Effects of Zinc on the Right Cardiovascular Circuit in Long-Term Hypobaric Hypoxia in Wistar Rats.

Hypobaric hypoxia under chromic conditions triggers hypoxic pulmonary vasoconstriction (HPV) and right ventricular hypertrophy (RVH). The role of zinc (Zn) under hypoxia is controversial and remains unclear. We evaluated the effect of Zn supplementation in prolonged hypobaric hypoxia on HIF2α/MTF-1/MT/ZIP12/PKCε pathway in the lung and RVH. Wistar rats were exposed to hypobaric hypoxia for 30 days and randomly allocated into three groups: chronic hypoxia (CH); intermittent hypoxia (2 days hypoxia/2 days normoxia; CIH); and normoxia (sea level control; NX). Each group was subdivided (n = 8) to receive either 1% Zn sulfate solution (z) or saline (s) intraperitoneally. Body weight, hemoglobin, and RVH were measured. Zn levels were evaluated in plasma and lung tissue. Additionally, the lipid peroxidation levels, HIF2α/MTF-1/MT/ZIP12/PKCε protein expression and pulmonary artery remodeling were measured in the lung. The CIH and CH groups showed decreased plasma Zn and body weight and increased hemoglobin, RVH, and vascular remodeling; the CH group also showed increased lipid peroxidation. Zn administration under hypobaric hypoxia upregulated the HIF2α/MTF-1/MT/ZIP12/PKCε pathway and increased RVH in the intermittent zinc group. Under intermittent hypobaric hypoxia, Zn dysregulation could participate in RVH development through alterations in the pulmonary HIF2α/MTF1/MT/ZIP12/PKCε pathway.

Inflammation in Pulmonary Hypertension and Edema Induced by Hypobaric Hypoxia Exposure.

Exposure to high altitudes generates a decrease in the partial pressure of oxygen, triggering a hypobaric hypoxic condition. This condition produces pathophysiologic alterations in an organism. In the lung, one of the principal responses to hypoxia is the development of hypoxic pulmonary vasoconstriction (HPV), which improves gas exchange. However, when HPV is exacerbated, it induces high-altitude pulmonary hypertension (HAPH). Another important illness in hypobaric hypoxia is high-altitude pulmonary edema (HAPE), which occurs under acute exposure. Several studies have shown that inflammatory processes are activated in high-altitude illnesses, highlighting the importance of the crosstalk between hypoxia and inflammation. The aim of this review is to determine the inflammatory pathways involved in hypobaric hypoxia, to investigate the key role of inflammation in lung pathologies, such as HAPH and HAPE, and to summarize different anti-inflammatory treatment approaches for these high-altitude illnesses. In conclusion, both HAPE and HAPH show an increase in inflammatory cell infiltration (macrophages and neutrophils), cytokine levels (IL-6, TNF-α and IL-1ß), chemokine levels (MCP-1), and cell adhesion molecule levels (ICAM-1 and VCAM-1), and anti-inflammatory treatments (decreasing all inflammatory components mentioned above) seem to be promising mitigation strategies for treating lung pathologies associated with high-altitude exposure.

Impact of Zinc on Oxidative Signaling Pathways in the Development of Pulmonary Vasoconstriction Induced by Hypobaric Hypoxia.

Hypobaric hypoxia is a condition that occurs at high altitudes (>2500 m) where the partial pressure of gases, particularly oxygen (PO2), decreases. This condition triggers several physiological and molecular responses. One of the principal responses is pulmonary vascular contraction, which seeks to optimize gas exchange under this condition, known as hypoxic pulmonary vasoconstriction (HPV); however, when this physiological response is exacerbated, it contributes to the development of high-altitude pulmonary hypertension (HAPH). Increased levels of zinc (Zn2+) and oxidative stress (known as the "ROS hypothesis") have been demonstrated in the vasoconstriction process. Therefore, the aim of this review is to determine the relationship between molecular pathways associated with altered Zn2+ levels and oxidative stress in HPV in hypobaric hypoxic conditions. The results indicate an increased level of Zn2+, which is related to increasing mitochondrial ROS (mtROS), alterations in nitric oxide (NO), metallothionein (MT), zinc-regulated, iron-regulated transporter-like protein (ZIP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced protein kinase C epsilon (PKCε) activation in the development of HPV. In conclusion, there is an association between elevated Zn2+ levels and oxidative stress in HPV under different models of hypoxia, which contribute to understanding the molecular mechanism involved in HPV to prevent the development of HAPH.

AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension.

Hypoxic pulmonary hypertension (HPH) is characterized by sustained elevation of pulmonary artery pressure produced by vasoconstriction and hyperproliferative remodeling of the pulmonary artery and subsequent right ventricular hypertrophy (RVH). The search for therapeutic targets for cardiovascular pathophysiology has extended in many directions. However, studies focused on mitigating high-altitude pulmonary hypertension (HAPH) have been rare. Because AMP-activated protein kinase (AMPK) is involved in cardiovascular and metabolic pathology, AMPK is often studied as a potential therapeutic target. AMPK is best characterized as a sensor of cellular energy that can also restore cellular metabolic homeostasis. However, AMPK has been implicated in other pathways with vasculoprotective effects. Notably, cellular metabolic stress increases the intracellular ADP/ATP or AMP/ATP ratio, and AMPK activation restores ATP levels by activating energy-producing catabolic pathways and inhibiting energy-consuming anabolic pathways, such as cell growth and proliferation pathways, promoting cardiovascular protection. Thus, AMPK activation plays an important role in antiproliferative, antihypertrophic and antioxidant pathways in the pulmonary artery in HPH. However, AMPK plays contradictory roles in promoting HPH development. This review describes the main findings related to AMPK participation in HPH and its potential as a therapeutic target. It also extrapolates known AMPK functions to discuss the less-studied HAPH context.

Oxidative Stress and Diseases Associated with High-Altitude Exposure.

Several diseases associated with high-altitude exposure affect unacclimated individuals. These diseases include acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and, notably, high-altitude pulmonary hypertension (HAPH), which can eventually lead to right ventricle hypertrophy and heart failure. The development of these pathologies involves different molecules and molecular pathways that might be related to oxidative stress. Studies have shown that acute, intermittent, and chronic exposure to hypobaric hypoxia induce oxidative stress, causing alterations to molecular pathways and cellular components (lipids, proteins, and DNA). Therefore, the aim of this review is to discuss the oxidative molecules and pathways involved in the development of high-altitude diseases. In summary, all high-altitude pathologies are related to oxidative stress, as indicated by increases in the malondialdehyde (MDA) biomarker and decreases in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant activity. In addition, in CMS, the levels of 8-iso-PGF2α and H2O2 are increased, and evidence strongly indicates an increase in Nox4 activity in HAPH. Therefore, antioxidant treatments seem to be a promising approach to mitigating high-altitude pathologies.

Association of Genes of the NO Pathway with Altitude Disease and Hypoxic Pulmonary Hypertension.

Chronic intermittent hypoxia leads to high-altitude pulmonary hypertension, which is associated with high asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis. Therefore, we aimed to understand the relation of single nucleotide polymorphisms in this pathway to high-altitude pulmonary hypertension (HAPH). We genotyped 69 healthy male Chileans subjected to chronic intermittent hypoxia. Acclimatization to altitude was determined using the Lake Louise Score and the presence of acute mountain sickness. Echocardiography was performed after six months in 24 individuals to estimate pulmonary arterial pressure. The minor allele of dimethylarginine dimethylaminohydrolase (DDAH)1 rs233112 was associated with high-baseline plasma ADMA concentration, while individuals homozygous for the major allele of DDAH2 rs805304 had a significantly greater increase in ADMA during chronic intermittent hypoxia. The major allele of alanine glyoxylate aminotransferase-2 (AGXT2) rs37369 was associated with a greater reduction of plasma symmetric dimethylarginine (SDMA). Several genes were associated with high-altitude pulmonary hypertension, and the nitric oxide synthase (NOS)3 and DDAH2 genes were related to acute mountain sickness. In conclusion, DDAH1 determines baseline plasma ADMA, while DDAH2 modulates ADMA increase in hypoxia. AGXT2 may be up-regulated in hypoxia. Genomic variation in the dimethylarginine pathway affects the development of HAPH and altitude acclimatization.

Oxidative Stress, Kinase Activation, and Inflammatory Pathways Involved in Effects on Smooth Muscle Cells During Pulmonary Artery Hypertension Under Hypobaric Hypoxia Exposure.

High-altitude exposure results in hypobaric hypoxia, which affects organisms by activating several mechanisms at the physiological, cellular, and molecular levels and triggering the development of several pathologies. One such pathology is high-altitude pulmonary hypertension (HAPH), which is initiated through hypoxic pulmonary vasoconstriction to distribute blood to more adequately ventilated areas of the lungs. Importantly, all layers of the pulmonary artery (adventitia, smooth muscle, and endothelium) contribute to or are involved in the development of HAPH. However, the principal action sites of HAPH are pulmonary artery smooth muscle cells (PASMCs), which interact with several extracellular and intracellular molecules and participate in mechanisms leading to proliferation, apoptosis, and fibrosis. This review summarizes the alterations in molecular pathways related to oxidative stress, inflammation, kinase activation, and other processes that occur in PASMCs during pulmonary hypertension under hypobaric hypoxia and proposes updates to pharmacological treatments to mitigate the pathological changes in PASMCs under such conditions. In general, PASMCs exposed to hypobaric hypoxia undergo oxidative stress mediated by Nox4, inflammation mediated by increases in interleukin-6 levels and inflammatory cell infiltration, and activation of the protein kinase ERK1/2, which lead to the proliferation of PASMCs and contribute to the development of hypobaric hypoxia-induced pulmonary hypertension.

Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia.

One of the consequences of high altitude (hypobaric hypoxia) exposure is the development of right ventricular hypertrophy (RVH). One particular type of exposure is long-term chronic intermittent hypobaric hypoxia (CIH); the molecular alterations in RVH in this particular condition are less known. Studies show an important role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-induced oxidative stress and protein kinase activation in different models of cardiac hypertrophy. The aim was to determine the oxidative level, NADPH oxidase expression and MAPK activation in rats with RVH induced by CIH. Male Wistar rats were randomly subjected to CIH (2 days hypoxia/2 days normoxia; n = 10) and normoxia (NX; n = 10) for 30 days. Hypoxia was simulated with a hypobaric chamber. Measurements in the RV included the following: hypertrophy, Nox2, Nox4, p22phox, LOX-1 and HIF-1α expression, lipid peroxidation and H2O2 concentration, and p38α and Akt activation. All CIH rats developed RVH and showed an upregulation of LOX-1, Nox2 and p22phox and an increase in lipid peroxidation, HIF-1α stabilization and p38α activation. Rats with long-term CIH-induced RVH clearly showed Nox2, p22phox and LOX-1 upregulation and increased lipid peroxidation, HIF-1α stabilization and p38α activation. Therefore, these molecules may be considered new targets in CIH-induced RVH.

Long-term chronic intermittent hypoxia: a particular form of chronic high-altitude pulmonary hypertension.

In some subjects, high-altitude hypobaric hypoxia leads to high-altitude pulmonary hypertension. The threshold for the diagnosis of high-altitude pulmonary hypertension is a mean pulmonary artery pressure of 30 mmHg, even though for general pulmonary hypertension is ≥25 mmHg. High-altitude pulmonary hypertension has been associated with high hematocrit findings (chronic mountain sickness), and although these are two separate entities, they have a synergistic effect that should be considered. In recent years, a new condition associated with high altitude was described in South America named long-term chronic intermittent hypoxia and has appeared in individuals who commute to work at high altitude but live and rest at sea level. In this review, we discuss the initial epidemiological pattern from the early studies done in Chile, the clinical presentation and possible molecular mechanism and a discussion of the potential management of this condition.

Involvement of overweight and lipid metabolism in the development of pulmonary hypertension under conditions of chronic intermittent hypoxia.

There is growing evidence that exposure to hypoxia, regardless of the source, elicits several metabolic responses in individuals. These responses are constitutive and are usually observed under hypoxia but vary according to the type of exposure. The aim of this review was to describe the involvement of obesity and lipid metabolism in the development of high-altitude pulmonary hypertension and in the development of acute mountain sickness under chronic intermittent hypoxia. Overweight or obesity, which are common in individuals with long-term chronic intermittent hypoxia exposure (high-altitude miners, shift workers, and soldiers), are thought to play a major role in the development of acute mountain sickness and high-altitude pulmonary hypertension. This association may be rooted in the interactions between obesity-related metabolic and physical alterations, such as increased waist circumference and neck circumference, among others, which lead to critical ventilation impairments; these impairments aggravate hypoxemia at high altitude, thereby triggering high-altitude diseases. Overweight and obesity are strongly associated with higher mean pulmonary artery pressure in the context of long-term chronic intermittent hypoxia. Remarkably, de novo synthesis of triglycerides by the sterol regulatory element-binding protein-1c pathway has been demonstrated, mainly due to the upregulation of stearoyl-CoA desaturase-1, which is also associated with the same outcomes. Therefore, overweight, obesity, and other metabolic conditions may hinder proper acclimatization. The involved mechanisms include respiratory impairment, alteration of the nitric oxide pathways, inflammatory status, reactive oxygen species imbalance, and other metabolic changes; however, further studies are required.

Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia.

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-1ß, 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-1ß, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.

Lower Body Weight in Rats Under Hypobaric Hypoxia Exposure Would Lead to Reduced Right Ventricular Hypertrophy and Increased AMPK Activation.

BACKGROUND: Both chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypoxic conditions. METHODS: Sixty male adult rats were separated into two groups (n = 30 per group) according to their previous diet: a caloric restriction (CR) group and an ad libitum (AL) group. Rats in both groups were randomly assigned to 3 groups: a normoxic group (NX, n = 10), a CIH group (2 days hypoxia/2 days normoxia; n = 10) and a CH group (n = 10). The CR group was previously fed 10 g daily, and the other was fed ad libitum. Rats were exposed to simulated hypobaric hypoxia in a hypobaric chamber set to 428 Torr (the equivalent pressure to that at an altitude of 4,600 m above sea level) for 30 days. Measurements included body weight; hematocrit; serum insulin; glycemia; the degree of RVH (Fulton's index and histology); and AMPK, mTOR, and PP2C expression levels in the right ventricle determined by western blotting. RESULTS: A lower degree of RVH, higher AMPK activation, and no activation of mTOR were found in the CR groups exposed to hypobaric hypoxia compared to the AL groups (p < 0.05). Additionally, decreased glycemia and serum insulin levels were observed. Interestingly, PP2C expression showed an increase in the AL groups but not in the CR groups (p < 0.05). CONCLUSION: Maintaining a low weight before and during exposure to high-altitude hypoxia, during either CH or CIH, could prevent a major degree of RVH. This cardioprotection would likely be due to the activation of AMPK. Thus, body weight is a factor that might contribute to RVH at high altitudes.

Pre-Analytical and Clinical Validation of a Dried Blood Spot Assay for Asymmetric Dimethylarginine and L-Arginine.

Asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthesis. It is a risk marker for cardiovascular events and mortality in patients with cardiometabolic diseases and in population-based studies. Plasma or serum analysis of ADMA may be hampered by pre-analytical sample handling. We validated a dried blood spot (DBS) assay for ADMA and L-arginine and show here that this assay has excellent variabilities and reproducibilities. Filter paper is impregnated with the arginase inhibitor nor-NOHA (Nω-hydroxy-nor-Arginine) to avoid L-arginine degradation. Clinical validation of this DBS assay confirms elevated ADMA concentration in hemodialysis patients as compared to healthy controls, higher ADMA concentrations in men versus women, and elevated L-arginine concentration in subjects supplemented with L-arginine. The DBS assay was used in a cohort study involving 100 primarily healthy subjects in the Andean region to assess the impact of chronic intermittent hypoxia on ADMA and L-arginine; ADMA DBS concentration at sea level was prospectively associated with pulmonary hypertension after six months of exposure to 3500 m. In a cohort of 753 individuals, L-arginine/ADMA ratio significantly decreased with increasing number of traditional cardiovascular risk factors. Analysis of ADMA and L-arginine in DBS is a reliable and reproducible method for quantitation of these markers in field studies.

Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude.

Background: Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high-altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) regulates pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, we investigated whether ADMA concentration at sea level predicts HAPH among Chilean frontiers personnel exposed to 6 months of CIH. Methods: In this prospective study, 123 healthy army draftees were subjected to CIH (5 days at 3,550 m, 2 days at sea level) for 6 months. In 100 study participants with complete data, ADMA, symmetric dimethylarginine (SDMA), L-arginine, arterial oxygen saturation (SaO2), systemic blood pressure, and hematocrit were assessed at months 0 (sea level), 1, 4, and 6. Acclimatization to altitude was determined using the Lake Louise Score (LLS) and the presence of acute mountain sickness (AMS). Echocardiography was performed after 6 months of CIH in 43 individuals with either good (n = 23) or poor (n = 20) acclimatization. Results: SaO2 acutely decreased at altitude and plateaued at 90% thereafter. ADMA increased and SDMA decreased during the study course. The incidence of AMS and the LLS was high after the first ascent (53 and 3.1 ± 2.4) and at 1 month of CIH (47 and 3.0 ± 2.6), but decreased to 20 and 1.4 ± 2.0 at month 6 (both p < 0.001). Eighteen participants (42%) showed a mean pulmonary arterial pressure (mPAP) >25 mm Hg, out of which 9 (21%) were classified as HAPH (mPAP ≥ 30 mm Hg). ADMA at sea level was significantly associated with mPAP at high altitude in month 6 (R = 0.413; p = 0.007). In ROC analysis, a cutoff for baseline ADMA of 0.665 µmol/L was determined to predict HAPH (mPAP > 30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. Conclusions: ADMA concentration increases during CIH. ADMA at sea level is an independent predictive biomarker of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of HAPH.

Long-Term Chronic Intermittent Hypobaric Hypoxia Induces Glucose Transporter (GLUT4) Translocation Through AMP-Activated Protein Kinase (AMPK) in the Soleus Muscle in Lean Rats.

Background: In chronic hypoxia (CH) and short-term chronic intermittent hypoxia (CIH) exposure, glycemia and insulin levels decrease and insulin sensitivity increases, which can be explained by changes in glucose transport at skeletal muscles involving GLUT1, GLUT4, Akt, and AMPK, as well as GLUT4 translocation to cell membranes. However, during long-term CIH, there is no information regarding whether these changes occur similarly or differently than in other types of hypoxia exposure. This study evaluated the levels of AMPK and Akt and the location of GLUT4 in the soleus muscles of lean rats exposed to long-term CIH, CH, and normoxia (NX) and compared the findings. Methods: Thirty male adult rats were randomly assigned to three groups: a NX (760 Torr) group (n = 10), a CIH group (2 days hypoxia/2 days NX; n = 10) and a CH group (n = 10). Rats were exposed to hypoxia for 30 days in a hypobaric chamber set at 428 Torr (4,600 m). Feeding (10 g daily) and fasting times were accurately controlled. Measurements included food intake (every 4 days), weight, hematocrit, hemoglobin, glycemia, serum insulin (by ELISA), and insulin sensitivity at days 0 and 30. GLUT1, GLUT4, AMPK levels and Akt activation in rat soleus muscles were determined by western blot. GLUT4 translocation was measured with confocal microscopy at day 30. Results: (1) Weight loss and increases in hematocrit and hemoglobin were found in both hypoxic groups (p < 0.05). (2) A moderate decrease in glycemia and plasma insulin was found. (3) Insulin sensitivity was greater in the CIH group (p < 0.05). (4) There were no changes in GLUT1, GLUT4 levels or in Akt activation. (5) The level of activated AMPK was increased only in the CIH group (p < 0.05). (6) Increased GLUT4 translocation to the plasma membrane of soleus muscle cells was observed in the CIH group (p < 0.05). Conclusion: In lean rats experiencing long-term CIH, glycemia and insulin levels decrease and insulin sensitivity increases. Interestingly, there is no increase of GLUT1 or GLUT4 levels or in Akt activation. Therefore, cellular regulation of glucose seems to primarily involve GLUT4 translocation to the cell membrane in response to hypoxia-mediated AMPK activation.

Reactive Oxygen Species and Pulmonary Vasculature During Hypobaric Hypoxia.

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.

Long-Term Intermittent Work at High Altitude: Right Heart Functional and Morphological Status and Associated Cardiometabolic Factors.

Background: Living at high altitude or with chronic hypoxia implies functional and morphological changes in the right ventricle and pulmonary vasculature with a 10% prevalence of high-altitude pulmonary hypertension (HAPH). The implications of working intermittently (day shifts) at high altitude (hypobaric hypoxia) over the long term are still not well-defined. The aim of this study was to evaluate the right cardiac circuit status along with potentially contributory metabolic variables and distinctive responses after long exposure to the latter condition. Methods: A cross-sectional study of 120 healthy miners working at an altitude of 4,400-4,800 m for over 5 years in 7-day commuting shifts was designed. Echocardiography was performed on day 2 at sea level. Additionally, biomedical and biochemical variables, Lake Louise scores (LLSs), sleep disturbances and physiological variables were measured at altitude and at sea level. Results: The population was 41.8 ± 0.7 years old, with an average of 14 ± 0.5 (range 5-29) years spent at altitude. Most subjects still suffered from mild to moderate symptoms of acute mountain sickness (mild was an LLS of 3-5 points, including cephalea; moderate was LLS of 6-10 points) (38.3%) at the end of day 1 of the shift. Echocardiography showed a 23% mean pulmonary artery pressure (mPAP) >25 mmHg, 9% HAPH (≥30 mmHg), 85% mild increase in right ventricle wall thickness (≥5 mm), 64% mild right ventricle dilation, low pulmonary vascular resistance (PVR) and fairly good ventricle performance. Asymmetric dimethylarginine (ADMA) (OR 8.84 (1.18-66.39); p < 0.05) and insulin (OR: 1.11 (1.02-1.20); p < 0.05) were associated with elevated mPAP and were defined as a cut-off. Interestingly, the correspondence analysis identified association patterns of several other variables (metabolic, labor, and biomedical) with higher mPAP. Conclusions: Working intermittently at high altitude involves a distinctive pattern. The most relevant and novel characteristics are a greater prevalence of elevated mPAP and HAPH than previously reported at chronic intermittent hypobaric hypoxia (CIHH), which is accompanied by subsequent morphological characteristics. These findings are associated with cardiometabolic factors (insulin and ADMA). However, the functional repercussions seem to be minor or negligible. This research contributes to our understanding and surveillance of this unique model of chronic intermittent high-altitude exposure.

Obesity as a Conditioning Factor for High-Altitude Diseases.

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.

Long-Term Intermittent Exposure to High Altitude Elevates Asymmetric Dimethylarginine in First Exposed Young Adults.

Lüneburg, Nicole, Patricia Siques, Julio Brito, Juan José De La Cruz, Fabiola León-Velarde, Juliane Hannemann, Cristian Ibanez, and Rainer Böger. Long-term intermittent exposure to high altitude elevates asymmetric dimethylarginine in first exposed young adults. High Alt Med Biol. 18:226-233, 2017.-Hypoxia-induced dysregulation of pulmonary and cerebral circulation may be related to an impaired nitric oxide (NO) pathway. We investigated the effect of chronic intermittent hypobaric hypoxia (CIH) on metabolites of the NO pathway. We measured asymmetric and symmetric dimethylarginine (ADMA and SDMA) and monomethyl-L-arginine (L-NMMA) and assessed their associations with acclimatization in male draftees (n = 72) undergoing CIH shifts at altitude (3550 m) during 3 months. Sixteen Andean natives living at altitude (3675 m) (chronic hypobaric hypoxia [CH]) were included for comparison. In CIH, ADMA and L-NMMA plasma concentrations increased from 1.14 ± 0.04 to 1.95 ± 0.09 µmol/L (mean ± SE) and from 0.22 ± 0.07 to 0.39 ± 0.03 µmol/L, respectively, (p < 0.001 for both) after 3 months, whereas SDMA did not change. The concentrations of ADMA and L-NMMA were higher in CH (3.48 ± 0.07, 0.53 ± 0.08 µmol/L; p < 0.001) as compared with CIH. In both CIH and CH, ADMA correlated with hematocrit (r2 = 0.07, p < 0.05; r2 = 0.26; p < 0.01). In CIH, an association of ADMA levels with poor acclimatization status was observed. We conclude that the endogenous NO synthase inhibitors, ADMA and L-NMMA, are elevated in hypoxia. This may contribute to impaired NO production at altitude and may also be predictive of altitude-associated health impairment.

Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension?

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.