mechanisms leading to cerebral edema in hypoxia in the rat brain

Chen et al. (2014b) demonstrated by expression analysis in rat brains and in cultured primary astrocytes as well as by in transfection experiments in cell cultures that hypoxia triggers the cortical release of corticotropin releasing factor (CRF), which activates a singling pathway that causes phosphorylation and thus activation of the aquaporin-4 causing swelling of astrocytes. HIF-1α is appears not to be involved in astrocyte swelling. Furthermore, hypoxia activated CRF receptor type 1 (CRFR1) and endothelin-1 modulated by CRFR1 and NFk-B contribute to apoptosis. These studies give an excellent insight into the mechanisms underlying hypoxic cytotoxic brain edema in rats rapidly exposed to 7000 m demonstrated by a decrease of the apparent diffusion coefficient and an increase of whole brain water content. How these findings relate to human high altitude cerebral edema that may occur at much lower altitudes and that is characterized by vasogenic edema causing micro hemorrhages in the corpus callosum remains to be determined.

Twin study on cardiorespiratory response to acute exposure to normobaric hypoxia

Masschelein et al. (2014) exposed 13 pairs of monozygotic twins to normobaric normoxia and hypoxia (FIO₂=0.107 corresponding to an ambient PO₂ at 5300 m) within 5 hours and assessed the maximal and submaximal exercise response within the next 3 hours at the respective environment. Between-pair variance was substantially larger than within-pair variance for the hypoxia induced changes such as the decreases of SpO₂ (3-4 fold), VO_2max (4-fold), maximal heart rate (8 fold), and increases of submaximal heart rate (7 fold), hypoxic ventilatory response (6 fold) and the incidence of acute mountain sickness (AMS). This study shows that genetic factors contribute to cardiorespiratory regulation, the maintenance of exercise capacity as well as the development of AMS, which was associated with a lower hypoxic ventilator response and a lower urinary norepinephrine excretion.

Inhaled budesonide for prevention of acute mountain sickness

Chen et al. (2014a) found that inhalation of 200 μg budesonide twice a day reduced in particular more severe acute mountain sickness in healthy male predominantly smoking individuals (20±3 years) 20 and 72 hours after arrival at high altitude compared with inhalation of 160 mg budesonide and 4.5 mg formoterol twice a day, or an oral beta2 agonist (procaterol 25 μg twice a day), or placebo tablets. The medications were taken during 3 days prior to a 2.5 hours flight from 500 to 3700 m and discontinued after arrival at 3700 m. The data of this partly open trial support the results of a study by the same group (Zheng et al., 2014) commented in a previous sighting of this journal. However, it is somewhat surprising and not clear why the combination of budesonide and formoterol was not effective. Lung function was normal at low altitude and unchanged 20 h after arrival at 3700 m.

24 h ambulatory blood pressure measurements during trekking to and prolonged staying at 5400 m

Parati et al. (2014) performed 24 h ambulatory blood pressure measurements in healthy normotensive individuals under placebo or telmisartan (80 mg per day) during trekking to Everest base camp and during a stay of 12 days at 5400 m. Blood pressure increased at 3700 m and 5400 with ambulatory measurements showing greater increases than punctual conventional daily assessments. The rise in blood pressure was accompanied by an increase of plasma noradrenalin and a suppression of then renin-angiotensin-aldosterone system. Telmisartan lowered ambulatory blood pressure at sea level and 3400 m, but not at 5400 m. The study shows that the blood pressure rise in normotensive individuals during prolonged stay at 54000 m is on average moderate, does not rise further after staying 12 days at 5400 m but does not normalize with an angiotensin receptor blocker at this altitude.

Rapid increase and decrease of total hemoglobin mass during and after a prolonged stay at 5260 m—the challenge of a classical dogma

Textbooks say that a significant increase in total hemoglobin mass at altitude takes 2–3 weeks and that the decrease at low altitude is defined by the half-life of erythrocytes, which may be enhanced by neocytolysis. The AltitudeOmics group (Ryan et al., 2014) demonstrates how by measuring total hemoglobin with a CO-rebreathing method that hemoglobin mass at 5260 m increases significantly within 7 days, continues to increase over the next 10 days, and is back to pre-exposure values after return from 5260 m to 1525 m within 7 days. Increase in serum ferritin after return is compatible with increased destruction of erythrocytes. If the findings of this study can be confirmed by the gold standard method of labelling erythrocytes this unexpected results will drive new research about the regulation of hemoglobin mass in response to hypoxia.

The younger young are less susceptible to acute mountain sickness than the older young

A well standardized study with regard to recruitment, ascent rate, and activity at high altitude including a very large sample size of 856 altitude-naïve male Chinese lowland dwellers (age 18–35 years looked at the influence of age on the incidence of acute mountain sickness (AMS) at 3700 m (Tang et al., 2014). Subjects were flown from 500 to 3700 m in 2 hours and avoided exercise during the study. AMS was assessed in the morning of day 2 using the Lake Louise score. Mild AMS (LLS 3-4) was not significantly different between each age group with an incidence of 24–28% while more sever AMS (LLS>4) increased significantly with age: 26% (≤20 years), 30% (21–25 years), 44% (26–30 years) and 49% (31–35) years. The three items—headache, difficulty sleeping, and weakness or fatigue—all contributed to this difference. Thus, avoiding confounders like previous altitude experience, rate of ascent, or level of exercise, it appears that older age is a risk factor for AMS in a male population between 18 and 35 years if age. One wonders whether the often-described protective effect of age >60 years in epidemiologic studies in mountaineering populations can be attributed predominantly to self-selection or having learned over the years how to avoid AMS.

Isoflavones in the treatment of chronic mountain sickness

Soy isoflavones are natural phytoestrogens and have beneficial effects in various cardiovascular conditions, in part by stimulation of endogenous vascular nitric oxide (NO) production as estradiol does. Cui et al (2014) after having shown that genistein inhibits pulmonary vascular remodeling and right ventricular hypertrophy in chronically hypoxic rats, explored whether it can be used to treat chronic mountain sickness (CMS). They treated 28 Chinese men with CMS living at 5200 meters with 20 mg twice a day for 45 days and compared pre- and post-treatment outcomes on CMS scores, arterial O₂ saturation, hematocrit, circulating NO metabolites, oxidative stress, and echocardiographic assessment of right ventricular (RV) dimensions. CMS scores fell by 20–25% and mean arterial oxygen saturation rose by 2% with mean hematocrit falling from 71 to 67%. Circulating NO metabolites rose by 10% and malondialdehyde (a marker of oxidative stress) fell by 25%. RV function by echo was improved with overall reduction in measures of RV dilation. These results compare favorably and equally with other published drug treatments of CMS, including acetazolamide and various angiotensin converting enzyme inhibitors. A large randomized placebo-controlled study of these treatment options would be useful and hopefully provide guidance in best drug selection.

Lower plasma soluble erythropoietin receptor (sEpoR) concentration in chronic mountain sickness

The excessive erythrocytosis of chronic mountain sickness (CMS) is driven by greater Epo-mediated erythropoiesis. However, attempts to discover differences in erythropoietin concentration, Epo gene, and protein differences, as well as Epo receptor functional differences between those that develop CMS and those that do not have been unsuccessful. The Epo receptor (EpoR) exists in the cell membrane (mEpoR) of bone marrow erythroid precursors where upon ligation with Epo it prevents programmed cell death (apoptosis) and allows full maturation of these cells to proceed. In a circulating form a soluble Epo receptor (sEpoR) binds Epo and thus prevents its access to the biologically active mEpoR. Villafuerte et al (2014) now report significantly lower sEpoR concentrations and higher values of the Epo/sEpoR ratio in subjects with CMS compared to health subjects at 4340 m in Cerro de Pasco, Peru. Additionally they found that hematocrit is correlated to a higher Epo/sEpoR ratio and inversely with arterial oxygen saturation. These results help to explain why earlier studies in CMS failed to illuminate a center stage role for Epo in the pathogenesis of the disease.

Gender differences in ventilatory responses and periodic breathing at altitude

Males tend to have greater periodic breathing at high altitude than females and the mechanism(s) for this difference is not well understood. Acetazolamide is highly effective in suppressing periodic breathing. Caravita et al (2014) studied 23 men and 21 women at sea level and then again on the first day and night after arrival at 4559 m with randomization to acetazolamide or placebo. Acetazolamide reduced periodic breathing and improved sleep oxygenation, but more so in men than women. The males had increased hypoxic chemosensitivity at sea level and more periodic breathing than the women. There were no gender differences in hypercapnic ventilatory responsiveness. Hypoxic chemosensitivity directly correlated with the number of hypopneas and apneas in the placebo group, but not with the diminished extent of periodic breathing in those taking acetazolamide. This study supports the general concept that periodic breathing at high altitude stems from strong ventilatory responses that destabilize the control of breathing during sleep. This appears to be a greater problem in men.

Muscles wasting away at high altitude

The weight loss and sarcopenia that develop at high altitude are well known. To study this phenomenon in greater detail, Levett et al. (2014) employed proteomic and immunoassay techniques on vastus lateralis muscle biopsies in 5 trekkers to 5300 m over 19 days and in 5 climbers to 8848 m over 66 days. Both groups had a roughly one-third loss of muscle creatine kinase and glycolytic enzyme abundance. Most enzymes in the tricarboxylic acid (TCA) cycle were decreased, and much more so in the climbers. Other changes included a reduction in elongation factor 2 alpha, a protein controlling protein translation and an increase in heat shock protein cognate 71 involved in chaperone-mediated autophagy. Damage to the sarcomeric structures was evident by a decrement in voltage-dependent anion channels 1 and 2, and in myosin-binding protein C. Thus it appears that chronic high altitude hypoxia, despite any anabolic effect of exercise leads to considerable changes in skeletal muscle suggestive of a metabolic reprogramming to support the TCA cycle, control protein translation, and reduce energy expenditure. Activating chaperone-mediated autophagy may be a strategy to efficiently maintain muscle metabolism in the face of declining muscle mass.

Lack of any apparent benefit to increased blood-oxygen binding affinity in Tibetans and Han Chinese at 4200 m

Although birds and mammals native to high altitude all have hemoglobins with high intrinsic O₂ binding affinity (lower P50 values) investigations in humans have not yet yielded consistent results. Simonson et al (2014) studied 31 Tibetan males and 9 Han Chinese males residing at 4200 m. Standard P50 values in both groups were 24.5 mmHg with a slighter greater standard deviation in the Han Chinese. These values of sea level control subjects was about 2 mmHg higher, suggestive of a more left shifted hemoglobin oxygen dissociation curve at high altitude, which is the case for high altitude animals. However, there was not relationship between P50 and a range of hemoglobin concentration among the Tibetan subjects (15.2–22.9 g/dl), nor was there any correlation of P50 with maximal exercise oxygen consumption or the alveolar-arterial PO₂ difference. Thus in this study, while there may be a slight shift to a greater hemoglobin O₂ affinity in high altitude populations (mechanism unknown, but not related to amino acid differences in the hemoglobin structure) no benefit seems to accrue from greater hemoglobin O₂ binding.

More on the genetics of Tibetans leading to less polycythemia at high altitude

Two genes have emerged as playing a central role in much lower hemoglobin concentrations of Tibetans; EPAS-1 or HIF 2 alpha and EGLN-1 or prolyl hydroxylase 2 (PHD2). PHD2 in the presence of sufficient oxygen leads to immediate degradation of HIF by hydroxylation of several amino acids in the transcription factor. Lorenzo et al (2014) found a missense mutation in the PHD2 gene comprising amino acid substitutions at position 12 (C>G) and 380 (G>C) that is highly prevalent in Tibetans and likely confers a protection against polycythemia and its attendant problems of greater blood viscosity. The proliferation of erythroid progenitors with this mutation is significantly impaired under hypoxic conditions due to abrogated hypoxic-induced HIF-mediated augmentation of erythropoiesis. Thus this EGLN variant likely has a lower Km for oxygen and promotes increased HIF degradation despite the ambient hypoxia.