Abstract
High Altitude Enhances Host Defense against Tuberculosis
Before chemotherapy of tuberculosis (TB) became available in the late 1940s, many patients were treated in alpine sanatoriums, such as in Davos, Switzerland—made famous by Thomas Mann in his novel “The Magic Mountain.” In addition to escape from crowded polluted cities, rest, and better nutrition; the rarefied air of high altitude itself was considered salutary. Epidemiologically, TB mortality is lower above 2000 m and Mycobacterium tuberculosis (MTb) grows less well in hypoxic conditions, such as in the lung collapsed by iatrogenic pneumothorax, a common treatment of those times. Eisen et al. (2013) report in 15 healthy lowlanders ascending to 3400 m and in 47 high altitude residents that their whole blood in vitro reduced growth of a BCG strain of MTb by more than 75% when compared with blood taken from the lowlanders at sea level. These findings reveal an, as yet unexplained, altitude enhancement of host defense against TB that possibly could be utilized in persons with extremely drug-resistant MTb infection.
Studies of Central Nervous System Adaptation and Maladaptation to High Altitude
In a recently completed expedition (AltitudeOmics) in Bolivia studying the physiology and genetics of healthy subjects taken to 5260 m, Rob Roach and colleagues examined a variety of central nervous system changes with acute hypoxia and subsequent acclimatization over 16 days. Global and regional cerebral O2 delivery (DO2) assessed by ultrasonic cerebral blood flow (CBF) measurements and arterial O2 content (CaO2) showed that DO2 was maintained equivalent to sea level at days 1 and 16 in the cortex and increased by 25% in the posterior circulation, a region subserving more vital homeostatic functions (Subudhi et al., 2013). In these same subjects, exercise-induced supraspinal fatigue, a centrally mediated limitation to maximal effort was reduced with acclimatization, perhaps as a consequence of increased cortico-spinal activity secondary to the increase in DO2 in the posterior circulation (Goodall et al., 2013) They found also that acute mountain sickness (AMS) was not related to the altitude impairment in cerebral autoregulation noted on the first day and still present and unchanged by day 7 when AMS had resolved (Subudhi et al., 2013).
Intrapulmonary Arterio-venous Anastomoses Do not Increase with High Altitude Hypoxia
Whether lungs have small intrapulmonary arterio-venous anastomoses (IPAVA) has been a topic of much debate. In animals, IPAVAs are detectable using injected microspheres trapped before the capillary bed, but in humans micro-bubbles of air, injected intravenously in agitated saline and detected in the left ventricle (LV) by echosonograhy has been the only practical means of testing. Several groups have found acute hypoxia increases blood flow through IPAVAs suggesting dynamic oxygen-control to reduce pressure even at the expense of slightly worsened gas exchange. Foster et al. (2014) studied what happens to IPAVAs detected at sea level in individuals going to 5050 m in Nepal for several weeks and in native high altitude Sherpas. They found in 8 lowlanders with IPAVAs at sea level, these disappeared in all but one at 5050 m and IPAVAs were present only in 4 of 7 Sherpas. These findings suggest that IPAVAs do not contribute to pulmonary vascular adaptation at high altitude.
Differences in Carotid Body Carbon Monoxide and Hydrogen Sulfide in Hypoxic Responses
Carotid body hypoxic sensing is critical to regulation of ventilation and blood pressure. However, animals and humans vary almost 5-fold in the magnitude of the hypoxic ventilatory response (HVR) and this may have a genetic basis. Recently, carbon monoxide (CO) and hydrogen sulfide (H2S) have been identified as endogenous gaseous signaling molecules in cardiovascular regulation, neurotransmission, and immune responses. Peng et al. (2014) studied 3 rat strains with a wide range of O2 chemosensitivity. Compared to Sprague Dawley (SD) rats, Brown Norway (BN) rats have blunted O2 sensing and develop hypoxic pulmonary edema due to lesser HVR and thus more hypoxic pulmonary vasoconstriction (HPV). Spontaneously hypertensive (SH) rats have greater O2 chemosensitivity and systemic hypertension. In carotid bodies of these rats, higher CO levels were associated with greater substrate affinity of heme-oxygenase-2 (HO-2), the enzyme generating CO. CO appears to suppress H2S generation and O2 chemosensing. This was tested by manipulating CO levels by HO-2 inhibition or stimulation to lower or raise CO, respectively. In all cases, higher CO led to less H2S formation and lower O2 chemosensitivity and the predicted changes in systemic blood pressure and ventilation.
Genetics of Hypoxic Hyporesponsiveness in Tibetans Living at Low Altitude Compared to Han Chinese
Tibetans with the longest residence at altitude (25,000 years) have recently been found to undergone marked and rapid natural selection at two genetic loci (EGLN-1 and EPAS-1) with importance to hypoxia tolerance. These genes encode crucial proteins in the hypoxia-inducible transcriptional factor (HIF) pathway that determine organismal integrative responses to hypoxia. Petousi et al. (2013) studied these genes and several phenotypic characteristics linked to HIFs (hematocrit, HVR and HPV) in Tibetans living at sea level and their most closely related ethnic group, lowland Han Chinese. They found the relative cellular expression in lymphocytes of these genes and other hypoxic induction of HIF-regulated genes was significantly lower in Tibetans compared to Han Chinese. In the case of hypoxia-induced erythropoietin formation, there was a significant correlation between both EPAS-1 and EGLN-1 genotypes. Their results add to growing evidence revealing a hypo-responsive HIF transcriptional system in this best adapted high altitude population. It would appear that robust HIF-mediated hypoxic responses have been selected for at low altitude, but selected against at high altitude, where in the longer run they become disadvantageous.
EPAS-1 and EGLN-1 Gene Differences May Play a Role in High Altitude Illnesses
Polymorphisms of EPAS-1 and EGLN-1 genes that lead to relative and likely adaptive population responses to high altitude may also be involved in three high altitude illnesses: acute mountain sickness (AMS), chronic mountain sickness (CMS), and high altitude pulmonary edema (HAPE) in Asian populations. Buroker et al. (2012) studied 85 Han Chinese with AMS and compared them to 79 without AMS, and also 45 CMS patients with 34 unaffected Tibetan subjects. They found several single nucleotide polymorphisms (SNP) of EPAS-1 and EGLN-1 were more prevalent in the sick individuals when compared to their Han Chinese and Tibetan healthy controls. With regard to HAPE, Mishra et al. (2013) screened EGLN-1 polymorphisms in many hundreds with and without a history of HAPE in the Indian Himalayan regions and in healthy Ladakhi highland natives. They identified seven polymorphisms that differed significantly between those with HAPE susceptibility and those either no HAPE or high altitude residence. Those SNPs in HAPE-prone persons were linked with a 4.5-fold greater gene expression and the risk alleles were associated with lower arterial oxygen saturation and higher pulmonary artery pressures, typical hallmarks of HAPE susceptibility.
Explorations of the Proteomic Response to Acute High Altitude Hypoxia
In addition to the explosion of genomic analyses of high altitude adaptation, proteomic investigations promise to reveal new pathways not predicted by current understanding. Julian et al. (2013) studied 10 healthy subjects with and without acute mountain sickness (AMS) (Lake Louise scores of 4.2 and 0.5) after nine hours of hypobaric hypoxia (equivalent to 4875 m). In pooled plasma (after depletion of albumin and other proteins of highest concentration) of both groups before and at nine hours, they found that those with AMS had 2–3-fold up-regulation of several proteins with antioxidant properties (peroxiredoxin-6, glutathione peroxidase and sulfhydryl oxidase-1). They propose that the oxidant stress of hypoxia, greater in those with AMS, may lead to overcompensation in antioxidant defense, leading to loss of some protective oxidant-based signaling. Whether this is harmful remains uncertain, but antioxidant combinations have failed in AMS prophylaxis. In this study analysis of individual values correlated to symptoms might have made a stronger case for their hypothesis. Lastly the necessity of depleting albumin, which indiscriminately binds many compounds, to enhance the detection of compounds at much lower concentration may lead to depletion of some molecules of potential significance.
Explorations of the Proteomic Response to Chronic High Altitude Hypoxia
Ahmad et al. (2013) studied 10 healthy high altitude residents of the Ladakh region of northern India, born and raised between 3500 and 4000 m, and 10 healthy sea level residents. In this study, plasma samples, also depleted of albumin and immunoglobulins, were not pooled and results of individual subjects were reported. Numerous up- and down-regulated proteins in high altitude natives were found in comparison to the sea level controls. Space does not permit the listing of the 12 proteins, but all play a role in inflammatory pathways. The changes noted in the high altitude natives suggest a broad more anti-inflammatory profile that may be advantageous at high altitude. Interestingly, this concept of greater anti-inflammatory response was suggested in an earlier study by Julian et al (2011) in subjects without acute mountain sickness (AMS) compared to those with AMS.
High Altitude Impairs Soccer Performance in Natives and New Comers
An international collaboration between researchers of Australia, Bolivia, Qatar, and Germany (Gore et al., 2013) investigated the effects of high altitude on soccer performance after acute exposure and after an acclimatization over 13 days in La Paz, Bolivia (3600 m). They present their results about running performance, hematologic, ventilatory and cardiovascular acclimatization, as well as about acute mountain sickness and sleep in eight articles in a supplement of the British Journal of Sports Medicine. One of the major conclusions is that neither 13 days of acclimatization nor lifelong residence protects against detrimental effects of altitude on the match activity profile compared to playing at low altitude (Aughey et al., 2013). The most interesting question of how the handling of the ball was affected by altitude in natives and new comers has apparently not been investigated or has not yet been reported.
Microhemorrhages in the Brain as Footprint of High Altitude Cerebral Edema (HACE)
A cross-sectional study in 37 mountaineers with and without a history of acute mountain sickness or HACE and altitude exposures up to 8848 m showed that microhemorrhages (MH) in the corpus callosum detected by susceptibility weighted MRI were almost exclusively seen after HACE (Schommer et al., 2013). MHs were found throughout the brain in more severe cases or when arterial pressure was increased by seizure or in a hypertensive patient. These “HACE-specific” lesions in the corpus callosum were also reported in a patient who underwent long-term ventilation (Esser et al., 2014) and in a patient after morphine intoxication (Friedrich et al., 2013) suggesting that severe hypoxia at low altitude, possibly in combination with severe hypertension may also lead to MH in the corpus callosum.
Is History of Acute Mountain Sickness (AMS) a Weak Predictor for Future AMS?
A meta-analysis suggests that a history of AMS is a weak predictor for future AMS (Macinnis et al., 2013) but the authors also admit that the quality of the included studies is not sufficient to come to firm conclusions questioning the value of meta-analysis based on low quality studies. Furthermore, they ignore the fact that previous studies have shown that rate of ascent and degree of pre-acclimatization are as important as history of AMS for prediction. Thus all these factors have to be considered for risk assessment. Reliable prediction is only possible based on the history of a comparable previous ascent with regard to altitude, rate of ascent, and degree of pre-acclimatization.
Cluster Analysis Suggests that Sleep Is Poorly Related to Other Symptoms of Acute Mountain Sickness (AMS)
Symptoms of AMS were obtained by visual analog scale and Lake Louise score repeatedly in 103 subjects in 3650 and 5200 m and in 189 subjects ascending Kilimanjaro at 4730 m (Hall et al., 2014). Cluster analysis revealed three clusters, of which two clusters showed discrepant values for the symptoms headache and sleep disturbance. Correlation analysis across the whole population demonstrated that headache, nausea, dizziness and fatigue are correlated among each other but not with sleep. The authors suggest reassessing consensus diagnostic criteria for AMS.
Increased High Sensitivity Cardiac Troponin after Trekking at 5000 m
High sensitivity cardiac troponin (hs cTn), a highly specific marker for myocardial cell injury, was repeatedly measured in 10 male and 9 female healthy subjects (18–50 years) during trekking (Boos et al., 2013). Blood sampling and echocardiography were performed post exercise (several hours of trekking) and 12 hours later at 3440, 4270 and 5150 m. At 5150 m there was a significant increase of hs cTn post exercise with detectable values >5ng/L in 56% of subjects (5.8% at 3440 m) and normalized within 12 hours. There were no deleterious effects on cardiac function and hs cTn correlated with the decrease in SpO2, and with increases of pulmonary artery pressure and cardiac output. Increases of troponin in healthy individuals without cardiac disease have already been reported after marathon running. The study shows that moderate exercise of trekking is sufficient to elicit such a response at 5150 m.
Cerebral Autoregulation during Squat Exercise not Impaired at High Altitude and in Acute Mountain Sickness (AMS)
The significance of assessing cerebral autoregulation by transfer function analysis (TFA) obtained from spontaneous blood pressure variation at altitude is not clear and the literature regarding autoregulation of cerebral blood flow in AMS derived from such measurements is controversial. Therefore TFA was measured after inducing large increases of blood pressure by squat exercise in lowlanders at 5050 m acutely and after partial acclimatization and comparing them to measurements in high altitude natives at 5050 m (Smirl et al., 2014). When blood pressure was driven by exercise, both frequency- and time-domain metrics were unaltered in lowlanders at high altitude and comparable to the responses of high altitude natives. AMS was unrelated to TFA metrics. This study shows that cerebral autoregulation is unaltered at 5050 m and in AMS and that spontaneous change in TFA metrics do not necessarily reflect physiologic important alterations in the capacity of the brain to regulate blood pressure.
Upregulation of Calpain Involved in Platelet Activation at Extreme Altitude
Six hours of exposure of rats to 7620 m in a low pressure chamber resulted in in vitro platelet activation and platelet proteome analysis suggested a role for the up-regulated calpain subunit 1 (CALPS1), a protein involved in calcium homeostasis, in platelet activation by hypoxia, since a calpain-specific inhibitor could partially reverse platelet activation (Tyagi et al., 2014). This inhibitor could also reduce thrombus formation in localized hypoxia in an animal model of flow restriction by ligation of the vena cava inferior. Relevance of these findings for humans is suggested by demonstrating increased calpain activity and higher soluble P-selectin, an indicator of platelet activation, in patients free of thrombophilia, who had developed deep vein thrombosis DVT) at above 34,648 m vs. healthy controls. The authors do, however, not provide data from comparable patients after DVT at low altitude.