High Altitude Pulmonary Edema Patients Research Articles

TNF-α and RPLP0 drive the apoptosis of endothelial cells and increase susceptibility to high-altitude pulmonary edema

High-altitude pulmonary edema (HAPE) is a fatal threat for sojourners who ascend rapidly without sufficient acclimatization. Acclimatized sojourners and adapted natives are both insensitive to HAPE but have different physiological traits and molecular bases. In this study, based on GSE52209, the gene expression profiles of HAPE patients were compared with those of acclimatized sojourners and adapted natives, with the common and divergent differentially expressed genes (DEGs) and their hub genes identified, respectively. Bioinformatic methodologies for functional enrichment analysis, immune infiltration, diagnostic model construction, competing endogenous RNA (ceRNA) analysis and drug prediction were performed to detect potential biological functions and molecular mechanisms. Next, an array of in vivo experiments in a HAPE rat model and in vitro experiments in HUVECs were conducted to verify the results of the bioinformatic analysis. The enriched pathways of DEGs and immune landscapes for HAPE were significantly different between sojourners and natives, and the common DEGs were enriched mainly in the pathways of development and immunity. Nomograms revealed that the upregulation of TNF-α and downregulation of RPLP0 exhibited high diagnostic efficiency for HAPE in both sojourners and natives, which was further validated in the HAPE rat model. The addition of TNF-α and RPLP0 knockdown activated apoptosis signaling in endothelial cells (ECs) and enhanced endothelial permeability. In conclusion, TNF-α and RPLP0 are shared biomarkers and molecular bases for HAPE susceptibility during the acclimatization/adaptation/maladaptation processes in sojourners and natives, inspiring new ideas for predicting and treating HAPE.

The Association of Methylation Level in the CYP39A1 Gene with High Altitude Pulmonary Edema in the Chinese Population.

High altitude pulmonary edema (HAPE) is still the most common fatal disease at high altitudes. DNA methylation proceeds with an important role in HAPE progression. This study was designed to investigate the association between CYP39A1 methylation and HAPE. Peripheral blood samples were enrolled from 106 participants (53 HAPE patients and 53 healthy subjects) to study the association of CYP39A1 methylation with HAPE. DNA methylation site in the promoter region of CYP39A1 was detected by Sequenom MassARRAY EpiTYPER platform. Probability analysis showed that the methylation probabilities of CYP39A1_1_CpG_5 and CYP39A1_3_CpG_21 are significant differences between the cases and controls (p< 0.05). The methylation level analysis indicated that CYP39A1_1_CpG_2.3.4, CYP39A1_5_CpG_6.7, and CYP39A1_5_CpG_9.10 were higher methylation in HAPE compared to the controls (p< 0.05). CYP39A1_3_CpG_21 and CYP39A1_4_CpG_3 exhibited a lower methylation level in HAPE than that in the controls (p< 0.05). The association analysis given that CYP39A1_1_CpG_2.3.4 (OR 2.56, p= 0.035), CYP39A1_5_CpG_6.7 (OR 3.99, p= 0.003), CYP39A1_5_CpG_9.10 (OR 3.99, p= 0.003), CYP39A1_5_CpG_16.17.18 (OR 2.53, p= 0.033), and CYP39A1_5_CpG_20 (OR 3.05, p= 0.031) are associated with an increased risk of HAPE. Whereas CYP39A1_1_CpG_5 (OR 0.33, p= 0.016) and CYP39A1_3_CpG_21 (OR 0.18, p= 0.005) have a protective role in HAPE. Besides, age-stratification analysis showed that CYP39A1_1_CpG_5 (OR 0.16, p= 0.014) and CYP39A1_3_CpG_21 (OR 0.08, p= 0.023) had a protective impact on HAPE in people aged ≤32 years. CYP39A1_5_CpG_6.7 (OR 6.70, p= 0.008) and CYP39A1_5_CpG_9.10 (OR 6.70, p= 0.008) were related to an increased susceptibility to HAPE aged >32 years. Moreover, the diagnostic value of CYP39A1_3_CpG_21 (AUC = 0.712, p< 0.001) was significantly better than other CpG sites. The methylation level of CYP39A1 was associated with a risk of HAPE in the Chinese population, which provided new perspective for preventing and diagnosing of HAPE.

Clinical characteristics of venous thromboembolism onset from severe high altitude pulmonary edema in plateau regions

BackgroundTo investigate venous thromboembolism (VTE) in hospitalized patients with severe high altitude pulmonary edema (HAPE), we performed a single center retrospective study to evaluate its clinical characteristics, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center in plateau regions.MethodsWe studied a total of 18 patients with severe HAPE from January 1, 2012 to December 31, 2021. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities and cardiac ultrasound, and computed tomographic pulmonary angiography (CTPA) variables were obtained, and comparisons were made between groups with and without VTE.ResultsOf the 18 patients hospitalized with severe HAPE (age 43 (range, 34–54) years, 14 [77.8%] men), 7 patients developed VTE (38.9%), including 5 with deep vein thrombosis (DVT) and pulmonary embolism (PE), 2 of whom had DVT only. Eighteen patients are all firstly rapid ascent to high altitudes which the mean altitude was 3700 m (3656–4050 m). Compared with patients who did not have VTE, patients with VTE had a longer time in hospital (13 [11, 19] versus 9 [7, 12]; P = 0.027), respiratory failure (6 [85.7%] versus 2 [18.2%]; P = 0.013), the shortened APTT (21.50 [19.00, 27.50] versus 26.30 [24.80, 30.10]; P = 0.044) and the higher level of D-dimer (7.81 [4.62, 9.60] versus 2.90 [1.75, 3.37]; P = 0.003). The proportion of thromboprophylaxis is too low in our cohort which 2 of 18 (11.1%) patients were given VTE prophylaxis. There was no statistically significant difference between the VTE and non-VTE groups (0 [0.0%] versus 2 [18.2%]; P = 0.497).ConclusionsThe prevalence of VTE is high in hospitalized patients with severe high altitude pulmonary edema (HAPE). Prophylaxis for venous thromboembolism may be protective in severe HAPE patients after admission. Our data seem to suggest that VTE is probably an additional prognostic factors in patients with severe HAPE.

The Telomere-Telomerase System Is Detrimental to Health at High-Altitude.

The hypobaric-hypoxia environment at high-altitude (HA, >2500 m) may influence DNA damage due to the production of reactive molecular species and high UV radiation. The telomere system, vital to chromosomal integrity and cellular viability, is prone to oxidative damages contributing to the severity of high-altitude disorders such as high-altitude pulmonary edema (HAPE). However, at the same time, it is suggested to sustain physical performance. This case-control study, comprising 210 HAPE-free (HAPE-f) sojourners, 183 HAPE-patients (HAPE-p) and 200 healthy highland natives (HLs) residing at ~3500 m, investigated telomere length, telomerase activity, and oxidative stress biomarkers. Fluidigm SNP genotyping screened 65 single nucleotide polymorphisms (SNPs) in 11 telomere-maintaining genes. Significance was attained at p ≤ 0.05 after adjusting for confounders and correction for multiple comparisons. Shorter telomere length, decreased telomerase activity and increased oxidative stress were observed in HAPE patients; contrarily, longer telomere length and elevated telomerase activity were observed in healthy HA natives compared to HAPE-f. Four SNPs and three haplotypes are associated with HAPE, whereas eight SNPs and nine haplotypes are associated with HA adaptation. Various gene-gene interactions and correlations between/among clinical parameters and biomarkers suggested the presence of a complex interplay underlining HAPE and HA adaptation physiology. A distinctive contribution of the telomere-telomerase system contributing to HA physiology is evident in this study. A normal telomere system may be advantageous in endurance training.

Mean corpuscular haemoglobin concentration (MCHC): a new biomarker for high-altitude pulmonary edema in the Ecuadorian Andes

Ascent to high altitude (> 3000 m height above sea level or m.a.s.l) exposes people to hypobaric atmospheric pressure and hypoxemia, which provokes mountain sickness and whose symptoms vary from the mild acute mountain sickness to the life-threatening, high-altitude pulmonary edema (HAPE). This study analysed the risk factors underlying HAPE in dwellers and travellers of the Ecuadorian Andes after sojourning over 3000 m height. A group of HAPE patients (N = 58) was compared to a NO HAPE group (N = 713), through demographic (ethnicity, sex, and age), red blood cell parameters (erythrocytes counts, hematocrit, median corpuscular volume, median corpuscular haemoglobin, and median corpuscular haemoglobin concentration (MCHC)), altitude (threshold: 3000 m.a.s.l.), and health status (vital signs) variables. Analysis of Deviance for Generalised Linear Model Fits (logit regression) revealed patterns of significant associations. High-altitude dwellers, particularly children and elder people, were HAPE-prone, while women were more tolerant of HAPE than men. Interestingly, HAPE prevalence was strongly related to an increment of MCH. The residence at middle altitude was inversely related to the odds of suffering HAPE. Ethnicity did not have a significant influence in HAPE susceptibility. Elevated MCHC emerges like a blood adaptation of Andean highlanders to high altitude and biomarker of HAPE risk.

MIR17HG polymorphisms contribute to high-altitude pulmonary edema susceptibility in the Chinese population

High-altitude pulmonary edema (HAPE) is a common acute altitude sickness. This study was designed to investigate the effect of MIR17HG polymorphisms on HAPE risk in the Chinese population. The Agena MassARRAY platform was used to genotype six single-nucleotide polymorphisms (SNPs) in the MIR17HG gene in 244 HAPE patients and 243 non-HAPE controls. The odds ratio (OR) and 95% confidence interval were used to evaluate the association between each MIR17HG polymorphisms and the risk of HAPE under a polygenetic model. Statistical analysis was performed using the χ2 test. Multifactor dimensionality reduction (MDR) analysis was used to analyze the impacts of SNP–SNP interactions on the risk of HAPE. According to the allele model, the HAPE risk of people with the rs7318578 A allele of MIR17HG was lower than that of people with the C allele (OR 0.74, p = 0.036).Logistic regression analysis of four models for all selected MIR17HG SNPs showed significant differences in the frequencies of rs7318578 (OR 0.74, p = 0.037) and rs17735387 (OR 1.51, p = 0.036) between cases and controls. The results of the sex stratification analysis showed that among males, rs17735387 in the MIR17HG gene is associated with an increased risk of HAPE. MDR analysis showed that the best combination model was a three-locus model incorporating rs72640334, rs7318578, and rs7336610. This study revealed the correlations between rs7318578 and rs17735387 on the MIR17HG gene and the risk of HAPE in the Chinese population, providing a theoretical basis for the early screening, prevention, and diagnosis of HAPE in high-risk populations.

Association Between the Polymorphism of Steroid Hormone Metabolism Genes and High-Altitude Pulmonary Edema in the Chinese Han Population.

PurposeSteroid hormone metabolism plays an essential role in high-altitude pulmonary edema (HAPE) progression. This study aimed to investigate the association between polymorphism in seven steroid hormone metabolism genes (STAR, HSD3B1, HSD3B2, CYP17A1, CYP21A2, CYP11B1, and CYP11B2) and HAPE susceptibility among Han Chinese.Patients and MethodsA total of 41 tagSNPs in the seven genes were genotyped using Sequenom MassARRAY SNP assays from 169 HAPE patients (HAPE-p) and 309 matched Han Chinese individuals resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated.ResultsFour SNPs, including the allele C of rs6203 (p = 0.034, OR [95% CI] = 1.344 [1.022−1.767]) in HSD3B1, allele G of rs3740397 (p = 0.044, OR [95% CI] = 1.314 [1.007−1.714]) and allele C of rs10786712 (p = 0.039, OR [95% CI] = 0.751 [0.572−0.986]) in CYP17A1, and allele T of rs6402 (p = 0.006, OR [95% CI] = 0.504 [0.306−0.830]) in CYP11B1, were significantly associated with HAPE. The distribution of the genotypes of these SNPs also significantly differed between the HAPE-p and HAPE-r groups. Moreover, six haplotypes (the linkage disequilibrium block including rs10883783, rs4919686, rs3740397, rs3824755, and rs10786712) of CYP17A1 were also significantly associated with HAPE.ConclusionThe four SNPs located in HSD3B1 (rs6203), CYP17A1 (rs3740397 and rs10786712), and CYP11B1 (rs6402) and the six haplotypes of CYP17A1 are likely to have an effect on HAPE.

Characteristics of High Altitude Pulmonary Edema in Naqu at the Altitude of 4500 m

BackgroundWe aimed to review records from 429 patients with high altitude pulmonary edema (HAPE) to identify some of the salient characteristics associated with this condition. Materials and MethodsGeneral information and clinical symptoms, along with laboratory test results from HAPE patients were collected and analyzed. Blood assay results and imaging at admission were compared with those at discharge. Results from routine blood assays were compared among three subgroups of these patients that were generated based upon the duration of their hypoxia exposure. ResultsOf these 429 HAPE patients, 9.32% also showed high altitude cerebral edema (HACE). White blood cell and neutrophil counts, as well as levels of alanine aminotransferase and aspartate aminotransferase, uric acid, lactic dehydrogenase and creatine kinase were all increased in HAPE patients, with further increases observed in those with HAPE combined with HACE. Levels of white blood cells, neutrophils, lymphocytes, and hemoglobin concentrations in HAPE patients at admission were significantly higher than that obtained at discharge. White blood cell and neutrophil counts were lower in patients who developed HAPE after a duration of 7 days of high altitude exposure as compared with those who developed the condition within 1 or 3 days. ConclusionsA combination of HAPE and HACE was present in 9.32% of the patients with HAPE. HAPE was more prevalent in males. Hepatocytes and the myocardium were likely sites of damage in patients with HAPE, with more severe damage observed in the patients with HAPE/HACE. White blood cell and neutrophil counts were significantly higher than normal ranges and these levels were negatively correlated with the duration of hypoxia exposure.

Shorter telomere length, higher telomerase activity in association with tankyrase gene polymorphism contribute to high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High-altitude pulmonary edema patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200) and highland permanent healthy residents (HLs, n = 200). Variants of TNKS were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Plasma TNKS level was estimated using enzyme-linked immunosorbent assay, expression of TNKS and relative telomere length were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and telomerase activity was assessed by the telomere repeat amplification protocol assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (P =0.006). TNKS was upregulated 9.27 folds in HAPE-p (P = 1.01E-06) and downregulated in HLs by 3.3 folds (P = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (P =0.03) and HLs (P= 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (P= 0.01) and HLs (P= 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031ng/μl) and the highest telomerase activity (0.0268 amoles/μl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.

Genome-wide association study of mitochondrial DNA in Chinese men identifies seven new susceptibility loci for high-altitude pulmonary oedema

Background/Aim. High-altitude pulmonary oedema (HAPE), which normally occurs at altitudes higher than 3,000 m, is a potentially fatal disease due to hypoxia. The role of mitochondrial genomes in determining an individual's susceptibility to HAPE has not been determined yet. However, a number of genetic polymorphisms have recently been found to be overrepresented in HAPE patients. The majority of published genome-wide association studies have investigated only a small number of top-ranking single-nucleotide polymorphisms (SNPs)/genes by the overview of nuclear DNA and considered each of the identified SNPs/genes in-dependently. Little research has been conducted on mitochondrial genomes in relapsing HAPE patients by genome-wide association studies. Methods. To identify biological pathways important to HAPE occurrence, we examined approximately 500,000 SNPs genome-wide from 10 unrelated cases of relapsing HAPE and we compared the SNPs in these cases with those in the Chinese in Beijing, China population (45 controls) to discover the association between genotypes and HAPE susceptibility among the mitochondrial function-related genes. We used the FUMA platform to expand those SNPs to selected candidate SNPs. Results. A total of 369 candidate SNPs, 4 lead SNPs, 4 genomic risk loci and 5 mapped genes were obtained. The 7 mapped genes were ADAMTS9-AS2, NEK1, CLCN3, C4orf27(HPF1), RP11-219J21.2, ANKRD26 and YME1L1. Conclusion. This study confirms the association of ADAMTS9-AS2, NEK1, CLCN3, C4orf27(HPF1), RP11- 219J21.2, ANKRD26 and YME1L1 with HAPE, which may provide future targets for the treatment of this disease.

Structural and functional alterations of nitric oxide synthase 3 due to missense variants associate with high-altitude pulmonary edema through dynamic study

The human endothelial nitric oxide synthase (NOS3) is 28 Kbp at 7q36.1 and encodes protein comprising of 1280 amino acids. Being a major source of nitric oxide, the enzyme is crucial to the vascular homeostasis and thereby to be an important pharmaceutical target. We hence have been investigating this molecule in a high-altitude disorder namely, high-altitude pulmonary edema (HAPE). We performed a genome-wide association study (GWAS) in a case-control design of sojourners that included healthy controls and HAPE patients (n = 200) each. Four NOS3 missense SNPs i.e. rs1799983 (E298D), rs3918232 (V827M), rs3918201 (R885M) and rs3918234 (Q982L), were associated significantly with HAPE (P-value < 0.05). Furthermore, extensive in silico analyses were performed to predict the detrimental effect of the four variant types and their three most relevant co-factors namely, heme, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) that are accountable for amendment of protein stability leading to structural de-construction. Subsequently, we validated the findings in a larger sample size of the two study groups. HAPE patients had a higher frequency of the four variants and significantly decreased levels of circulating nitric oxide (NO) (P-value < 0.001). The in silico and human subjects findings complement each other. This study explored the impact of HAPE-associated NOS3 variants with its protein structure stability and holds promise to be current and future drug targets.Communicated by Ramaswamy H. Sarma

High-altitude pulmonary oedema: Newer treatment modalities for an age-old problem.

Background & objectives:High-altitude pulmonary oedema (HAPE) continues to challenge the healthcare providers at remote, resource-constrained settings. High-altitude terrain itself precludes convenience of resources. This study was conducted to evaluate the rise in peripheral capillary saturation of oxygen (SpO2) by the use of a partial rebreathing mask (PRM) in comparison to Hudson's mask among patients with HAPE.Methods:This was a single-centre, randomized crossover study to determine the efficiency of PRM in comparison to Hudson's mask. A total of 88 patients with HAPE referred to a secondary healthcare facility at an altitude of 11,500 feet from January to October 2013 were studied. A crossover after adequate wash-out on both modalities was conducted for first two days of hospital admission. All patients with HAPE were managed with bed rest and stand-alone oxygen supplementation with no adjuvant pharmacotherapy.Results:The mean SpO2 on ambient air on arrival was 66.92±10.8 per cent for all patients with HAPE. Higher SpO2 values were achieved with PRM in comparison to Hudson's mask on day one (86.08±5.15 vs. 77.23±9.09%) and day two (89.94±2.96 vs. 83.39±5.93%). The difference was more pronounced on day one as compared to day two.Interpretation & conclusions:Mean SpO2 values were found to be significantly higher among HAPE patients using PRM compared to those on Hudson's mask. Further studies to understand the translation of this incremental response in SpO2 to clinical benefits (recovery times, mortality rates and hospital stay) need to be undertaken.

NR3C2 Gene is Associated with Susceptibility to High-Altitude Pulmonary Edema in Han Chinese

The mineralocorticoid receptor is encoded by the NR3C2 gene and plays an important role in regulating vascular tone in high-altitude pulmonary edema (HAPE). This study aimed to investigate the association of the polymorphisms in the NR3C2 gene with HAPE susceptibility in Han Chinese. We enrolled 133 HAPE patients and 131 matched healthy Han Chinese from the Yushu area in Qinghai, where the altitude is greater than 3500 m. Two single nucleotide polymorphisms (SNPs) of the NR3C2 gene, rs2070951 and rs5522, were genotyped by the Sequenom MassARRAY SNP assay. The genotypic distributions and allele frequencies of NR3C2 SNP rs5522 were significantly different between the HAPE and control groups (P<0.05). The frequency of the A allele of rs5522 was significantly higher in the HAPE group than in the control group (P<0.05) with an odds ratio of 1.7 (95% CI: 1.0-2.8). There were no significant differences in the genotypic distributions and allele frequencies of NR3C2 SNP rs2070951 between the HAPE and control groups. The frequencies of the C-A and C-G haplotypes were significantly higher in the HAPE group than in control group. The rs5522 polymorphism of the NR3C2 gene was associated with HAPE susceptibility in Chinese subjects. The A allele may contribute to the susceptibility to HAPE. The frequency of the C-A and C-G haplotypes of rs2070951 and rs5522 in the NR3C2 gene may increase the risk of HAPE.

The plasma level changes of VEGF and soluble VEGF receptor-1 are associated with high-altitude pulmonary edema.

Hypoxia-induced plasma levels of VEGF and sFlt-1 are responsible for increased vascular permeability occurred in both brain and pulmonary edema. Currently, it remains unclear the exact roles of VEGF and sFlt-1 in High Altitude Pulmonary Edema (HAPE) pathogenesis. In this study, plasma levels of VEGF and sFlt-1 from 10 HAPE and 10 non-HAPE subjects were measured and compared. The results showed that plasma levels of both VEGF and sFlt-1 in HAPE patients were significantly increased as compared to the non-HAPE group. Interestingly, increased plasma levels of these two protein factors were markedly reduced after treatments. As compared to VEGF, sFlt-1 was much more affected by hypoxia and treatments, suggesting this factor was a key factor contributed to HAPE pathogenesis. Importantly, the ratio of sFlt-1 and VEGF in group of either non-HAPE or HAPE after recovery was significantly lower than the ratio in HAPE patients prior to treatments. Our findings suggested that sFlt-1 was a key factor that involved in HAPE pathogenesis and the sFlt-1/VEGF ratio could be used as a sensitive diagnostic marker for HAPE. J. Med. Invest. 65:64-68, February, 2018.

Clinical, Laboratory and Imaging Features of High Altitude Pulmonary Edema in Tibetan Plateau.

Objective To analyze characteristics of high altitude pulmonary edema (HAPE) in Chinese patients.Methods We performed a retrospective study of 98 patients with HAPE. We reviewed the medical records and summarized the clinical, laboratory and imaging characteristics of these cases, and compared the results on admission with those determined before discharge.Results Forty-eight (49.0%) patients developed HAPE at the altitude of 2800 m to 3000 m. Ninty-five (96.9%) patients were man. Moist rales were audible from the both lungs, and moist rales over the right lung were clearer than those over the left lung in fourteen patients. The white blood cells [(12.83±5.55) versus (8.95±3.23) ×10 9/L, P=0.001)] as well as neutrophil counts [(11.34±3.81) versus (7.49±2.83)×10 9/L, P=0.001)] were higher, whereas the counts of other subsets of white blood cells were lower on admission than those after recovery (all P<0.05). Serum levels of alkaline phosphatase (115.8±37.6 versus 85.7±32.4 mmol/L, P=0.020), cholinesterase (7226.2±1631.8 versus 6285.3±1693.3 mmol/L, P=0.040), creatinine (85.2±17.1 versus75.1±12.8 mmol/L, P=0.021), uric acid (401.9±114.2 versus 326.0±154.3 mmol/L, P=0.041), and uric glucose (7.20±1.10 versus 5.51±1.11 mmol/L, P=0.001) were higher, but carbondioxide combining power (CO2CP, 26.7±4.4 versus 28.9±4.5 mmol/L, P=0.042) and serous calcium (2.32±0.13 versus 2.41±0.10 mmol/L, P=0.006) were lower on admission. Arterial blood gas results showed hypoxemia and respiratory alkalosis on admission. Conclusions In the present research, men were more susceptible to HAPE than women, and in the process of HAPE, the lesions of the right lung were more serious than those of the left lung. Some indicators of routine blood test and blood biochemistry of HAPE patients changed.

Association between regulator of telomere elongation helicase1 (RTEL1) gene and HAPE risk: A case-control study.

High altitude pulmonary edema (HAPE) is a paradigm of pulmonary edema. Mutations in regulator of telomere elongation helicase1 (RTEL1) represent an important contributor to risk for pulmonary fibrosis. However, little information is found about the association between RTEL1 and HAPE risk. The present study was undertaken to tentatively explore the potential relation between single-nucleotide polymorphisms (SNPs) in RTEL1 and HAPE risk in Chinese Han population. A total of 265 HAPE patients and 303 healthy controls were included in our case-control study. Four SNPs in RTEL1 were selected and genotyped using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression with adjustment for gender and age. All P values were Bonferroni corrected, and statistical significance was set at P < .0025 (.05/20). In allelic model analysis, we found that the allele “G” of rs6089953 and rs6010621 and the allele “A” of rs2297441 were associated with decreased risk of HAPE. In the genetic model analysis, we found that rs6010621, rs6089953, and rs2297441 were relevant to decreased HAPE risk under dominant model (rs6010621: OR = 0.55; 95% CI = 0.39–0.78; P = .001; rs6089953: OR = 0.68; 95% CI = 0.48–0.96; P = .027; rs2297441: OR = 0.63; 95% CI = 0.45–0.89; P = .008, respectively) and additive model (rs6010621: OR = 0.51; 95% CI = 0.46–0.81; P < .001; rs6089953: OR = 0.72; 95% CI = 0.55–0.95; P = .022; rs2297441: OR = 0.73; 95% CI = 0.57–0.95; P = .019, respectively). SNPs rs6010621 remained significant after Bonferroni correction (P < .0025). In addition, haplotype “GG, GT, AT” of rs6089953-rs6010621 were detected significantly associated with HAPE risk (P < .05), haplotype “GG” remained significant after Bonferroni correction (P < .0025). Our findings provide new evidence for the association between SNPs in RTEL1 and a decreased risk HAPE in the Chinese population. The results need further confirmation.

Genome-wide association study of high-altitude pulmonary edema in a Han Chinese population.

A two-stage genome-wide association study (GWAS) was performed to identify and analyze genes and single nucleotide polymorphisms (SNPs) associated with high-altitude pulmonary edema (HAPE) in a Han Chinese patient population. In the first stage, DNA samples from 68 patients with recurrent HAPE were scanned using Affymetrix SNP Array 6.0 Chips, and allele frequencies were compared to those of 84 HapMap CHB samples to identify candidate SNPs. In the second stage, the 77 identified candidate SNPs were examined in an independent cohort of samples from 199 HAPE patients and 304 controls. Associations between SNPs and HAPE risk were tested using various genetic models. Of the 77 original SNPs, 7 were found to be associated with HAPE susceptibility in the second stage of the study. GO and pathway enrichment analysis of the 7 SNPs revealed 5 adjacent genes involved in various processes, including regulation of nucleoside diphosphate metabolism, thyroid hormone catabolism, and low-density lipoprotein receptor activity. These results suggest the identified SNPs and genes may contribute to the physiopathology of HAPE.

Association between genetic polymorphism of telomere-associated gene ACYP2 and the risk of HAPE among the Chinese Han population: A Case-control study.

High-altitude pulmonary edema (HAPE) is a hypoxia-induced, life-threatening, pulmonary edema, which is characterized by exaggerated pulmonary hypertension caused by stress failure. ACYP2 was found to associated with telomere length, the aim of this study was to identify whether ACYP2 polymorphisms increase or decrease HAPE risk in the Chinese Han individuals.In present study, we have genotyped 7 single-nucleotide polymorphisms (SNPs) in ACYP2 to determine the haplotypes in a case–control study with 265 HAPE patients and 303 healthy individuals. Genotypes were determined using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression with adjustment for gender and age. We found 3 SNPs yielded significant evidence for association with HAPE risk which had not been investigated before. Rs6713088 was found to have a 1.85- and 1.30-fold increased risk of HAPE in the recessive and additive model. The GT of rs843752 also conferred an increased risk of HAPE (GT/TT: OR = 1.51, 95% CI: 1.05–2.16, P = 0.026) and the genotype frequency distributions of rs843752 had significant difference between cases and controls. The CC genotype of rs17045754 had a protect effect on HAPE patients, and it was found to have a 0.29-fold reduced risk of HAPE in the recessive model.Although additional, larger population-based studies are needed to confirm these findings, our study shed light on the association between ACYP2 variant and HAPE risk in Han Chinese population for the first time.

Novel drugs in the management of acute mountain sickness and high altitude pulmonary edema.

Dear editor We read with great interest the review article titled “Wilderness medicine at high altitude: recent developments in the field” by Shah et al.1 The authors have comprehensively summarized the recent advances in the field of high altitude medicine relevant to sports and travel medicine. However, Shah et al have described potential drugs for management of high-altitude illnesses, such as acute mountain sickness (AMS), high altitude cerebral edema, and high altitude pulmonary edema (HAPE) as one group under the section “Novel drug treatment for AMS”. The pathophysiologies of these two sets of diseases (AMS/high altitude cerebral edema as one and HAPE as another set) are different2 and hence it would have been nice to have had the novel drugs described separately to elucidate the therapeutic approach for the two different classes of diseases. Shah et al have highlighted the possible beneficial use of dietary nitrate supplementation (as a source of nitric oxide [NO]) in AMS, but drugs such as inhaled NO and prostaglandin (Iloprost) for HAPE deserve a mention in this list of potential therapeutic agents.3,4 Anand et al have suggested significant beneficial effects of inhaled NO in HAPE patients.3 Iloprost in combination with NO has been found to decrease pulmonary arterial pressures in HAPE-susceptible individuals.4 Although, the latest guidelines on prevention and treatment of HAPE by the Wilderness Medical Society do not include these drugs, this is probably due to the limited work done on these drugs under field conditions of high altitude. Shah et al have also emphasized on specific phosphodiesterase type 5 inhibitors as potential therapeutic agents for AMS and HAPE. However, an expert panel from the Wilderness Medical Society do not recommend the use of phosphodiesterase type 5 inhibitors for AMS, but the same can be used for prevention (recommendation grade: 1C) and treatment (recommendation grade: 2C) of HAPE.2

ROCK2 and MYLK variants under hypobaric hypoxic environment of high altitude associate with high altitude pulmonary edema and adaptation.

ObjectiveTo date, a major class of kinases, serine–threonine kinase, has been scantly investigated in stress-induced rare, fatal (if not treated early), and morbid disorder, high altitude pulmonary edema (HAPE). This study examined three major serine–threonine kinases, ROCK2, MYLK, and JNK1, along with six other genes, tyrosine hydroxylase, G-protein subunits GNA11 and GNB3, and alpha1 adrenergic receptor isoforms 1A, 1B, and 1D as candidate gene markers of HAPE and adaptation.MethodsFor this, 57 variants across these nine genes were genotyped in HAPE patients (n=225), HAPE controls (n=210), and highlanders (n=259) by Sequenom MS (TOF)-based MassARRAY® platform using iPLEX™ Gold technology. In addition, to study the gene expression, quantitative real-time polymerase chain reaction was performed in human peripheral blood mononuclear cells of the three study groups.ResultsA significant association was observed for C allele (ROCK2 single-nucleotide polymorphism, rs10929728) with HAPE (P=0.03) and C, T, and A alleles (MYLK single-nucleotide polymorphisms, rs11717814, rs40305, and rs820336) with both HAPE and adaptation (P=0.001, P=0.006, and P=0.02, respectively). ROCK2 88 kb GGGTTGGT haplotype was associated with lower risk of HAPE (P=0.0009). MYLK 7 kb haplotype CTA, composed of variant alleles, was associated with higher risk of HAPE (P=0.0006) and lower association with adaptation (P=1E–06), whereas haplotype GCG, composed of wild-type alleles, was associated with lower risk of HAPE (P=0.001) and higher association with adaptation (P=1E–06). Haplotype–haplotype and gene–gene interactions demonstrated a correlation in working of ROCK2 and MYLK.ConclusionThe data suggest the association of ROCK2 with HAPE and MYLK with HAPE and adaptation in Indian population. The outcome has provided new insights into the physiology of HAPE and adaptation.