Patricia Siques

Blood Pressure Responses in Young Adults First Exposed to High Altitude for 12 Months at 3550 m

To determine the changes in blood pressure (BP) and related variables in sea-level young adults with chronic exposure to high altitude, a longitudinal study was performed in male army recruits (n = 346; age 17.9 +/- 0.1 yr; BMI, 22.5 +/- 0.3 kg/m(2)) first exposed to 3550-m altitude for 12 months. Fifty male recruits (age 17.8 +/- 0.6 and BMI 22.6 +/- 0.3 kg/m(2)) never exposed to altitude were used as controls. A sustained higher mean diastolic BP (DBP) (82.1 +/- 1.0 mmHg at month 3; 81.3 +/- 0.9 mmHg at month 12) was observed, compared to first exposure and the control group (p < 0.001). The BP values were always higher than those of the sea-level control group (systolic blood pressure (SBP) 109 +/- 2.3 and DBP 67.4 +/- 0.8; p < 0.001), and a large proportion of subjects steadily presented overoptimal values for either systolic BP (SBP) (64%) or DBP (77%) and hypertensive DBP values (40%). The higher DBP was associated with lower Sao(2) (OR = 0.919; p < 0.05). In addition, the acute mountain sickness (AMS) score showed a slight decrease during re-exposure (3.9 +/- 0.3 vs.3.4 +/- 0.3; p < 0.001) and an inverse association to the before-descending Sao(2) at month 3 (OR = 0.906, p < 0.01). These data suggest that BP stabilization can take longer than currently thought and that each parameter has a different profile of change. Further, a sustained high DBP should be a matter of epidemiological concern and emphasizes the need for BP monitoring among young lowlanders exposed to high altitude.

Nitric Oxide and Superoxide Anion Balance in Rats Exposed to Chronic and Long Term Intermittent Hypoxia

Work at high altitude in shifts exposes humans to a new form of chronic intermittent hypoxia, with still unknown health consequences. We have established a rat model resembling this situation, which develops a milder form of right ventricular hypertrophy and pulmonary artery remodelling compared to continuous chronic exposure. We aimed to compare the alterations in pulmonary artery nitric oxide (NO) availability induced by these forms of hypoxia and the mechanisms implicated. Rats were exposed for 46 days to normoxia or hypobaric hypoxia, either continuous (CH) or intermittent (2 day shifts, CIH2x2), and assessed: NO and superoxide anion availability (fluorescent indicators and confocal microscopy); expression of phosphorylated endothelial NO synthase (eNOS), NADPH-oxidase (p22phox), and 3-nitrotyrosine (western blotting); and NADPH-oxidase location (immunohistochemistry). Compared to normoxia, (1) NO availability was reduced and superoxide anion was increased in both hypoxic groups, with a larger effect in CH, (2) eNOS expression was only reduced in CH, (3) NADPH-oxidase was similarly increased in both hypoxic groups, and (4) 3-nitrotyrosine was increased to a larger extent in CH. In conclusion, intermittent hypoxia reduces NO availability through superoxide anion destruction, without reducing its synthesis, while continuous hypoxia affects both, producing larger nitrosative damage which could be related to the more severe cardiovascular alterations.

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.

Upregulation of Arginase Expression and Activity in Hypertensive Rats Exposed to Chronic Intermittent Hypobaric Hypoxia

The aim of this study was to analyze the activity and expression levels of arginase I and II and to monitor the cardiovascular and hematological responses in tolerant and intolerant rats exposed to chronic intermittent hypobaric hypoxia (CIHH). Male Wistar rats (age: 3.0 +/- 0.4 months, weight: 250 +/- 25 g; n = 30) were randomly divided into two groups: CIHH2 x 2 (2 days hypoxia, 2 days normoxia, n = 20) and NX (normoxia, n = 10). The hypoxia was simulated in a hypobaric chamber at 428 torr. Tolerance was determined according to a previous protocol. Arginase activity was measured in lung and heart tissues, and the expression levels were determined by a (RT-PCR) assay in lung tissue. Results showed that the intolerants rats had lower body weight, higher hematocrit (Hct) (74 +/- 4% vs. 61 +/- 2%, p < 0.05), higher values of systolic blood pressure (SBP) (183 +/- 3.7 mmHg vs. 147 +/- 5.4 mmHg, p < 0.05), and higher arginase activity. In addition, RT-PCR analysis from lung tissue showed an overexpression of arginase II in the intolerant group (p < 0.01). However, tolerants had similar values as the NX group (p = ns). Further, a correlation was found between arginase activity and SBP in the heart (r(2) = 0.596, p < 0.001). An upregulation of arginase type II could be pivotal in understanding the pathogenesis of systolic hypertension and probably other phenomena associated with intermittent hypobaric hypoxia. A schematic explanation of these relations is proposed.

Varying exposure regimes to long term chronic intermittent hypoxia exert different outcomes and morphological effects on Wistar rats at 4600 m

The aim of this study was to compare differences in morphological effects following two regimens of simulated chronic intermittent hypoxia (4600 m) during 12 months, compared to chronic hypoxia and normoxia. Male Wistar rats were randomly assigned to four groups: Chronic intermittent hypoxia (CIH) 2 × 2 (2 days hypoxia, 2 days normoxia, n = 50), CIH4 × 4 (4 days hypoxia, 4 days normoxia, n =50), chronic hypoxia (CH) (permanent, n = 28) and control (NX) (normoxia, n = 24). Hypoxia was simulated in a hypobaric chamber (428 torr). The following parameters were assessed: ventricle wall thickness, presence of congestion, edema, hemorrhage, thrombosis, necrosis, and renal casts. In general, mortality was significantly associated with heart congestion, pulmonary edema, pulmonary hemorrhage, and liver necrosis. Intermittent as well as chronic exposure produced a common pattern of manifestations in all organs, with varying severity and time of occurrence. Right ventricle hypertrophy was observed in CIH2 × 2 and CIH4 × 4 but attained lower values than in CH. Further, the coefficient of right ventricular wall thickness rose markedly dependent upon exposure duration. Renal casts and thrombosis were also shown to be the signs of hypoxic damage. Morphological effects in intermittent hypoxia resembled an intermediate severity position compared to CH and tended to occur later, indicating that a shorter regimen seemed to be less harmful.

Adventitial Alterations Are the Main Features in Pulmonary Artery Remodeling due to Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats

Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, n = 9) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, n = 10) in a chamber (428 Torr, 4,600 m of altitude) for 46 days and compared to rats under normoxia (NX, n = 10). Body weight, hematocrit, and right ventricle ratio were measured. Pulmonary artery remodeling was assessed using confocal microscopy of tissues stained with a nuclear dye (DAPI) and CD11b antibody. Both hypoxic conditions exhibited increased hematocrit and hypertrophy of the right ventricle, tunica adventitia, and tunica media, with no changes in lumen size. The medial hypertrophy area (larger in CH) depicted a significant increase in smooth muscle cell number. Additionally, CIH2x2 increased the adventitial hypertrophy area, with an increased cellularity and a larger prevalence of clustered inflammatory cells. In conclusion, CIH2x2 elicits milder effects on pulmonary artery medial layer muscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layer.

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.

Relation of Breast Cancer and Malathion Aerial Spraying in Arica, Chile

La mortalidad por cancer de mama ha ido aumentando en Arica Chile, donde ha sobrepasado las tasas nacionales 11 veces entre los anos 1990 y 2010. La ciudad de Arica recibio aspersiones del pesticida organofosforado malation, con el fin de controlar la mosca mediterranea, por primera vez hace 33 anos. Por otra parte hemos demostrado que un tratamiento con malation induce la formacion de carcinomas mamarios en ratas hembras Sprague Dowley. El objetivo de este trabajo es encontrar una relacion entre las aspersiones con malation y el aumento en la tasa de mortalidad por cancer de mama que se ha observado en Arica en los ultimos anos. Se extrajeron de bases de datos, los casos de cancer mamario diagnosticados entre 1995 y 2005, en los Hospitales Dr. Juan Noe Crevani de Arica y Ernesto Torres de Iquique. El numero de pacientes diagnosticados con cancer de mama fue 100 en Arica y 58 en Iquique, ciudad que nunca fue fumigada con malation y con una poblacion similar a la de Arica durante esos anos. El analisis estadistico de las caracteristicas de la muestra, en relacion a los factores de riesgo de cancer mamario, mostro que no hay diferencia significativa entre las mujeres de Arica y de Iquique. Sin embargo, las mujeres con mayor tiempo de exposicion al malation fueron 5,7 veces mas propensas a ser diagnosticadas con cancer de mama (OR = 5,7, p <0.02). Ademas el 30,5% del grupo expuesto a malation presento metastasis y en el grupo no expuesto solo el 16% (p <0.05). Este estudio sugiere que el aumento de la tasa de mortalidad por cancer de mama que se ha producido en Arica tiene una correlacion significativa con la exposicion al malation esparcido sobre la ciudad hace mas de 30 anos.

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.

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.