Abstract
High Altitude Is (Is Not) For the Birds: Point Counterpoint
In this debate, G. R. Scott et al from McMaster University (Scott et al., 2011) defend the idea that birds are far superior to mammals at adapting and thriving at high altitudes, based largely on the bar-headed goose that flies over Everest and has been recorded soaring to 11000 m altitude. A. J. Llanos et al, a group from Chilean, US and UK universities, suggest that the bird embryo demonstrates some fragility at high altitude, which contrasts markedly with the more resilient Llama mammalian mother and placenta duo, in which the embryo and fetus adapted to high altitude develop at comparatively relative ease in this extreme environment. They claim that physiological, cellular and molecular levels strongly demonstrate a variety of successful evolutionary adaptive strategies in the llama which thus far have not been replicated in embryos and in hatchlings of high altitude birds. Scott et all rebut that avian embryos from several highland species hatch successfully between altitudes of 4000–6500 m at the top of the range and even well above the llama's home in the Andean altiplano. Although avian adaptations may not be identical to those described for mammals, a suite of adaptive strategies have been described for bird embryos in hypoxic environments. Llanos et al reply that even in the lowland-derived sheep, the fetal brain has a remarkable capacity to maintain its O2 consumption by increasing its blood flow up to quite a severe degree of hypoxia, at least until a point of decompensation is reached. The high altitude llama fetus uses a different strategy of cerebral hypometabolism, without apparent brain damage during hypoxia. They infer that this empiric evidence trumps any theoretical discussion of avian over mammalian superiority at tolerating hypoxia.
High Systemic Vascular Reactivity to Hypoxia and Adrenergic Agents in Newborn Llamas
Llamas have many genetic adaptations to high altitude. One more was shown by Moraga et al (2011) who report that the llama newborn demonstrates 3.6 times greater peripheral vascular reactivity to hypoxia compared to neonatal lowland sheep. The contractile responses to noradrenaline and phenylephrine were higher in femoral vessels from newborn llamas than newborn sheep. Competitive inhibition with prazosin of noradrenaline-induced contraction was consistent with greater α1B-adrenergic receptor transcript expression in small femoral arteries from neonatal llama.
Doppler Cerebral Blood Flow Error in Severe Hypoxia Due to Unsuspected Middle Cerebral Artery Dilation
Transcranial Doppler is a widely used noninvasive technique for assessing middle cerebral artery blood flow. All previous high altitude studies assessing cerebral blood flow (CBF) in the field using Doppler to measure arterial blood velocity have assumed constant vessel diameter. Wilson et al (2011) demonstrate this is not the case. They used transcranial 2D ultrasound to assess MCA caliber in a study of CBF on Everest and demonstrate that above 5300 m, middle cerebral artery (MCA) diameter increased from 5.30 mm at sea level to 5.23 mm at 5300 m (n=24), to 6.66 mm at 6400 m (n=14) and to 9.34 mm at 7950 m (n=5). The MCA flow (mL/s) rose from 13.3 at SL to 15.0 at 5300 m, 23.7 at 6400 m and 41.2 at 7950 m. At 7950 m, breathing oxygen reversed the dilation and flow fell to 15.3. The authors generated similar dilation during hypoxia (FiO2=12% for 3 hours) in a 3-T magnetic resonance imaging study at sea level (n=7). These remarkable data challenge much prior data on CBF at altitude.
Brain Oxygen Delivery during Exercise at Altitude
Total oxygen delivery to the brain is reduced during maximum exercise at altitude. Vogiatzis et al (2011) report 60% fall in frontal cortex O2 delivery at 4000 m altitude in maximum work as PaCO2 falls, causing cerebral vasoconstriction.
The authors suggest that such a reduction in frontal cerebral cortex oxygen delivery could potentially constitute the signal to limit maximal exercise capacity in hypoxia but whether brain oxygen delivery reduction limits performance at altitude remains unknown.
Biomarkers Related to Acute Mountain Sickness
Julian et al (2011) related the severity of acute mountain sickness (AMS) to biomarkers thought to protect against or contribute to blood brain barrier disruption in 20 healthy volunteers repeatedly exposed to 10 hr of hypobaric hypoxia at Pb 425 mmHg. Subjects were pretreated with placebo, acetazolamide (250 mg), or dexamethasone (4 mg). Blood was sampled and AMS assessed before and at 0.5, 4, and 9 h of hypobaria. Biomarkers analyzed were interleukin receptor agonist (IL-1RA), heat shock protein (HSP)-70, and adrenomedullin, the proinflammatory interleukins IL-6, IL-8, IL-2, IL-1β, and substance P, macrophage inflammatory protein-1β, VEGF, TNFα, monocyte chemotactic protein-1, and matrix metalloproteinase-9. AMS-resistant subjects had higher anti-inflammatory and/or anti-permeability substances IL-1RA (4 and 9 h and overall), HSP-70 (0 h and overall), and adrenomedullin (overall) compared with AMS-susceptible subjects. Acetazolamide raised IL-1RA and HSP-70 compared with placebo in AMS-susceptible subjects. Dexamethasone also increased HSP-70 and adrenomedullin in AMS-susceptible subjects. Other biomarkers were unrelated to AMS. Subjects resistant to AMS generated more anti-inflammatory and/or anti-permeability biomarkers. AMS susceptibility correlated with macrophage inflammatory protein-1β but was not associated with an exaggerated inflammatory response.
Acute Mountain Sickness and Maximum Expiratory Flow Rate at South Pole
Scientists flown to the South Pole at 2835 m altitude experience rapid moderate sustained hypoxia. One hundred and two volunteers among this group were evaluated by Lalande et al (2011) for acute mountain sickness (AMS) by Lake Louise score and for alterations in forced expiratory flow rate (FEF) (25–75) after the second night at altitude, and compared with their sea level control values. Curiously, AMS incidence was 41% in the 79 subjects with increased FEF (25–75) but only 22% in the 23 with reduced FEF (75–25), a sign of interstitial pulmonary edema (p<0.05). These 23 subjects showed a 6-fold greater increase in epinephrine and a higher interleukin-1 increase than the 79. This study therefore supports the lack of correlation between cerebral and pulmonary effects of high altitude.
Linking the Inflammatory Response System to High Altitude Pulmonary Edema
Ahmad et al (2011) investigated the plasma proteome in 20 patients with high altitude pulmonary edema (HAPE) and 10 healthy sea level controls. 14 of 25 protein spots showed altered changes in HAPE patients. Among the acute phase proteins, haptoglobin alpha2 chain, haptoglobin beta chain, transthyretin, plasma retinol binding precursor and apolipoprotein A-I are upregulated in plasma of HAPE patients. The authors suggest that these proteins may provide a fast and effective control of inflammatory damage until the subsequent mechanisms can begin to operate.
Preconditioned Heat-Shock Protein 70 Protects Lung in Severe Hypoxia
Hypobaric hypoxia preconditioning (HHP) induces the overexpression of heat-shock protein 70 (HSP70). Lin et al (2011) show that HHP thereby reduces acute hypoxic lung injury in a 24 h exposure of rats to 6000 m altitude. HHP significantly attenuated hypoxic pulmonary edema, inflammation, and ischemic and oxidative damage in the lungs compared to unpreconditioned controls. These protective effects were diminished by pretreatment with a neutralizing anti-HSP70 antibody.
Sildenafil and Bosentan Improve Arterial Oxygenation during Acute Hypoxic Exercise
The reported advantageous effects of phosphodiesterase 5 inhibitors on exercise at altitude were further studied in 16 healthy sea level student volunteers exercising in a chamber at 11% O2 by Olfert et al (2011). Both drugs resulted in small, but significant increases in arterial PO2 (2-3 Torr) and O2 saturation (3-4%) at rest and during hypoxic exercise, in both men and women. Arterial PCO2 and ventilation were not altered but heart rate (both at rest and during exercise) was increased.
Exercise Induces Rapid interstitial Lung Water Accumulation in Patients with Chronic Mountain Sickness
Exercise-induced pulmonary hypertension is markedly exaggerated in chronic mountain sickness (CMS). Pratali et al (2011) report that exercise induces rapid interstitial lung fluid accumulation and hypoxemia in patients with CMS. They assessed extravascular lung water (chest ultrasound), pulmonary artery pressure, and left ventricular function in 15 patients with CMS and 20 control subjects at rest and during exercise in La Paz, Bolivia (3600 m altitude). In CMS but not in controls, exercise further aggravated the pre-existing hypoxemia accompanied by a more than 2-times larger increase of pulmonary artery pressure than in controls but no evidence of left ventricular dysfunction. Oxygen inhalation markedly attenuated the exercise-induced pulmonary hypertension and interstitial fluid in patients with CMS, but had no detectable effects in controls. The authors conclude that this exercise-induced rapid interstitial lung fluid accumulation and hypoxemia in patients with CMS is due to their exaggerated pulmonary hypertension.
Acetazolamide Facilitates Sleep at Altitude in Patients with Obstructive Sleep Apnea
Normal subjects experience less Cheyne Stoke breathing and airway obstruction at altitude if they use acetazolamide. Patients with obstructive sleep apnea (OSA) at sea level are expected to suffer even more at altitude if, for convenience while traveling, they give up the use of CPAP. Nussbaumer-Ochsner et al (2011) demonsrate a similar sleep improvement with acetazolamide in 45 OSA patients during 3 day exposures to 1860m and 2590m altitudes. Mean SpO2 values were 89% and 85% at these altitudes in controls vs 91% and 88% with acetazolamide. Acetazolamide reduced apnea/hypopnea indices and nocturnal transcutaneous PCO2, improved sleep efficiency and subjective insomnia and prevented excessive blood pressure elevations at altitude.
Systemic Vascular Dysfunction in Patients with Chronic Mountain Sickness
Rimoldi et al (2011) studied 23 patients with chronic mountain sickness (CMS) without additional classical cardiovascular risk factors and 27 age-matched healthy mountain dwellers born and permanently living in Bolivia at 3600 m altitude. In CMS, they report 40% impaired systemic endothelial function (by flow-mediated dilation, FMD), 25% greater pulse wave velocity and 21% increased carotid intima-media thickness. Oxygen inhalation improved but did not normalize FMD in patients with CMS whereas it normalized FMD in hypoxemic controls (SaO2<90%) and had no detectable effect in normoxemic (SaO2≥90%) control subjects. The authors suggest that these structural and functional alterations in the CMS group may predispose them to premature cardiovascular disease.
Fat storage Deficit at Everest Base Camp
Despite the evidence of depletion of fat at altitude, acylation-stimulating protein (ASP), which influences fat storage in adipose tissue, has not been measured at high altitude. Smith et al (2011) obtained serial samples in 7 men and 3 women trekkers ascending over 9 days from sea level (SL) to 4000 m, 4750 m, and 5300 m. As expected, body mass decreased and plasma non-esterified fatty acids and triglycerides increased while HDL cholesterol decreased. During the progressive weight loss, ASP progressively rose from a SL value of 42.2±40.2 nm to 82.2±20.2 nm at 5300 m. Adiponectin rose from SL 10.4±6.5 ng/mL, to 14.7±8.0 ng/mL at 5300 m. Insulin and Interleukin-6 levels rose 71% and 168%, respectively with no change in leptin, complement C3, high sensitivity C-reactive protein or cortisol levels. Thus ASP is not responsible for weight loss, but its rise is insufficient to prevent weight loss.
A Neuropsychological Deficit Found in Children Living above 4000 m Altitude in Bolivia
Virues-Ortega et al (2011) conducted physiological and neuropsychological assessments in 62 Bolivian children and adolescents living at La Paz (approximately 3700 m) and El Alto (approximately 4100 m). Groups were equivalent in terms of age, gender, social class, schooling, parental education and genetic admixture. Apart from SpO2, participants did not differ in their basal cardiac and cerebrovascular performance or cerebral blood flow velocity at the basilar, anterior, middle and posterior cerebral arteries. A comprehensive neuropsychological assessment was administered, including tests of executive functions, attention, memory and psychomotor performance. Participants living at extreme altitude showed lower levels of performance in all executive tests whereas all other domains remained unaffected by altitude of residence. The authors suggest that, above 4000 m, the developing brain may be vulnerable to certain neuropsychological deficits.
An fMRI Comparison of Spatial Working Memory Between High and Low Altitude Natives
Two groups of college students were recruited for a study of spatial memory. One group (HA) was ethnic Hon who were born and grew up on the Tibetan plateau (2616–4200 m altitude) until early adulthood. The control group was born and grew up near sea level (SL); the two groups were matched for age, gender ratio, educational level, ancestral lines, and peripheral physiology (especially the hemoglobin concentration). A 2-back spatial working memory task was performed by each subject in the scanner while fMRI data were acquired. The HA group showed equal response accuracy, with more variance in reaction time and a larger average value. fMRI data indicated that both groups showed common activation patterns in the neural pathway typically associated with working memory. The HA group had greater activation at the left pyramis and the left superior temporal gyrus and less activation at the left middle occipital gyrus. Significant correlations were found within each group between the reaction times and BOLD signal change amplitudes at the frontal cortex and the precentral cortex. This study demonstrated that among subjects who went through prolonged exposure to HA during early development, minimal behavioral deficiency was found in a spatial working memory task. The two groups were comparable in performance accuracy, although the HA group showed increased average reaction time with larger variance. The fMRI study further revealed adaptive compensatory neural mechanisms, such as the common activation and deactivation patterns in the neural pathway typically associated with spatial working memory, as well as increased activation at the superior temporal gyrus and the pyramis which are involved in attention modulation, indicating increased attention levels as compensatory mechanisms to ensure comparable behavioral performance (Yan et al., 2011).
Is High Suicide Rate at High Altitude Hypoxia-Dependant or an Ecological Fallacy?
Betz et al (2011) report 3-fold higher incidence of suicide at high altitude, confirming the larger data set reported in this journal this year (Brenner et al., 2011) and several earlier reports. This article presents the altitude differences of extensive demographic data and suicide characteristics of the victims. The authors suggest the possibility that the observed differences in suicide rates at different altitudes might be explained by an ecological fallacy. That is, there may be no basis for the inference that hypoxia or high altitude operates on an individual level to increase the risk of suicide. High and low altitude victims differed with respect to race, ethnicity, rural residence, intoxication, depressed mood preceding the suicide, firearm use and recent financial, job, legal, or interpersonal problems. Even after multivariate adjustment, there were significant differences in personal, mental health, and suicide characteristics among altitude groups. High altitude victims had higher odds of having family or friends report of a depressed mood preceding the suicide and having a crisis within 2 weeks before death. Multiple demographic and psychiatric factors rather than hypoxia or altitude itself may underlie increased suicide rates at high altitude.