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 acclim...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2019-05-01
|
Series: | Frontiers in Physiology |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.00651/full |
id |
doaj-3177b798ff204c1fa59f0fd313802397 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patricia Siques Patricia Siques Julio Brito Julio Brito Edzard Schwedhelm Eduardo Pena Eduardo Pena Fabiola León-Velarde Fabiola León-Velarde Juan José De La Cruz Rainer H. Böger Rainer H. Böger Juliane Hannemann Juliane Hannemann |
spellingShingle |
Patricia Siques Patricia Siques Julio Brito Julio Brito Edzard Schwedhelm Eduardo Pena Eduardo Pena Fabiola León-Velarde Fabiola León-Velarde Juan José De La Cruz Rainer H. Böger Rainer H. Böger Juliane Hannemann Juliane Hannemann Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude Frontiers in Physiology ADMA SDMA nitric oxide hypobaric hypoxia right ventricle endothelium |
author_facet |
Patricia Siques Patricia Siques Julio Brito Julio Brito Edzard Schwedhelm Eduardo Pena Eduardo Pena Fabiola León-Velarde Fabiola León-Velarde Juan José De La Cruz Rainer H. Böger Rainer H. Böger Juliane Hannemann Juliane Hannemann |
author_sort |
Patricia Siques |
title |
Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude |
title_short |
Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude |
title_full |
Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude |
title_fullStr |
Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude |
title_full_unstemmed |
Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude |
title_sort |
asymmetric dimethylarginine at sea level is a predictive marker of hypoxic pulmonary arterial hypertension at high altitude |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2019-05-01 |
description |
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. |
topic |
ADMA SDMA nitric oxide hypobaric hypoxia right ventricle endothelium |
url |
https://www.frontiersin.org/article/10.3389/fphys.2019.00651/full |
work_keys_str_mv |
AT patriciasiques asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT patriciasiques asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT juliobrito asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT juliobrito asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT edzardschwedhelm asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT eduardopena asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT eduardopena asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT fabiolaleonvelarde asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT fabiolaleonvelarde asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT juanjosedelacruz asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT rainerhboger asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT rainerhboger asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT julianehannemann asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude AT julianehannemann asymmetricdimethylarginineatsealevelisapredictivemarkerofhypoxicpulmonaryarterialhypertensionathighaltitude |
_version_ |
1724984477727326208 |
spelling |
doaj-3177b798ff204c1fa59f0fd3138023972020-11-25T01:55:11ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-05-011010.3389/fphys.2019.00651452305Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High AltitudePatricia Siques0Patricia Siques1Julio Brito2Julio Brito3Edzard Schwedhelm4Eduardo Pena5Eduardo Pena6Fabiola León-Velarde7Fabiola León-Velarde8Juan José De La Cruz9Rainer H. Böger10Rainer H. Böger11Juliane Hannemann12Juliane Hannemann13Institute of Health Studies, Universidad Arturo Prat, Iquique, ChileInstitute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany and Iquique, ChileInstitute of Health Studies, Universidad Arturo Prat, Iquique, ChileInstitute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany and Iquique, ChileInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Health Studies, Universidad Arturo Prat, Iquique, ChileInstitute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany and Iquique, ChileInstitute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany and Iquique, ChileDepartment of Biological and Physiological Sciences, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, PeruDepartment of Preventive Medicine and Public Health, Universidad Autónoma de Madrid, Madrid, SpainInstitute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany and Iquique, ChileInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany and Iquique, ChileInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyBackground: 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.https://www.frontiersin.org/article/10.3389/fphys.2019.00651/fullADMASDMAnitric oxidehypobaric hypoxiaright ventricleendothelium |