Exercise at Altitude Induces Lung Edema in Chronic Mountain Polycythemics

Some long-term dwellers at high altitude develop severe polycythemia, previously called chronic mountain sickness (CMS). Exercise induces exaggerated pulmonary hypertension in these subjects. Pratali et al (2012), using chest ultrasonography, show that exercise rapidly induced pulmonary interstitial fluid accumulation and further aggravated the preexisting hypoxemia in 14 of 15 CMS subjects at 3600 m, but not in 16 of 20 control subjects. CMS subjects, despite their greater increase of pulmonary artery pressure than control subjects, showed no evidence of left ventricular dysfunction. Oxygen inhalation markedly attenuated the exercise-induced pulmonary hypertension and interstitial fluid accumulation in patients with CMS but had no detectable effects in control subjects.

Acute Altitude Induced Pulmonary Hypertension is Age Dependent in Children

In 118 non-acclimatized healthy children and adolescents Allemann et al (2012) assessed pulmonary artery pressure (PAP) and right and left ventricular function by echocardiography at low altitude and 40 hours after rapid ascent to 3450 m. PAP mean at altitude was 35±11 vs. control 16±3 mmHg. In the 6–9 yr olds, the increase was twice that in the 14–16 year old participants. Right ventricular systolic function increased, and none of the children developed HAPE (high altitude pulmonary edema).

Association of Gene Polymorphisms with High Altitude Pulmonary Edema Susceptibility

Luo, Zou, and Gao (2012) review the many genetic differences that have been identified by others relating to HAPE. They include the renin-angiotensin-aldosterone system pathway, the nitric oxide pathway and the hypoxia inducible factor pathway, tyrosine hydroxylase, vascular endothelial growth factor (VEGF), pulmonary surfactant proteins and β₂-adrenergic receptor and polymorphisms of NOS3, ACE, CYP11B2, Hsp70 and endothelin-1 and pulmonary surfactant proteins A1 and A2.

Genetic Associations with High Altitude Illness in Han and Tibetans.

Buroker et al (2012) compared 85 patients with AMS (acute mountain sickness) to 79 control Han and 45 CMS (chronic mountain sickness (polycythemia)) patients to 34 healthy Tibetans. AMS and CMS were found to be significantly associated with the EPAS1 and EGLN1 genes compared to their Han and Tibetan control groups implying some physiological effect related to high altitude sickness.

Keratinocyte Growth Factor-2 (KGF-2) Reduces High Altitude Pulmonary Edema (HAPE)

In a rat model of HAPE, intratracheal instillation of KGF-2 (5 mg/kg) significantly decreased mortality, improved oxygenation and reduced lung wet-to-dry weight ratio by preventing alveolar-capillary barrier disruption as evidenced by histological examination and increasing alveolar fluid clearance. KGF-2 significantly inhibited decrease of transendothelial permeability after exposure to hypoxia by inhibiting endothelial cell apoptosis, preserving alveolar-capillary barrier integrity, and promoting pulmonary edema absorption in HAPE. Thus, KGF-2 may represent a potential drug candidate for the prevention of HAPE (She et al., 2012).

ACE2 Blunts Hypoxic Pulmonary Hypertension in Pigs

ACE2 (recombinant angiotensin-converting enzyme 2) is involved in pulmonary arterial pressure regulation. In 6 test and 6 control pigs during acute hypoxia (30–150 min), Kleinsasser et al (2012) report that ACE2 (400 μg/kg) reduced the rise of pulmonary vascular resistance by 45% and the maximum pulmonary arterial pressure by 24%. Cardiac variables, systemic arterial pressure, ventilation/perfusion relationships and PaO₂ did not differ between groups. The authors suggest testing recombinant ACE2 to treat or prevent high altitude pulmonary edema and hypoxia-associated pulmonary hypertension.

Nitric Oxide (NO) at Altitude

Beall, Laskowski, and Erzurum (2012) review published levels of NO in the lungs and NO-derived liquid-phase molecules in newcomers to or above 2500 m and in high altitude natives. In newcomers, NO levels in the lung, plasma, and/or red blood cells fell within 2h, but then returned toward baseline or slightly higher by 48 h and increased above baseline by 5 days. NO levels were lower in those with high altitude pulmonary edema (HAPE) (or a history of it) than those of their healthy counterparts. Tibetan NO levels were at least double and in some cases orders of magnitude greater than other populations regardless of altitude, and more than 200 times higher in erythrocytes. Other highland populations have somewhat elevated levels. Data are needed in long-term lowlanders at altitude and Tibetans at low altitude and whether hypoxia upregulates NO synthase gene.

Effects of NO Inhibitors on Hypoxic Brain Injury in Mice

Martinez-Romero et al (2012) studied the effect of pharmacological inhibitors of NO production or PARP (poly ADP ribose polymerase) activity in the response of the mouse cerebral cortex to 4 h of exposure to a simulated altitude of 31,000 ft. Reduction of NO did not affect reactive oxygen species production but significantly 1) dampened the posthypoxic increase in neuronal NOS and inducible NOS expression without altering endothelial NOS protein level; 2) prevented PARP activation; 3) decreased HIF-1alpha response to hypoxia; 4) achieved a higher long-term HIF-1 transcriptional activity by reducing factor inhibiting HIF expression; and 5) reduced hypoxic damage. The studies suggest some beneficial effects of controlling NO production in hypoxia.

Ibuprofen Prophylaxis of Acute Mount Sickness

Acute mountain sickness (AMS) is frequent in people who travel to high altitude. Acetazolamide (ACZ) is commonly used and is effective in minimizing AMS. Previous trials of nonsteroidal anti-inflammatory drugs have not been proven comparably effective. In a double-blinded study of 86 sea level dwellers, Lipman et al (2012) demonstrate that ibuprofen is about as effective as ACZ. The test group of 44 received ibuprofen 600 mg or placebo 3 times daily, starting 6 hours before ascent from 1,240 m to 3,810 m in the White Mountains of California. AMS was diagnosed as Lake Louise Questionnaire acute mountain sickness score ≥3 with headache and 1 other symptom. 43% fewer participants in the ibuprofen group developed AMS and score severity was higher in the placebo group (4.4±2.6) than with drug (3.2±2.4)(CI 0.3–3.0).

Acetazolamide Use at Altitude

The carbonic anhydrase inhibitor acetazolamide (ACZ) reduces periodic sleep apnea, partly by inhibiting the conversion of blood bicarbonate to CO₂ during transit through pulmonary capillaries especially during the few deep breaths taken upon awakening from sleep apnea. A few seconds after leaving the capillaries, blood reaches equilibrium with PaCO₂ higher than PetCO₂. Fan et al (2012) tested whether ACZ (10 mg/kg IV) increased the sensitivity of middle cerebral artery blood flow velocity (MCAv) to changing PaCO₂ in 12 normal subjects at 5050 m altitude. They thought this could lower entilator drive and improve breathing stability during wakefulness, unlikely in my opinion since ACZ increases ventilation. Fan et al report that ACZ increased both MCAv and the cerebral vascular sensitivity to CO₂ both at sea level and altitude while the entilator sensitivity to hypercapnia or isocapnic hypoxia was unaltered following ACZ at both sea level and altitude. They noted that ACZ stabilized wakeful breathing at altitude.

Retina Thickens With Acute Ascent to Altitude

Fischer et al (2012) use spectral domain optical coherence tomography and microperimetry to quantify changes of central retinal structure and function in 14 healthy subjects during acute exposure to high altitude (4559 m). Total retinal thickness increased. Visual acuity was unaffected. Two weeks after return to low altitude there was no persisting structural change. The increased thickness was in regions with relatively higher retinal nerve fiber content and vascular arcades. The changes did not correlate with either central retinal function or acute mountain sickness.

Quechua Ancestry Correlates with Lung Residual Volume

A curious unique relationship was found between the degree of Native American ancestry of Peruvian altitude dwellers and their residual volume (n=65, P=0.004), but not their vital capacity (VC). VC is well known to correlate with altitude of birth and development (Kiyamu et al, 2012).

Mitochondrial Respiratory Function Unaffected by Short Term Altitude.

To resolve conflicting evidence of the effects of altitude on muscle mitochondria, Jacobs et al (2012) used high-resolution respirometry on skeletal muscle biopsies obtained from ten lowland natives prior to and again after a total of 9–11 days of exposure to 4559 m. Mitochondrial function as the capacity for fat oxidation or individualized respiration capacity through either complex I or complex II was unaffected. Respiratory chain function remained unaltered, as both coupling and respiratory control did not change in response to hypoxic exposure.

Mitochondrial Loss with Time at Extreme Altitude

Lowlanders returning from high altitude have known decreased muscle mitochondrial densities. Levett et al (2012) measured gene and protein expression plus ultrastructure in muscle biopsies of lowlanders at sea level and following sojourne on Everest. Subacute exposure (19 d after initiating ascent to Everest base camp, 5300 m) was not associated with mitochondrial loss. After 66 d at altitude and ascent beyond 6400 m (n=10), mitochondrial densities fell by 21%, with loss of 73% of subsarcolemmal mitochondria. Correspondingly, levels of the transcriptional coactivator PGC-1alpha fell by 35%, suggesting down-regulation of mitochondrial biogenesis. Sustained hypoxia also decreased expression of electron transport chain complexes I and IV and UCP3 levels. The mechanisms remain unexplained although the authors suggest several teleological possibilities.

Acute Mountain Sickness Susceptibility Compared with Hypoxic Ventilatory Response

Nespoulet et al (2012) compared 12 acute mountain sickness susceptible individuals with recurrent and severe symptoms (AMS+) with 12 AMS non-susceptible subjects (AMS-) during simulated altitude hypoxia. Mean SaO₂ during sleep was lower in AMS+ (81.6±2.6% vs. 86.0±2.4%. AMS+ subjects were more hypoxemic but had fewer respiratory events during sleep: Central apnoea-hypopnoea index (events per hour) was 18 in AMS+ vs. 33 AMS-. Isocapnic hypoxic ventilatory response (HVR, L•min⁻¹•%⁻¹) in AMS+ was 0.40 vs. 0.97. AMS+ subjects had a higher pulmonary artery systolic pressure in response to acute hypoxia, a lower lung diffusing capacity and a higher endothelin-1 level. The authors conclude that a lower HVR is a major causative factor of AMS despite causing fewer apneic events during sleep.

Altitude Sleep Apnea Reduced By Adding 500 ml Dead Space

Full polysomnographies were performed on 12 unacclimatized mountaineers at 3500 m altitude, reported as apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). In random order, half of the night was spent with a 500 ml increase in dead space through a custom designed full-face mask. Five had severe sleep disordered breathing (AHI>30) and 7 had AHI<30. In the 5 with severe sleep problems, dead space reduced AHI from 70 to 29 and ODI from 73 to 42 per hour whereas it had no significant effect in the second group. Microarousal index, sleep efficiency, and sleep architecture remained unchanged by dead space (Lovis et al, 2012).

Possible Placental Causes of Low Birth Weight in Newcomers at Altitude

Pregnancy at high altitude is associated with a reduction in birth weight of approximately 100 g per 1000 m of ascent. The underlying mechanisms are unclear. Yung et al (2012) investigated whether altered energy-demanding activities such as protein synthesis are involved. In placental tissues from pregnant women residing at 3100 m they observed dilation of endoplasmic reticulum (ER) cisternae, increased phosphorylation of eukaryotic initiation factor 2 subunit alpha (P-eIF2alpha), reduced AKT phosphorylation, and reduced P-4E-BP1 but increased 4E-BP1 protein compared to sea level controls. These findings suggest the presence of ER stress and protein synthesis inhibition. In-vitro studies of sea level placentas incubated in 1% O₂ showed reductions of approximately 40% of trophoblast-like JEG-3 cells, 60% of BeWo cells, and 18% of placental fibroblasts. The authors conclude that chronic hypobaric hypoxia causes mild placental ER stress, which, in turn, modulates protein synthesis and slows proliferation perhaps accounting for the reduced placental villous volume, thereby contributing to the low birth weight that typifies high altitude populations.

Improved Survival in Heart Transplant Patients Living at High Altitude.

Higher altitudes are associated with chronic hypoxia and elevated pulmonary vascular resistance, both possibly detrimental to patients requiring heart transplantation. Wozniak et al (2012) analyzed the United Network of Organ Sharing database for adult patients undergoing heart transplantation from 1990 to 2008 (n=36,529). Altitude was determined by ZIP code. Patients living above 2000 ft had a 16% reduction in the risk of death at 1 year after transplant, 6% at 5 and 6% at 10 years. In patients living above 4000 ft, the 1-, 5-, and 10-year reduction in risk of death was 20%, 12% and 15% compared with those living below 2000 ft. Patients at high altitude had a lower incidence of diabetes, used tobacco less often, and accounted for the greatest proportion of status 2 heart transplants. The involved life style differences or mechanisms of protection remain unknown.

Advantages of the Caudwell Xtreme Everest (CXE) Closed Circuit Breathing System

McMorrow et al (2012) report a randomized, controlled crossover trial of the Caudwell Xtreme Everest (CXE) closed circuit breathing system compared with an open circuit in six healthy hypoxic volunteers at rest and exercise at Everest Base Camp at 5300 m. SaO₂ was equal at rest with both circuits. During exercise, from an ambient air control SaO₂ of 70.8%, SaO₂ was 98.8% with the CXE closed circuit vs 87.5% with the open circuit. Ambulatory closed circuits may offer twin advantages of supplying higher inspired oxygen concentrations with reduced oxygen consumption.