RESUMO
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.
RESUMO
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.
Assuntos
Aclimatação/fisiologia , Altitude , Arginina/análogos & derivados , Hipóxia/sangue , ômega-N-Metilarginina/sangue , Adolescente , Doença da Altitude/etiologia , Arginina/sangue , Chile , Humanos , Masculino , Militares , Doenças Profissionais/etiologia , Adulto JovemRESUMO
Lipid metabolism under chronic hypoxia (CH) has not received equal attention as intermittent hypoxia (IH). To determine the CH-induced changes in plasma and liver, as well as the mRNA and protein expression of two key enzymes in the triglyceride and cholesterol biosynthesis pathways, SREBP-1 (HMG-CoA reductase) and SREBP-2 (SCD-1), we exposed adult male Wistar rats to CH (4600 m; n=15) for 30 days compared to normoxic rats (n=15). The CH rats exhibited weight loss (p<0.001), higher hematocrit (%), and higher hemoglobin (g/dL) (p<0.01). In the plasma of CH rats, total cholesterol and LDL-cholesterol increased at day 15. VLDL-cholesterol and triglycerides (p<0.01) greatly increased (35%), while HDL-cholesterol decreased (p<0.01). Triglycerides and VLDL-cholesterol remained elevated by 28% at day 30 (p<0.01). Hepatic triglycerides increased two-fold, while total cholesterol increased by 51% (p<0.001; p<0.05). Upregulation of SCD-1 mRNA and protein was observed in the CH rats (p<0.01); however, no differences were observed in HMG-CoA reductase mRNA or protein expression in both groups. In conclusion, CH, like IH, alters lipid profiles by increasing triglycerides in the plasma and liver and upregulating triglyceride biosynthesis without affecting the cholesterol biosynthetic pathway. Additional involved mechanisms require further study because of the importance of lipids in cardiovascular risk.
Assuntos
Colesterol/metabolismo , Hipóxia/metabolismo , Fígado/metabolismo , Triglicerídeos/metabolismo , Animais , Biomarcadores/metabolismo , Western Blotting , Doença Crônica , Hematócrito , Hemoglobinas/metabolismo , Hidroximetilglutaril-CoA Redutases/metabolismo , Hipóxia/etiologia , Fígado/enzimologia , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estearoil-CoA Dessaturase/metabolismo , Regulação para CimaRESUMO
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.
Assuntos
Aclimatação/fisiologia , Altitude , Colesterol/sangue , Hemoglobinas/fisiologia , Leucócitos/fisiologia , Adolescente , Adulto , Análise de Variância , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Hematócrito , Humanos , Masculino , Valores de Referência , Estatísticas não Paramétricas , Triglicerídeos/sangueRESUMO
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.