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1.
Genome Biol Evol ; 13(2)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33566097

RESUMO

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.

2.
Int J Mol Sci ; 21(22)2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33202984

RESUMO

One of the consequences of high altitude (hypobaric hypoxia) exposure is the development of right ventricular hypertrophy (RVH). One particular type of exposure is long-term chronic intermittent hypobaric hypoxia (CIH); the molecular alterations in RVH in this particular condition are less known. Studies show an important role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-induced oxidative stress and protein kinase activation in different models of cardiac hypertrophy. The aim was to determine the oxidative level, NADPH oxidase expression and MAPK activation in rats with RVH induced by CIH. Male Wistar rats were randomly subjected to CIH (2 days hypoxia/2 days normoxia; n = 10) and normoxia (NX; n = 10) for 30 days. Hypoxia was simulated with a hypobaric chamber. Measurements in the RV included the following: hypertrophy, Nox2, Nox4, p22phox, LOX-1 and HIF-1α expression, lipid peroxidation and H2O2 concentration, and p38α and Akt activation. All CIH rats developed RVH and showed an upregulation of LOX-1, Nox2 and p22phox and an increase in lipid peroxidation, HIF-1α stabilization and p38α activation. Rats with long-term CIH-induced RVH clearly showed Nox2, p22phox and LOX-1 upregulation and increased lipid peroxidation, HIF-1α stabilization and p38α activation. Therefore, these molecules may be considered new targets in CIH-induced RVH.

3.
Genome Biol Evol ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33185669

RESUMO

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled Nitric Oxide (FeNO) also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.

5.
Front Physiol ; 11: 342, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32372974

RESUMO

Background: Both chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypoxic conditions. Methods: Sixty male adult rats were separated into two groups (n = 30 per group) according to their previous diet: a caloric restriction (CR) group and an ad libitum (AL) group. Rats in both groups were randomly assigned to 3 groups: a normoxic group (NX, n = 10), a CIH group (2 days hypoxia/2 days normoxia; n = 10) and a CH group (n = 10). The CR group was previously fed 10 g daily, and the other was fed ad libitum. Rats were exposed to simulated hypobaric hypoxia in a hypobaric chamber set to 428 Torr (the equivalent pressure to that at an altitude of 4,600 m above sea level) for 30 days. Measurements included body weight; hematocrit; serum insulin; glycemia; the degree of RVH (Fulton's index and histology); and AMPK, mTOR, and PP2C expression levels in the right ventricle determined by western blotting. Results: A lower degree of RVH, higher AMPK activation, and no activation of mTOR were found in the CR groups exposed to hypobaric hypoxia compared to the AL groups (p < 0.05). Additionally, decreased glycemia and serum insulin levels were observed. Interestingly, PP2C expression showed an increase in the AL groups but not in the CR groups (p < 0.05). Conclusion: Maintaining a low weight before and during exposure to high-altitude hypoxia, during either CH or CIH, could prevent a major degree of RVH. This cardioprotection would likely be due to the activation of AMPK. Thus, body weight is a factor that might contribute to RVH at high altitudes.

6.
High Alt Med Biol ; 21(1): 92-98, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31977247

RESUMO

Background: The soluble form of the erythropoietin (Epo) receptor (sEpoR) is an endogenous antagonist of Epo. Decreasing plasma sEpoR increases free Epo, thereby increasing the availability of the hormone. In humans, short-term intermittent normobaric hypoxia exposure reduces sEpoR concentration in plasma. However, whether similar changes occur during continuous hypoxia, such as during high-altitude exposure with ongoing acclimatization, is yet unknown. Therefore, this study aimed to characterize the time-course concentration profile of sEpoR, and also of Epo, reticulocyte count (RC), and hematocrit in healthy lowlanders during 4 days at high altitude. Methods: Twenty-two men residents at sea level traveled by road (∼7 hours) from Lima to Cerro de Pasco (4340 m) for 72 hours. Oxygen saturation as measured by pulse oximetry (SpO2), heart rate, systolic and diastolic blood pressure, Lake Louise Score, sEpoR, Epo, RC, and hematocrit were evaluated every 12 hours, starting 12 hours before the ascent. Results: Plasma sEpoR decreased by 19% and remained below baseline values throughout high-altitude exposure. In parallel, Epo levels increased during the first hours, reaching a peak at 48 hours, and then progressively decreased until 72 hours. As a result, the Epo-to-sEpoR ratio (Epo/sEpoR) remained significantly elevated compared with baseline values. RC increased linearly until the end of the protocol, and hematocrit only showed a marginal increase. Conclusion: Our results show that high-altitude hypoxia causes a significant and stable reduction of plasma sEpoR concentration within the first 24 hours, whereas plasma Epo constantly decreases after having reached a maximum by 48 hours. This simultaneous change leads to a relatively high Epo/sEpoR after 72 hours at high altitude. The early increase in hematocrit likely relates to hemoconcentration, but the steady increase in RC reflects a sustained erythropoietic drive that will lead to elevate hematocrit to a new steady state after acclimatization.

7.
Proc Natl Acad Sci U S A ; 116(48): 24006-24011, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31712437

RESUMO

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L⋅min-1 and mL⋅min-1⋅kg-1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min-1⋅kg-1 vs. CC = 30.5 mL⋅min-1⋅kg-1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.


Assuntos
Altitude , Prolina Dioxigenases do Fator Induzível por Hipóxia/fisiologia , Hipóxia/genética , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Aclimatação , Adaptação Fisiológica , Feminino , Frequência do Gene , Genótipo , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Povos Indígenas , Masculino , Peru , Seleção Genética , Estresse Fisiológico
8.
Am J Phys Anthropol ; 170(3): 451-458, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31396964

RESUMO

OBJECTIVES: Andean and Tibetan high-altitude natives exhibit a high concentration of nitric oxide (NO) in the lungs, suggesting that NO plays an adaptive role in offsetting hypobaric hypoxia. We examined the exhaled NO concentration as well as partial pressure of several additional high-altitude native populations in order to examine the possibility that this putative adaptive trait, that is, high exhaled NO, is universal. METHODS: We recruited two geographically diverse highland native populations, Tawang Monpa (TM), a Tibetan derived population in North-Eastern India (n = 95, sampled at an altitude of ~3,200 m), and Peruvian Quechua from the highland Andes (n = 412). The latter included three distinct subgroups defined as those residing at altitude (Q-HAR, n = 110, sampled at 4,338 m), those born and residing at sea-level (Q-BSL, n = 152), and those born at altitude but migrant to sea-level (Q-M, n = 150). In addition, we recruited a referent sample of lowland natives of European ancestry from Syracuse, New York. Fraction of exhaled NO concentrations were measured using a NIOX NIMO following the protocol of the manufacturer. RESULTS: Partial pressure of exhaled nitric oxide (PENO) was significantly lower (p < .05) in both high-altitude resident groups (TM = 6.2 ± 0.5 nmHg and Q-HAR = 5.8 ± 0.5 nmHg), as compared to the groups measured at sea level (USA = 14.6 ± 0.7 nmHg, Q-BSL = 18.9 ± 1.6 nmHg, and Q-M = 19.2 ± 1.7 nmHg). PENO was not significantly different between TM and Q-HAR (p < .05). CONCLUSION: In contrast to previous work, we found lower PENO in populations at altitude (compared to sea-level) and no difference in PENO between Tibetan and Andean highland native populations. These results do not support the hypothesis that high nitric oxide in human lungs is a universal adaptive mechanism of highland native populations to offset hypobaric hypoxia.


Assuntos
Expiração , Óxido Nítrico/metabolismo , Adaptação Fisiológica , Adulto , Altitude , Feminino , Humanos , Índia , Índios Sul-Americanos , Masculino , Peru , Tibet/etnologia , Adulto Jovem
9.
Front Genet ; 10: 690, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417607

RESUMO

Chronic mountain sickness (CMS) is a pathological condition resulting from chronic exposure to high-altitude hypoxia. While its prevalence is high in native Andeans (>10%), little is known about the genetic architecture of this disease. Here, we performed the largest genome-wide association study (GWAS) of CMS (166 CMS patients and 146 controls living at 4,380 m in Peru) to detect genetic variants associated with CMS. We highlighted four new candidate loci, including the first CMS-associated variant reaching GWAS statistical significance (rs7304081; P = 4.58 × 10-9). By looking at differentially expressed genes between CMS patients and controls around these four loci, we suggested AEBP2, CAST, and MCTP2 as candidate CMS causal genes. None of the candidate loci were under strong natural selection, consistent with the observation that CMS affects fitness mainly after the reproductive years. Overall, our results reveal new insights on the genetic architecture of CMS and do not provide evidence that CMS-associated variants are linked to a strong ongoing adaptation to high altitude.

10.
PLoS Negl Trop Dis ; 13(7): e0007483, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31306424

RESUMO

OBJECTIVE: In Peru, the past three decades have witnessed impressive growth in biomedical research catalyzed from a single research university and its investigators who secured international partnerships and funding. We conducted a bibliometric analysis of publications by Peruvian authors to understand the roots of this growth and the spread of research networks within the country. METHODS: For 1997-2016, publications from Web of Science with at least one author affiliated with a Peruvian institution were examined by year, author affiliations, funding agencies, co-authorship linkages, and research topics. RESULTS: From 1997-2016, the annual number of publications from Peru increased 9-fold from 75 to 672 totaling 6032. Of these, 56% of the articles had co-authors from the US, 13% from the UK, 12% from Brazil, and 10% from Spain. Universidad Peruana Cayetano Heredia (UPCH) was clearly the lead research institution noted on one-third of publications. Of the 20 most published authors, 15 were Peruvians, 14 trained at some point at UPCH, and 13 received advanced training abroad. Plotting co-authorships documented the growth of institutional collaborations, the robust links between investigators and some lineages of mentorship. CONCLUSIONS: This analysis suggests that international training of Peruvian physician-scientists who built and sustained longstanding international partnerships with funding accelerated quality research on diseases of local importance. The role of a single research university, UPCH, was critical to advance a culture of biomedical research. Increased funding from the Peruvian Government and its Council for Science, Technology and Innovation will be needed to sustain this growth in the future. Middle-income countries might consider the Peruvian experience where long-term research and training partnerships yielded impressive advances to address key health priorities of the country.


Assuntos
Pesquisa Biomédica , Fortalecimento Institucional , Cooperação Internacional , Universidades , Academias e Institutos , Autoria , Distinções e Prêmios , Bibliometria/história , Bases de Dados Bibliográficas , História do Século XX , História do Século XXI , Humanos , Peru , Publicações/estatística & dados numéricos , Editoração/estatística & dados numéricos , Projetos de Pesquisa , Pesquisadores
11.
Front Physiol ; 10: 651, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191349

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.

12.
Epigenetics ; 14(1): 1-15, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30574831

RESUMO

Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.


Assuntos
Doença da Altitude/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Metilação de DNA , Elementos Nucleotídeos Longos e Dispersos/genética , Adaptação Fisiológica/genética , Adolescente , Adulto , Altitude , Doença da Altitude/etnologia , Epigênese Genética , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
13.
Front Physiol ; 9: 799, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30002630

RESUMO

Background: In chronic hypoxia (CH) and short-term chronic intermittent hypoxia (CIH) exposure, glycemia and insulin levels decrease and insulin sensitivity increases, which can be explained by changes in glucose transport at skeletal muscles involving GLUT1, GLUT4, Akt, and AMPK, as well as GLUT4 translocation to cell membranes. However, during long-term CIH, there is no information regarding whether these changes occur similarly or differently than in other types of hypoxia exposure. This study evaluated the levels of AMPK and Akt and the location of GLUT4 in the soleus muscles of lean rats exposed to long-term CIH, CH, and normoxia (NX) and compared the findings. Methods: Thirty male adult rats were randomly assigned to three groups: a NX (760 Torr) group (n = 10), a CIH group (2 days hypoxia/2 days NX; n = 10) and a CH group (n = 10). Rats were exposed to hypoxia for 30 days in a hypobaric chamber set at 428 Torr (4,600 m). Feeding (10 g daily) and fasting times were accurately controlled. Measurements included food intake (every 4 days), weight, hematocrit, hemoglobin, glycemia, serum insulin (by ELISA), and insulin sensitivity at days 0 and 30. GLUT1, GLUT4, AMPK levels and Akt activation in rat soleus muscles were determined by western blot. GLUT4 translocation was measured with confocal microscopy at day 30. Results: (1) Weight loss and increases in hematocrit and hemoglobin were found in both hypoxic groups (p < 0.05). (2) A moderate decrease in glycemia and plasma insulin was found. (3) Insulin sensitivity was greater in the CIH group (p < 0.05). (4) There were no changes in GLUT1, GLUT4 levels or in Akt activation. (5) The level of activated AMPK was increased only in the CIH group (p < 0.05). (6) Increased GLUT4 translocation to the plasma membrane of soleus muscle cells was observed in the CIH group (p < 0.05). Conclusion: In lean rats experiencing long-term CIH, glycemia and insulin levels decrease and insulin sensitivity increases. Interestingly, there is no increase of GLUT1 or GLUT4 levels or in Akt activation. Therefore, cellular regulation of glucose seems to primarily involve GLUT4 translocation to the cell membrane in response to hypoxia-mediated AMPK activation.

15.
High Alt Med Biol ; 19(3): 221-231, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29782186

RESUMO

Corante, Noemí, Cecilia Anza-Ramírez, Rómulo Figueroa-Mujíca, José Luis Macarlupú, Gustavo Vizcardo-Galindo, Grzegorz Bilo, Gianfranco Parati, Jorge L. Gamboa, Fabiola León-Velarde, and Francisco C. Villafuerte. Excessive erythrocytosis and cardiovascular risk in Andean highlanders. High Alt Med Biol. 19:221-231, 2018.-Cardiovascular diseases are the main cause of death worldwide. Life under high-altitude (HA) hypoxic conditions is believed to provide highlanders with a natural protection against cardiovascular and metabolic diseases compared with sea-level inhabitants. However, some HA dwellers become intolerant to chronic hypoxia and develop a progressive incapacitating syndrome known as chronic mountain sickness (CMS), characterized by excessive erythrocytosis (EE; Hb ≥21 g/dL in men, Hb ≥19 g/dL in women). Evidence from HA studies suggests that, in addition to CMS typical signs and symptoms, these highlanders may also suffer from metabolic and cardiovascular disorders. Thus, we hypothesize that this syndrome is also associated to the loss of the cardiometabolic protection observed in healthy highlanders (HH), and therefore to a higher cardiovascular risk (CVR). The aim of the present work was to evaluate the association between EE and CVR calculated using the Framingham General CVR Score and between EE and CVR factors in male highlanders. This cross-sectional study included 342 males from Cerro de Pasco, Peru at 4340 m (HH = 209, CMS = 133). Associations were assessed by multiple logistic regressions adjusted for potential confounders (BMI, pulse oxygen saturation and age). The adjusted models show that the odds of high CVR (>20%) in highlanders with EE was 3.63 times the odds in HH (CI 95%:1.22-10.78; p = 0.020), and that EE is associated to hypertension, elevated fasting serum glucose, insulin resistance, and elevated fasting serum triglycerides. Our results suggest that individuals who suffer from EE are at increased risk of developing cardiovascular events compared with their healthy counterparts.


Assuntos
Altitude , Pressão Sanguínea , Doenças Cardiovasculares/epidemiologia , Policitemia/epidemiologia , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Doenças Cardiovasculares/fisiopatologia , Estudos Transversais , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Policitemia/fisiopatologia , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
16.
Front Physiol ; 9: 248, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29623044

RESUMO

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.

17.
Obes Facts ; 10(4): 363-372, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28810235

RESUMO

Obesity, a worldwide epidemic, has become a major health burden because it is usually accompanied by an increased risk for insulin resistance, diabetes, hypertension, cardiovascular diseases, and even some kinds of cancer. It also results in associated increases in healthcare expenditures and labor and economic consequences. There are also other fields of medicine and biology where obesity or being overweight play a major role, such as high-altitude illnesses (acute mountain sickness, hypoxic pulmonary hypertension, and chronic mountain sickness), where an increasing relationship among these two morbid statuses has been demonstrated. This association could be rooted in the interactions between obesity-related metabolic alterations and critical ventilation impairments due to obesity, which would aggravate hypobaric hypoxia at high altitudes, leading to hypoxemia, which is a trigger for developing high-altitude diseases. This review examines the current literature to support the idea that obesity or overweight could be major conditioning factors at high altitude.


Assuntos
Doença da Altitude/etiologia , Obesidade/complicações , Doença Aguda , Altitude , Doença Crônica , Humanos , Hipóxia/etiologia , Sobrepeso/complicações , Doenças Respiratórias/etiologia , Fatores de Risco
18.
High Alt Med Biol ; 18(3): 226-233, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28453332

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 Jovem
19.
High Alt Med Biol ; 17(3): 208-213, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27454014

RESUMO

Healy, Katherine, Alain B. Labrique, J. Jaime Miranda, Robert H. Gilman, David Danz, Victor G. Davila-Roman, Luis Huicho, Fabiola León-Velarde, and William Checkley. Dark adaptation at high altitude: an unexpected pupillary response to chronic hypoxia in Andean highlanders. High Alt Med Biol. 17:208-213, 2016.-Chronic mountain sickness is a maladaptive response to high altitude (>2500 m above sea level) and is characterized by excessive erythrocytosis and hypoxemia resulting from long-term hypobaric hypoxia. There is no known early predictor of chronic mountain sickness and the diagnosis is based on the presence of excessive erythrocytosis and clinical features. Impaired dark adaptation, or an inability to visually adjust from high- to low-light settings, occurs in response to mild hypoxia and may serve as an early predictor of hypoxemia and chronic mountain sickness. We aimed to evaluate the association between pupillary response assessed by dark adaptometry and daytime hypoxemia in resident Andean highlanders aged ≥35 years living in Puno, Peru. Oxyhemoglobin saturation (SpO2) was recorded using a handheld pulse oximeter. Dark adaptation was quantitatively assessed as the magnitude of pupillary contraction to light stimuli of varying intensities (-2.9 to 0.1 log-cd/m2) using a portable dark adaptometer. Individual- and stimulus-specific multilevel analyses were conducted using mixed-effect models to elicit the relationship between SpO2 and pupillary responsiveness. Among 93 participants, mean age was 54.9 ± 11.0 years, 48% were male, 44% were night blind, and mean SpO2 was 89.3% ± 3.4%. The magnitude of pupillary contraction was greater with lower SpO2 (p < 0.01), and this dose relationship remained significant in multiple variable analyses (p = 0.047). Pupillary responsiveness to light stimuli under dark-adapted conditions was exaggerated with hypoxemia and may serve as an early predictor of chronic mountain sickness. This unexpected association is potentially explained as an excessive and unregulated sympathetic response to hypoxemia at altitude.

20.
Global Health ; 12(1): 29, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27255370

RESUMO

Human capital requires opportunities to develop and capacity to overcome challenges, together with an enabling environment that fosters critical and disruptive innovation. Exploring such features is necessary to establish the foundation of solid long-term partnerships. In this paper we describe the experience of the CRONICAS Centre of Excellence in Chronic Diseases, based at Universidad Peruana Cayetano Heredia in Lima, Peru, as a case study for fostering meaningful and sustainable partnerships for international collaborative research. The CRONICAS Centre of Excellence in Chronic Diseases was established in 2009 with the following Mission: "We support the development of young researchers and collaboration with national and international institutions. Our motivation is to improve population's health through high quality research." The Centre's identity is embedded in its core values - generosity, innovation, integrity, and quality- and its trajectory is a result of various interactions between multiple individuals, collaborators, teams, and institutions, which together with the challenges confronted, enables us to make an objective assessment of the partnership we would like to pursue, nurture and support. We do not intend to provide a single example of a successful partnership, but in contrast, to highlight what can be translated into opportunities to be faced by research groups based in low- and middle-income countries, and how these encounters can provide a strong platform for fruitful and sustainable partnerships. In defiant contexts, partnerships require to be nurtured and sustained. Acknowledging that all partnerships are not and should not be the same, we also need to learn from the evolution of such relationships, its key successes, hurdles and failures to contribute to the promotion of a culture of global solidarity where mutual goals, mutual gains, as well as mutual responsibilities are the norm. In so doing, we will all contribute to instil a new culture where expectations, roles and interactions among individuals and their teams are horizontal, the true nature of partnerships.


Assuntos
Saúde Global , Cooperação Internacional , Pesquisa Biomédica/organização & administração , Fortalecimento Institucional/organização & administração , Doença Crônica/prevenção & controle , Humanos , Estudos de Casos Organizacionais , Peru
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