Abstract 14359: Single Nucleotide Polymorphisms in Genes Involved in L-arginine / Dimethylarginine Metabolism Predispose for Pulmonary Hypertension and Acute Mountain Sickness at High Altitude

Introduction: Chronic (CH) and chronic-intermittent (CIH) exposure to hypoxia at high altitude causes acute or chronic mountain sickness and elevation of mean pulmonary arterial pressure (mPAP). This is paralleled by increased plasma levels of ADMA, an endogenous inhibitor of NO synthesis. ADMA is cleaved by dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), whilst symmetric dimethylarginine (SDMA) is cleaved by AGXT2. Arginase (ARG1 and ARG2) competes with endothelial NO synthase (NOS3) for L-arginine as substrate. We have shown previously that baseline ADMA (at sea level) determines mPAP after six months of CIH; cut-off values of 25 mm Hg and 30 mm Hg are being used to diagnose high altitude pulmonary hypertension. Hypothesis: We hypothesized that genetic variability in genes coding for core enzymes of ADMA, SDMA, and L-arginine metabolism may predispose individuals for high altitude disease and pulmonary hypertension. Methods: We genotyped 16 common single nucleotide polymorphisms in the NOS3, DDAH1, DDAH2, AGXT2, ARG1 and ARG2 genes of 69 healthy male Chilean subjects. Study participants adhered to a CIH regimen (5d at 3,550m, 2d at sea level) for six months. Metabolites were measured by LC-MS/MS; mPAP was estimated by echocardiography at six months, and altitude acclimatization was assessed by Lake Louise Score and arterial oxygen saturation. Results: Carriers of the minor allele of DDAH1 rs233112 had a higher mean baseline ADMA level (0.76±0.03 vs. 0.67±0.02 μmol/l; p<0.05), whilst the major allele of DDAH2 rs805304 was linked to an exacerbated increase of ADMA in hypoxia (0.10±0.03 vs. 0.04±0.04 μmol/l; p<0.02). Study participants carrying the minor allele of ARG1 rs2781667 had a relative risk of elevated mPAP (>25 mm Hg) of 1.70 (1.56-1.85; p<0.0001), and carriers of the minor allele of NOS3 rs2070744 had a relative risk of elevated mPAP (>30 mm Hg) of 1.58 (1.47-1.69; p<0.0001). The NOS3 and DDAH2 genes were associated with the incidence of acute mountain sickness. Conclusions: We conclude that genetic variability in the L-arginine / ADMA / NO pathway is an important determinant of high altitude pulmonary hypertension and acute mountain sickness. DDAH1 is linked to baseline ADMA, whilst DDAH2 determines the response of ADMA to hypoxia.

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Remote ischemic preconditioning does not attenuate acute mountain sickness and high altitude-induced pulmonary hypertension at 3450 m

10.26226/morressier.57108e32d462b80290b4ac2a ◽

2016 ◽

Author(s):

Franziska Macholz

Keyword(s):

Pulmonary Hypertension ◽

High Altitude ◽

Ischemic Preconditioning ◽

Acute Mountain Sickness ◽

Remote Ischemic Preconditioning ◽

Mountain Sickness

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Remote ischemic preconditioning does not prevent acute mountain sickness after rapid ascent to 3,450 m

Journal of Applied Physiology ◽

10.1152/japplphysiol.00505.2017 ◽

2017 ◽

Vol 123 (5) ◽

pp. 1228-1234 ◽

Cited By ~ 9

Author(s):

Marc M. Berger ◽

Franziska Macholz ◽

Lukas Lehmann ◽

Daniel Dankl ◽

Marcel Hochreiter ◽

...

Keyword(s):

Pulmonary Hypertension ◽

High Altitude ◽

Ischemic Preconditioning ◽

Acute Mountain Sickness ◽

Remote Ischemic Preconditioning ◽

Systolic Pulmonary Artery Pressure ◽

Transthoracic Doppler Echocardiography ◽

Rapid Ascent ◽

Mountain Sickness ◽

The Brain

Remote ischemic preconditioning (RIPC) has been shown to protect remote organs, such as the brain and the lung, from damage induced by subsequent hypoxia or ischemia. Acute mountain sickness (AMS) is a syndrome of nonspecific neurologic symptoms and in high-altitude pulmonary edema excessive hypoxic pulmonary vasoconstriction (HPV) plays a pivotal role. We hypothesized that RIPC protects the brain from AMS and attenuates the magnitude of HPV after rapid ascent to 3,450 m. Forty nonacclimatized volunteers were randomized into two groups. At low altitude (750 m) the RIPC group ( n = 20) underwent 4 × 5 min of lower-limb ischemia (induced by inflation of bilateral thigh cuffs to 200 mmHg) followed by 5 min of reperfusion. The control group ( n = 20) underwent a sham protocol (4 × 5 min of bilateral thigh cuff inflation to 20 mmHg). Thereafter, participants ascended to 3,450 m by train over 2 h and stayed there for 48 h. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score. Systolic pulmonary artery pressure (SPAP) was assessed by transthoracic Doppler echocardiography. RIPC had no effect on the overall incidence (RIPC: 35%, control: 35%, P = 1.0) and severity (RIPC vs. control: P = 0.496 for LLS; P = 0.320 for AMS-C score) of AMS. RIPC also had no significant effect on SPAP [maximum after 10 h at high altitude; RIPC: 33 (SD 8) mmHg; controls: 37 (SD 7) mmHg; P = 0.19]. This study indicates that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate AMS and the magnitude of high-altitude pulmonary hypertension. NEW & NOTEWORTHY Remote ischemic preconditioning (RIPC) has been reported to improve neurologic and pulmonary outcome following an acute ischemic or hypoxic insult, yet the effect of RIPC for protecting from high-altitude diseases remains to be determined. The present study shows that RIPC, performed immediately before passive ascent to 3,450 m, does not attenuate acute mountain sickness and the degree of high-altitude pulmonary hypertension. Therefore, RIPC cannot be recommended for prevention of high-altitude diseases.

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Single Nucleotide Polymorphisms in the Arginase 1 and 2 Genes Are Differentially Associated with Circulating l-Arginine Concentration in Unsupplemented and l-Arginine–Supplemented Adults

Journal of Nutrition ◽

10.1093/jn/nxaa325 ◽

2020 ◽

Author(s):

Juliane Hannemann ◽

Leonard Rendant-Gantzberg ◽

Julia Zummack ◽

Jonas Hillig ◽

Ina Eilermann ◽

...

Keyword(s):

Genetic Variability ◽

Single Nucleotide Polymorphisms ◽

Functional Relation ◽

Minor Allele ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Supplement Use ◽

Arginase 1 ◽

Study Results ◽

Arginine Concentration

ABSTRACT Background Genetic variation in arginase may underlie variability in whole blood l-arginine concentrations in unsupplemented and l-arginine–supplemented adults. Objectives We aimed to study whether single nucleotide polymorphisms (SNPs) in the arginase 1 (ARG1) and arginase 2 (ARG2) genes are associated with blood l-arginine concentrations in unsupplemented and l-arginine–supplemented individuals. Methods In 374 adults (mean ± SD age: 59.6 ± 14.6 y; 180 males), we analyzed SNPs in the ARG1 (rs2246012 and rs2781667) and ARG2 genes (rs3742879 and rs2759757) and their associations with blood l-arginine concentrations. We analyzed associations of haplotypes for the ARG1 gene and for the ARG1 and ARG2 genes combined with blood l-arginine concentrations in supplement users and unsupplemented participants. Results Of study participants, 120 had low (<42 μmol/L), 133 had medium (42–114 μmol/L), and 121 had high blood l-arginine concentrations (>114 μmol/L); 58 individuals were current l-arginine supplement users. We found a significantly higher prevalence of the minor allele of ARG1 rs2246012 in supplement users with higher blood l-arginine concentrations (P = 0.03). Mean ± SEM l-arginine concentration was 263 ± 9.76 μmol/L in supplement users homozygous for the minor allele of ARG1 rs2246012 (P = 0.004); it was 70.4 ± 25.6 μmol/L in unsupplemented participants homozygous for the minor allele of ARG2 rs3759757 (P = 0.03). The ARG1 haplotype was significantly associated with blood l-arginine concentrations in supplement users (P = 0.046), whereas the combined ARG1/ARG2 haplotype was significantly associated with blood l-arginine concentrations in the cohort as a whole (P = 0.012). Conclusions Genetic variability in the ARG1 and ARG2 genes is associated with blood l-arginine concentrations in humans: ARG1 is associated with blood l-arginine concentrations in l-arginine supplement users, whereas ARG2 is associated with blood l-arginine concentrations in unsupplemented participants. Our study is the first to describe a possible functional relation between ARG1 and ARG2 SNPs and blood l-arginine concentrations; genetic variability in ARG1 may explain variation in blood l-arginine concentrations during supplement use and discrepant study results.

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

Pulmonary Circulation ◽

10.1177/2045894020930626 ◽

2020 ◽

Vol 10 (1_suppl) ◽

pp. 42-49

Author(s):

Patricia Siques ◽

Julio Brito ◽

Stefany Ordenes ◽

Eduardo Pena

Keyword(s):

Pulmonary Hypertension ◽

Lipid Metabolism ◽

High Altitude ◽

Intermittent Hypoxia ◽

Acute Mountain Sickness ◽

Overweight And Obesity ◽

Chronic Intermittent Hypoxia ◽

Inflammatory Status ◽

Mountain Sickness

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.

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

Journal of Clinical Medicine ◽

10.3390/jcm10245761 ◽

2021 ◽

Vol 10 (24) ◽

pp. 5761

Author(s):

Juliane Hannemann ◽

Patricia Siques ◽

Lena Schmidt-Hutten ◽

Julia Zummack ◽

Julio Brito ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

High Altitude ◽

Intermittent Hypoxia ◽

Acute Mountain Sickness ◽

Genomic Variation ◽

Chronic Intermittent Hypoxia ◽

Plasma Adma ◽

Major Allele ◽

Mountain Sickness

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.

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Women at Altitude: Effect of Menstrual-Cycle Phase on Acute Mountain Sickness During Deployment to High Altitude Terrain

PsycEXTRA Dataset ◽

10.1037/e462652006-001 ◽

2001 ◽

Author(s):

Paul B. Rock ◽

Stephen R. Muza ◽

Charles S. Fulco ◽

Barry Braun ◽

Stacy Zamudio ◽

...

Keyword(s):

Menstrual Cycle ◽

High Altitude ◽

Acute Mountain Sickness ◽

Cycle Phase ◽

Menstrual Cycle Phase ◽

Altitude Effect ◽

Mountain Sickness

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Optic nerve sheath diameter changes at high altitude and in acute mountain sickness: meta-regression analyses

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-317717 ◽

2020 ◽

pp. bjophthalmol-2020-317717

Author(s):

Tou-Yuan Tsai ◽

George Gozari ◽

Yung-Cheng Su ◽

Yi-Kung Lee ◽

Yu-Kang Tu

Keyword(s):

Optic Nerve ◽

High Altitude ◽

Acute Mountain Sickness ◽

Optic Nerve Sheath Diameter ◽

Optic Nerve Sheath ◽

Cochrane Library ◽

Regression Analyses ◽

Spline Regression ◽

Nerve Sheath ◽

Mountain Sickness

Background/aimsTo assess changes in optic nerve sheath diameter (ONSD) at high altitude and in acute mountain sickness (AMS).MethodsCochrane Library, EMBASE, Google Scholar and PubMed were searched for articles published from their inception to 31st of July 2020. Outcome measures were mean changes of ONSD at high altitude and difference in ONSD change between subjects with and without AMS. Meta-regressions were conducted to investigate the relation of ONSD change to altitude and time spent at that altitude.ResultsEight studies with 248 participants comparing ONSD from sea level to high altitude, and five studies with 454 participants comparing subjects with or without AMS, were included. ONSD increased by 0.14 mm per 1000 m after adjustment for time (95% CI: 0.10 to 0.18; p<0.01). Restricted cubic spline regression revealed an almost linear relation between ONSD change and time within 2 days. ONSD was greater in subjects with AMS (mean difference=0.47; 95% CI: 0.14 to 0.80; p=0.01; I2=89.4%).ConclusionOur analysis shows that ONSD changes correlate with altitude and tend to increase in subjects with AMS. Small study number and high heterogeneity are the limitations of our study. Further large prospective studies are required to verify our findings.

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