The aim of this cross-sectional study was to assess the health status of subjects weekly commuting between sea level and 3550-m altitude for at least 12 yr (average 22.1 +/- 5.8). We studied 50 healthy army men (aged 48.7 +/- 2.0) working 4 days in Putre at 3550-m altitude, with 3 days rest at sea level (SL) at Arica, Chile. Blood pressure, heart rate, Sa(O(2) ), and altitude symptoms (AMS score and sleep status) were measured at altitude (days 1, 2, and 4) and at SL (days 1, 2, and 3). Hematological parameters, lipid profile, renal function, and echocardiography were performed at SL on day 1. The results showed signs of acute exposure to hypoxia (tachycardia, high blood pressure, low Sa(O(2) )), AMS symptoms, and sleep disturbances on day 1, which rapidly decreased on day 2. In addition, echocardiographic findings showed pulmonary hypertension (PAPm > 25 mmHg, RV and RA enlargement) in 2 subjects (4%), a PAPm > 20 mmHg in 14%, and a right ventricle thickness >40 mm in 12%. Hematocrit (45 +/- 2.7) and hemoglobin (15 +/- 1.0) were elevated, but lower than in permanent residents. There was a remarkably high triglyceride level (238 +/- 162) and a mild decrease of glomerular filtration rate (34% under 90 mL/min and 8% under 80 mL/min of creatinine clearance). In conclusion, in these preliminary results, in chronic intermittent hypoxia exposure even over longer periods, most subjects still show symptoms of acute altitude illnesses, but a faster recovery. Findings in triglycerides, in the pulmonary circulation and in renal function, are also a matter of concern.

Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p < 0.01) and endothelial NOS mRNA increased (p < 0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p < 0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p < 0.05). Although arginase activity increased (p < 0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p < 0.001). Moreover, NOX4 expression increased only under CH (p < 0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p < 0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH.

High altitude (hypobaric hypoxia) triggers several mechanisms to compensate for the decrease in oxygen bioavailability. One of them is pulmonary artery vasoconstriction and its subsequent pulmonary arterial remodeling. These changes can lead to pulmonary hypertension and the development of right ventricular hypertrophy (RVH), right heart failure (RHF) and, ultimately to death. The aim of this review is to describe the most recent molecular pathways involved in the above conditions under this type of hypobaric hypoxia, including oxidative stress, inflammation, protein kinases activation and fibrosis, and the current therapeutic approaches for these conditions. This review also includes the current knowledge of long-term chronic intermittent hypobaric hypoxia. Furthermore, this review highlights the signaling pathways related to oxidative stress (Nox-derived O2.- and H2O2), protein kinase (ERK5, p38α and PKCα) activation, inflammatory molecules (IL-1β, IL-6, TNF-α and NF-kB) and hypoxia condition (HIF-1α). On the other hand, recent therapeutic approaches have focused on abolishing hypoxia-induced RVH and RHF via attenuation of oxidative stress and inflammatory (IL-1β, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.

The aim of this study was to evaluate the effects of two periods of intermittent exposure to hypoxia (428 torr) in rats over 12 months. The conditions of CIH4x4 (4 days in hypoxia, 4 days in normoxia, n = 50) and CIH2x2 (2 days in hypoxia, 2 days in normoxia, n = 50) were selected for simulating in this animal model the chronic-intermittent exposure to high altitudes experienced by Andean miners. We assessed mortality, weight, hematological parameters, and time course of resting heart rate and systolic blood pressure. In general, mortality increased during the first month, with a tendency to stabilize during exposure; it was associated with lower weights and with higher hematocrit levels, making these possible predictor factors. Intermittence produced an increase in hematocrit and hemoglobin concentrations as previously seen in most hypoxic models, compared with normoxia (NX, n = 30), but attained lower levels compared with chronic hypoxia (CH, n = 28). CIH4x4 and CIH2x2 had similar sustained elevations of systolic blood pressure (171 +/- 3 and 174 +/- 2 mmHg, respectively) versus the basal level (163 +/- 3; 163 +/- 3 mmHg), whereas CH did not. Heart rate suffered an equally sustained decrease in all exposed groups (343 +/- 14 beats/min). Exposure to chronic-intermittent hypoxia led to a mild polycythemia and to a decrease in heart rate. The effects of hypoxia were already evident during the first month of exposure and attained a more pronounced expression and stabilization during the third month.

The aim of this epidemiological study was to determinate the effects on hematological and lipid profile in a young group of newcomers to altitude after being exposed chronically for 8 months to 3550 m (n = 50), age 17.8 +/- 0.7; and not overweight, BMI 22.9 +/- 0.5). Readings taken at altitude on day 1 and on month 8 were hematocrit (Hct, %), hemoglobin (Hb, g/dL), Sa(O(2)), total leukocyte and subset count (mm(3), %), and lipid profile (mg/dL). The same measurements were taken in a comparative group (CG) at sea level (SL). At altitude, elevations of Hct (44.6 +/- 0.4; 51.2 +/- 0.4) and Hb (15.5 +/- 0.1; 17.3 +/- 0.1) were seen (p < 0.001) and none with Hb >/= 21 g/dL. No correlation was observed between Hb and Sa(O(2)), r = 0.11, p > 0.05. Total leukocyte count showed no changes (6037 +/- 74; 6002 +/- 43), but a relative neutropenia (55.2 + -1.5; 50.6 + -1.3) and lymphocytosis (34.2 + 1; 42.4 + 1, p < 0.001) between periods were found and also when compared to SL. Also, an inverse relationship between Sa(O(2)) and total leukocytes on month 8 (r = 0.46; r(2) = 0.204), suggesting a probable representation of a hypoxia effect. Total cholesterol (153.8 +/- 4.5; 157.3 +/- 5.1; p, ns) showed no changes, but a mild decrease of LDL-cholesterol (88.4 +/- 3.3; 81.0 +/- 3.9; p < 0.05), and a rise in triglycerides (121.6 +/- 10.9; 178.8 +/- 11.7; p < 0.001) was found. Changes observed in leukocytes subset count and triglycerides could suggest a contributory role of hypoxic conditions, raising some future epidemiological concerns regarding immune system and fatty acid behaviour at altitude.

An increasing number of people are living or working at high altitudes (hypobaric hypoxia) and therefore suffering several physiological, biochemical, and molecular changes. Pulmonary vasculature is one of the main and first responses to hypoxia. These responses imply hypoxic pulmonary vasoconstriction (HPV), remodeling, and eventually pulmonary hypertension (PH). These events occur according to the type and extension of the exposure. There is also increasing evidence that these changes in the pulmonary vascular bed could be mainly attributed to a homeostatic imbalance as a result of increased levels of reactive oxygen species (ROS). The increase in ROS production during hypobaric hypoxia has been attributed to an enhanced activity and expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), though there is some dispute about which subunit is involved. This enzymatic complex may be directly induced by hypoxia-inducible factor-1α (HIF-1α). ROS has been found to be related to several pathways, cells, enzymes, and molecules in hypoxic pulmonary vasculature responses, from HPV to inflammation, and structural changes, such as remodeling and, ultimately, PH. Therefore, we performed a comprehensive review of the current evidence on the role of ROS in the development of pulmonary vasculature changes under hypoxic conditions, with a focus on hypobaric hypoxia. This review provides information supporting the role of oxidative stress (mainly ROS) in the pulmonary vasculature’s responses under hypobaric hypoxia and depicting possible future therapeutics or research targets. NADPH oxidase-produced oxidative stress is highlighted as a major source of ROS. Moreover, new molecules, such as asymmetric dimethylarginine, and critical inflammatory cells as fibroblasts, could be also involved. Several controversies remain regarding the role of ROS and the mechanisms involved in hypoxic responses that need to be elucidated.

Obesity, a worldwide epidemic, has become a major health burden because it is usually accompanied by an increased risk for insulin resistance, diabetes, hypertension, cardiovascular diseases, and even some kinds of cancer. It also results in associated increases in healthcare expenditures and labor and economic consequences. There are also other fields of medicine and biology where obesity or being overweight play a major role, such as high-altitude illnesses (acute mountain sickness, hypoxic pulmonary hypertension, and chronic mountain sickness), where an increasing relationship among these two morbid statuses has been demonstrated. This association could be rooted in the interactions between obesity-related metabolic alterations and critical ventilation impairments due to obesity, which would aggravate hypobaric hypoxia at high altitudes, leading to hypoxemia, which is a trigger for developing high-altitude diseases. This review examines the current literature to support the idea that obesity or overweight could be major conditioning factors at high altitude.

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