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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.

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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.

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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.

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Nitric oxide (NO) synthesis capacity is determined by the availability of substrate(s) such as L-arginine and the influence of nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). These factors may be important in black South Africans with a very high prevalence of hypertension. We compared ambulatory blood pressure (BP), markers of end organ damage and NO synthesis capacity markers [L-arginine, L-homoarginine, L-citrulline, L-arginine:ADMA, ADMA, SDMA and dimethylarginine (DMA)], between black and white teachers (n = 390). Associations of nighttime BP and markers of end organ damage with NO synthesis capacity markers were also investigated. Although black men and women had higher BP and albumin-to-creatinine ratio (ACR) (all p < 0.001), they also had higher L-arginine, L-homoarginine, L-arginine:ADMA and lower SDMA and DMA levels (all p < 0.05). Only in white men ADMA concentrations associated positively with nighttime systolic blood pressure (R (2) = 0.20, ß = 0.26, p = 0.009), nighttime diastolic blood pressure (R (2) = 0.23, ß = 0.27, p = 0.007), carotid intima media thickness (cIMT) (R (2) = 0.36, ß = 0.22, p = 0.008) and ACR (R (2) = 0.14, ß = 0.32, p = 0.001). Our findings suggest that despite an adverse cardiovascular profile in blacks, their NO synthesis capacity profile seems favourable, and that other factors, such as NO inactivation, may prove to be more important.

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Elevated circulating ADMA levels have been proposed as the pivotal link between insulin resistance, cardiovascular disease, and endothelial dysfunction in Caucasian population. To evaluate whether there is an association between plasma ADMA concentrations and insulin resistance in Hispanic population, we identified metabolic syndrome NCEP-ATP III criteria and measured ADMA and L-arginine plasma concentrations in 147 Colombian young males consecutively included in a cross-sectional study. In contrast to inflammatory markers, ADMA was not found to be elevated in subjects with metabolic syndrome, furthermore, no significant association between ADMA concentrations and insulin resistance degree was found. In conclusion, our results suggest that at least in our population, ADMA does not seem to be implicated in the pathophysiology of metabolic syndrome. Ethnic-specific or environmental differences in the etiologic mechanisms of metabolic syndrome need to be elucidated in further studies.

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