High-altitude Natives Research Articles

Polymorphisms and haplotype of ROCK2 associate with high altitude essential hypertension in native high altitude Ladakhi Indian population: a preliminary study

Background and objectives: High-altitude essential hypertension (HAEH) is a disease occurring in permanent residents of high-altitude regions. The disease is characterized with SBP ≥140 mmHg and DBP ≥90 mmHg. HAEH is known to run in families, i.e. the disease has genetic component. Rho-associated coiled-coil containing protein kinase 2 (ROCK2) is a stress-activated serine-threonine kinase known to disturb vascular-homeostasis leading to an increase in systemic vascular resistance, hallmark of HAEH. ROCK2 is implicated in sea-level essential hypertension but its role in HAEH is yet to be elucidated. Methods: The present study deals with genotyping 13 polymorphisms of ROCK2 gene in demographicaly matched human cases (n = 65) and controls (n = 38) by Sequenom MS (TOF)-based MassARRAY platform using iPLEX Gold technology. Results: A significant association was observed for GG genotype (SNP, rs978906), AA genotype (SNP, rs6753921), GG genotype (SNP, rs10495582) and AA genotype (SNP, rs2230774) with HAEH (p < 0.05). The 4 SNPs were tagged to each other and formed a 35 kb LD block (r2 > 0.90). Haplotype AGCC, composed of wild-type alleles of the SNPs was over represented in controls. In contrast, haplotype GAGA, composed of variant-alleles was observed to be in higher proportion in cases. Moreover, SBP levels (mmHg) were higher in cases with risk genotype against the ones having protective genotype (p = 0.05). Bioinformatic analysis revealed binding of a critical transcription factor, SRF to variant-allele G of SNP rs10495582. SRF has been reported in previous studies to promote ROCK2 transcriptional expression. Interpretation and conclusions: The data clearly suggests association of ROCK2 polymorphisms and haplotypes with HAEH.

Why Are High Altitude Natives So Strong at High Altitude? Nature vs. Nurture: Genetic Factors vs. Growth and Development.

Among high-altitude natives there is evidence of a general hypoxia tolerance leading to enhanced performance and/or increased capacity in several important domains. These domains likely include an enhanced physical work capacity, an enhanced reproductive capacity, and an ability to resist several common pathologies of chronic high-altitude exposure. The "strength" of the high-altitude native in this regard may have both a developmental and a genetic basis, although there is better evidence for the former (developmental effects) than for the latter. For example, early-life hypoxia exposure clearly results in lung growth and remodeling leading to an increased O2 diffusing capacity in adulthood. Genetic research has yet to reveal a population genetic basis for enhanced capacity in high-altitude natives, but several traits are clearly under genetic control in Andean and Tibetan populations e.g., resting and exercise arterial O2 saturation (SaO2). This chapter reviews the effects of nature and nurture on traits that are relevant to the process of gas exchange, including pulmonary volumes and diffusion capacity, the maximal oxygen consumption (VO2max), the SaO2, and the alveolar-arterial oxygen partial pressure difference (A-aDO2) during exercise.

Does the Sympathetic Nervous System Adapt to Chronic Altitude Exposure?

During continued exposure to hypobaric hypoxia in acclimatizing lowlanders increasing norepinephrine levels indirectly indicate sympathoexcitation, and in a few subjects serial measurements have suggested some adaptation over time. A few studies have provided direct microneurographic evidence for markedly increased muscle sympathetic nervous activity (MSNA) after 1-50 days of exposure of lowlanders to altitudes of 4100-5260 m above sea level. Only one study has provided two MSNA-measurements over time (10 and 50 days) in altitude (4100 m above sea level) and continued robust sympathoexcitation without adaptation was found in acclimatizing lowlanders. In this study, norepinephrine levels during rest and exercise also remained highly elevated over time. In comparison, acute exposure to hypoxic breathing (FiO2 0.126) at sea level caused no change in sympathetic nervous activity, although the same oxygen saturation in arterial blood (around 90 %) was present during acute (FiO2 0.126) and chronic hypoxic exposure (4100 m above sea level). These findings strongly suggest that the chemoreflex-mechanisms underlying acute hypoxia-induced increases in MSNA are sensitized over time. Collectively, the MSNA data suggests that sensitization of the sympathoexcitatory chemoreflex is evident but not complete within the first 24 h, but is complete after 10 days of altitude exposure. After return from high altitude to sea level the MSNA remains significantly elevated for at least 5 days but completely normalized after 3 months. The few MSNA measurements in high altitude natives have documented high sympathetic activity in all subjects studied. Because serial measurements of MSNA in high altitude natives during sea level exposure are lacking, it is unclear whether the sympathetic nervous system have somehow adapted to lifelong altitude exposure.

Why Are High-Altitude Natives So Strong at Altitude? Maximal Oxygen Transport to the Muscle Cell in Altitude Natives.

In hypoxia aerobic exercise performance of high-altitude natives is suggested to be superior to that of lowlanders; i.e., for a given altitude natives are reported to have higher maximal oxygen uptake (VO2max). The likely basis for this is a higher pulmonary diffusion capacity, which in turn ensures higher arterial O2 saturation (SaO2) and therefore also potentially a higher delivery of O2 to the exercising muscles. This review focuses on O2 transport in high-altitude Aymara. We have quantified femoral artery O2 delivery, arterial O2 extraction and calculated leg VO2 in Aymara, and compared their values with that of acclimatizing Danish lowlanders. All subjects were studied at 4100 m. At maximal exercise SaO2 dropped tremendously in the lowlanders, but did not change in the Aymara. Therefore arterial O2 content was also higher in the Aymara. At maximal exercise however, fractional O2 extraction was lower in the Aymara, and the a-vO2 difference was similar in both populations. The lower extraction levels in the Aymara were associated with lower muscle O2 conductance (a measure of muscle diffusion capacity). At any given submaximal exercise intensity, leg VO2 was always of similar magnitude in both groups, but at maximal exercise the lowlanders had higher leg blood flow, and hence also higher maximum leg VO2. With the induction of acute normoxia fractional arterial O2 extraction fell in the highlanders, but remained unchanged in the lowlanders. Hence high-altitude natives seem to be more diffusion limited at the muscle level as compared to lowlanders. In conclusion Aymara preserve very high SaO2 during hypoxic exercise (likely due to a higher lung diffusion capacity), but the effect on VO2max is reduced by a lower ability to extract O2 at the muscle level.

Cardiometabolic risk factors in native populations living at high altitudes.

It is generally accepted that metabolic changes that take place in individuals exposed to high elevation are because of ambient hypoxia, which occurs as a consequence of a low total atmospheric pressure. The discovery of hypoxia inducible factor 1 (HIF1), a transcription factor, has been a breakthrough in the understanding of adaption to high altitudes. The purpose of the present review was to discuss specific epidemiological aspects of cardiovascular disease (CVD) risk factors and their mechanisms in vulnerable, understudied populations living at high altitudes. Obesity prevalence has been inversely associated with elevation. HIF1 has been related to plasma leptin--a hormone secreted by adipose tissue that produces negative feedback on appetite--and inversely associated with obesity. Diverse factors, such as genetics, chronic hypoxia, diet and lifestyle behaviours, could have an influence on the high dyslipidaemia rates of high-altitude natives. Hypoxia could mediate the effects of altitude on human physiology, including lipid metabolism. Genetic studies suggest that dyslipidaemia could be related to the HIF1. Hypoxia inhibits oxidative phosphorylation and stimulates the oxygen signalling pathway through the HIF1. Low fasting glycaemia in individuals at high altitudes has been shown. An increased GLUT4 protein content in skeletal muscle in response to hypoxia has been reported and could be associated with lower glucose levels. Given the high prevalence of dyslipidaemia and the low prevalence of obesity and diabetes in these impoverished high-altitude communities, changes in lifestyle including decreased physical activity and the consumption of a more westernised diet would likely increase the prevalence of CVD related mortality. Control over major CVD risk factors, when identified early, could be the key to reducing morbidity and mortality in patients with limited access to medical services such as Native populations.

Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives.

BackgroundSea level sojourners, on ascent to high altitude, undergo acclimatization through integrated physiological processes for defending the body against oxygen deprivation while the high altitude natives (resident population) are adapted to the prevailing hypobaric hypoxic condition through natural selection. Separating the acclimatization processes from adaptive changes and identifying genetic markers in lowlanders that may be beneficial for offsetting the high altitude hypoxic stress, although challenging, is worth investigating. We genotyped nine candidate gene polymorphisms, suggested to be relevant in high altitude environment, in sea level acclimatized sojourners and adapted natives for understanding differences/commonality between the acclimatized and the adapted cohorts at the genetic level.ResultsStatistically similar genotypic and allelic frequencies were observed between the sea level sojourners (acclimatized) and the high altitude natives (adapted) in six loci viz., EDN1 (endothelin 1) -3A/-4A VNTR, ADRB2 (beta-2 adrenergic receptor, surface) Arg16Gly (rs1042713:A > G), ADRB3 (beta-3 adrenergic receptor) Trp64Arg (rs4994:T > C), eNOS (nitric oxide synthase, endothelial) Glu298Asp (rs1799983:T > G), TH (tyrosine hydroxylase) Val81Met (rs6356:G > A) and VEGF (vascular endothelial growth factor) 963C > T (rs3025039:C > T) while SCNN1B (amiloride-sensitive sodium channel, subunit beta) Thr594Met (rs1799979:C > T) was monomorphic. Genotypic and allelic frequencies in EDN1 9465G > A (rs2071942:G > A) and ADRB2 Gln27Glu (rs1042714:G > C) were significantly different between the acclimatized sojourners and the high altitude natives with higher frequency of GG and GA genotypes of EDN1 rs2071942 and CC genotype of ADRB2 rs1042714 being observed in Ladakh natives. Mutated A allele (AA genotype) of rs2071942 and carriers of G allele (GG + GC genotypes) of rs1042714 were less favorable during acclimatization under recessive and dominant genetic models of inheritance respectively indicating thereby that GG genotype and G allele of EDN1 rs2071942 and CC genotype of ADRB2 rs1042714 conferred acclimatization benefit.ConclusionSea level acclimatized individuals shared similarity with the adapted natives in certain high altitude relevant genetically based trait variation suggesting advantageous consequence as well as commonality in gene regulatory pathways in which these gene products function both during process of acclimatization and adaptation in high altitude environment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0268-y) contains supplementary material, which is available to authorized users.

HIGH LIFE: High altitude fatalities led to pulse oximetry

In 1875, Paul Bert linked high altitude danger to the low partial pressure of oxygen when 2 of 3 French balloonists died euphorically at about 8,600 m altitude. World War I fatal crashes of high altitude fighter pilots led to a century of efforts to use oximetry to warn pilots. The carotid body, discovered in 1932 to be the hypoxia detector, led to most current physiologic understanding of the body's respiratory responses to hypoxia and CO2. The author describes some of his UCSF group's work: In 1963, we reported both the brain's ventral medullary near-surface CO2 (and pH) chemosensors and the role of cerebrospinal fluid in acclimatization to altitude. In 1966, we reported the effect of altitude on cerebral blood flow and later the changes of carotid body sensitivity at altitude and the differences in natives of high altitude. In 1973, pulse oximetry was invented when Japanese biophysicist Takuo Aoyagi read and applied to pulses a largely forgotten 35-year-old discovery by English medical student J. R. Squire of a method of computing oxygen saturation from red and infrared light passing through both perfused and blanched tissue.

Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach.

BackgroundExtreme constitution “Prakriti” types of Ayurveda exhibit systemic physiological attributes. Our earlier genetic study has revealed differences in EGLN1, key modulator of hypoxia axis between Prakriti types. This was associated with differences in high altitude adaptation and susceptibility to high altitude pulmonary edema (HAPE). In this study we investigate other molecular differences that contribute to systemic attributes of Prakriti that would be relevant in predictive marker discovery.MethodsGenotyping of 96 individuals of the earlier cohort was carried out in a panel of 2,800 common genic SNPs represented in Indian Genomic Variation Consortium (IGVC) panel from 24 diverse populations. Frequency distribution patterns of Prakriti differentiating variations (FDR correction P < 0.05) was studied in IGVC and 55 global populations (HGDP–CEPH) panels. Genotypic interactions between VWF, identified from the present analysis, and EGLN1 was analyzed using multinomial logistic regression in Prakriti and Indian populations from contrasting altitudes. Spearman’s Rank correlation was used to study this genotypic interaction with respect to altitude in HGDP–CEPH panel. Validation of functional link between EGLN1 and VWF was carried out in a mouse model using chemical inhibition and siRNA studies.ResultSignificant differences in allele frequencies were observed in seven genes (SPTA1, VWF, OLR1, UCP2, OR6K3, LEPR, and OR10Z1) after FDR correction (P < 0.05). A non synonymous variation (C/T, rs1063856) associated with thrombosis/bleeding susceptibility respectively, differed significantly between Kapha (C-allele) and Pitta (T-allele) constitution types. A combination of derived EGLN1 allele (HAPE associated) and ancestral VWF allele (thrombosis associated) was significantly high in Kapha group compared to Pitta (p < 10–5). The combination of risk-associated Kapha alleles was nearly absent in natives of high altitude. Inhibition of EGLN1 using (DHB) and an EGLN1 specific siRNA in a mouse model lead to a marked increase in vWF levels as well as pro-thrombotic phenotype viz. reduced bleeding time and enhanced platelet count and activation.ConclusionWe demonstrate for the first time a genetic link between EGLN1 and VWF in a constitution specific manner which could modulate thrombosis/bleeding susceptibility and outcomes of hypoxia. Integration of Prakriti in population stratification may help assemble common variations in key physiological axes that confers differences in disease occurrence and patho-phenotypic outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0542-9) contains supplementary material, which is available to authorized users.

Developmental Effects Determine Submaximal Arterial Oxygen Saturation in Peruvian Quechua.

Kiyamu, Melisa, Fabiola León-Velarde, María Rivera-Chira, Gianpietro Elías, and Tom D. Brutsaert. Developmental effects determine submaximal arterial oxygen saturation in Peruvian Quechua. High Alt Med Biol 16, 138-146, 2015.--Andean high altitude natives show higher arterial oxygen saturation (Sao(2)) during exercise in hypoxia, compared to acclimatized sojourners. In order to evaluate the effects of life-long exposure to high altitude on Sao(2), we studied two groups of well-matched, self-identified Peruvian Quechua natives who differed in their developmental exposure to hypoxia before and after a 2-month training period. Male and female volunteers (18-35 years) were recruited in Lima, Peru (150 m). The two groups were: a) Individuals who were born and raised at sea-level (BSL, n=34) and b) Individuals who were born and raised at high altitude (BHA, n=32), but who migrated to sea-level as adults (>16 years old). Exercise testing was conducted using a submaximal exercise protocol in normobaric hypoxia in Lima (BP=750 mmHg, Fio(2)=0.12), in order to measure Sao(2) (%), ventilation (VE L/min) and oxygen consumption (Vo(2), L/min). Repeated-measures ANOVA, controlling for VE/VO(2) (L/min) and sex during the submaximal protocol showed that BHA maintained higher Sao(2) (%) compared to BSL at all workloads before (p=0.005) and after training (p=0.017). As expected, both groups showed a decrease in Sao(2) (%) (p<0.001), as workload increased. Resting Sao(2) levels were not found to be different between groups. The results suggest that developmental exposure to altitude contributes to the maintenance of higher Sao(2) levels during submaximal exercise at hypoxia.

Surviving Birth at Any Altitude

In the 16th century, Potosi (3976 m) was one of the most important cities in the world, because of its silver mountain. A Spaniard chronicle reported 100% mortality of newborns from Spaniard parents at that time, and women migrated to lower altitude cities to give birth. Several generations later, “the miracle of Saint Nicolas” occurred and a boy survived in Potosí after 6 dead siblings. Since that time, more and more children from sea level mothers (not high altitude natives) survive birth at high altitude, and the genes for postnatal adaptation to chronic hypobaric hypoxia are widespread in the 21st century. Some factors—such as birth weight, maternal anemia, pre-eclampsia, and existence of congenital diseases—have been clearly defined as prognostic for surviving birth. Pregnancy at high altitude is associated with a reduction in birth weight of approximately 100 g per 1000 m of ascent. Low birth weight affects mostly children from mothers without high altitude ancestry, but not native babies, and evidence of endoplasmatic reticulum stress and protein synthesis inhibition in the placenta of nonnative women at high altitude have been found. Children from natives may be protected by the augmented uterine artery flow described for this group. Also, there is the possibility that elevated enzymatic antioxidant activity contributes to the Andean protection against altitude-associated small for gestational age infants. Hemoglobin concentrations in mothers at high altitude are well studied. When appropriate adjustments were used, maternal anemia was associated with lower infant Apgar scores at both 1 minute and 5 minutes after birth, as well as complication of labor, lower gestational age at birth, and higher parity. Little is reported about congenital heart diseases, their natural history, especially regarding pulmonary hypertension, and the unique physiology of indigenous high altitude residents in this context. Our investigation team has been working on this last topic since 2003. We report the results of 4000 echocardiographic studies performed in 3500 patients born at 3600 m in La Paz, Bolivia, not older than 3 months. The patient group was selected by pediatricians and referred because of heart murmur, cyanosis, syndromal fenotype, heart failure, oxygen dependency, and enhanced cardiac size in the Rx. Of these, 20.1% of the children showed no abnormal finding, 18.1% showed pulmonary hypertension (defined as systolic pulmonary pressure of more than 40 mm Hg or more than two thirds from the systemic pressure) in the absence of congenital heart disease, 14.6% showed ventricular septal defect, 20% presented with patent ductus arteriosus, 14.2% atrial septal defect, 5.1% tricuspidal atresia, 2.6% complete atrioventricular channel, 2.5% tetralogy of Fallot, 2.5% Shone complex, and 0.4% others. We assume that the high incidence of pulmonary hypertension in this group, with oxygen dependency and right ventricle hypertrophy for weeks, is due to a prolonged postnatal adaptation period. The most important reason for this phenomenon is the late remodeling of the pulmonary artery branches, which implies the persistence of a thick musculary media. The persistent elevation of the pulmonary pressure and hypoxia are predisposing factors to patency of the ductus arteriosus. Right-sided congenital heart diseases like tricuspid atresia are 3 times more frequent in our patient cohort than at sea level; being left-sided significantly lowers their incidence. Environmental and genetic circumstances may both play a role in the pathogenesis of congenital heart disease at high altitude.

Increased blood-oxygen binding affinity in Tibetan and Han Chinese residents at 4200 m.

High-altitude natives are challenged by hypoxia, and a potential compensatory mechanism could be reduced blood oxygen-binding affinity (P50), as seen in several high-altitude mammalian species. In 21 Qinghai Tibetan and nine Han Chinese men, all resident at 4200m, standard P50 was calculated from measurements of arterial PO2 and forehead oximeter oxygen saturation, which was validated in a separate examination of 13 healthy subjects residing at sea level. In both Tibetans and Han Chinese, standard P50 was 24.5±1.4 and 24.5±2.0mmHg, respectively, and was lower than in the sea-level subjects (26.2±0.6mmHg, P<0.01). There was no relationship between P50 and haemoglobin concentration (the latter ranging from 15.2 to 22.9gdl(-1) in Tibetans). During peak exercise, P50 was not associated with alveolar-arterial PO2 difference or peak O2 uptake per kilogram. There appears to be no apparent benefit of a lower P50 in this adult high-altitude Tibetan population.

Descripción de la dinámica circulatoria en el corazón y pulmones de habitantes del nivel del mar y de las grandes alturas por medio de la técnica de dilución del colorante

La técnica de dilución ha sido usada para la descripción de la dinámica circulatoria en el corazón y pulmones de habitantes del nivel del mar y de las grandes alturas. El principal propósito de este trabajo ha sido la medida de la cantidad de sangre contenida en los pulmones de estos grupos de personas, por medio de la fórmula de Newman, con objeto de demostrar si los nativos de las grandes alturas tienen una mayor cantidad de sangre en los pulmones. Los siguientes cálculos se hicieron: tiempos circulatorios, volumen de expulsión del corazón, volumen sanguíneo intralorácico (Hamilton), volumen central (Newman) y volumen sanguíneo total. Al nivel del mar se estudiaron 20 hombres y 15 mujeres. En la altra (4,540 mts.) se estudiaron 10 hombres que habían nacido y seguían viviendo a 4,540 mts. Cuando los valores se corrigen por metro cuadrado de superficie corporal , no hay diferencia marcada entre hombres y mujeres a nivel del mar, aparte de las conocidas diferencias hematológicas. Los nativos de la altura muestran tiempos circulatorios más prolongados, un volumen de expulsión ligeramente mayor, mayor volumen sanguíneo y mayor cantidad de sangre contenida en los pulmones. Cuando el volumen de sangre pulmonar, calculado con la fórmula de Newman, se expresa como porcentaje del volumen sanguíneo total, el grupo de altura también muestra cifras mayores que los individuos del nivel del mar.

Aerobic capacity of Peruvian Quechua: a test of the developmental adaptation hypothesis.

High altitude natives are reported to have outstanding work capacity in spite of the challenge of oxygen transport and delivery in hypoxia. To evaluate the developmental effect of lifelong exposure to hypoxia on aerobic capacity, VO2peak was measured on two groups of Peruvian Quechua subjects (18-35 years), who differed in their developmental exposure to altitude. Male and female volunteers were recruited in Lima, Peru (150 m), and were divided in two groups, based on their developmental exposure to hypoxia, those: a) Born at sea-level individuals (BSL), with no developmental exposure to hypoxia (n = 34) and b) Born at high-altitude individuals (BHA) with full developmental exposure to hypoxia (n = 32), but who migrated to sea-level as adults (>16-years-old). Tests were conducted both in normoxia (BP = 750 mm Hg) and normobaric hypoxia at sea-level (BP = 750 mm Hg, FiO2 = 0.12, equivalent to 4,449 m), after a 2-month training period (in order to control for initial differences in physical fitness) at sea-level. BHA had a significantly higher VO2peak at hypoxia (40.31 ± 1.0 ml/min/kg) as compared to BSL (35.78 ± 0.96 ml/min/kg, P = 0.001), adjusting for sex. The decrease of VO2peak at HA relative to SL (ΔVO2peak ) was not different between groups, controlling for baseline levels (VO2peak at sea-level) and sex (BHA = 0.35 ± 0.04 l/min, BSL = 0.44 ± 0.04 l/min; P = 0.12). Forced vital capacity (controlling for height) and the residuals of VO2peak (controlling for weight) had a significant association in the BHA group only (r = 0.155; P = 0.031). In sum, results indicate that developmental exposure to altitude constitutes an important factor to determine superior exercise performance.

King of the mountains: Tibetan and Sherpa physiological adaptations for life at high altitude.

Anecdotal evidence surrounding Tibetans' and Sherpas' exceptional tolerance to hypobaric hypoxia has been recorded since the beginning of high-altitude exploration. These populations have successfully lived and reproduced at high altitude for hundreds of generations with hypoxia as a constant evolutionary pressure. Consequently, they are likely to have undergone natural selection toward a genotype (and phenotype) tending to offer beneficial adaptation to sustained hypoxia. With the advent of translational human hypoxic research, in which genotype/phenotype studies of healthy individuals at high altitude may be of benefit to hypoxemic critically ill patients in a hospital setting, high-altitude natives may provide a valuable and intriguing model. The aim of this review is to provide a comprehensive summary of the scientific literature encompassing Tibetan and Sherpa physiological adaptations to a high-altitude residence. The review demonstrates the extent to which evolutionary pressure has refined the physiology of this high-altitude population. Furthermore, although many physiological differences between highlanders and lowlanders have been found, it also suggests many more potential avenues of investigation.

Adaptation to High Altitude: Phenotypes and Genotypes

Populations residing for millennia on the high-altitude plateaus of the world started natural experiments that we can evaluate to address questions about the processes of evolution and adaptation. A 2001 assessment in this journal summarized abundant evidence that Tibetan and Andean high-altitude natives had different phenotypes, and the article made a case for the hypothesis that different genetic bases underlie traits in the two populations. Since then, knowledge of the prehistory of high-altitude populations has grown, information about East African highlanders has become available, genomic science has grown exponentially, and the genetic and molecular bases of oxygen homeostasis have been clarified. Those scientific advances have transformed the study of high-altitude populations. The present review aims to summarize recent advances in understanding with an emphasis on the genetic bases of adaptive phenotypes, particularly hemoglobin concentration among Tibetan highlanders. EGLN1 and EPAS1 encode two crucial proteins contributing to oxygen homeostasis, the oxygen sensor PHD2 and the transcription factor subunit HIF-2α, respectively; they show signals of natural selection such as marked allele frequency differentiation between Tibetans and lowland populations. EPAS1 genotypes associated in several studies with the dampened hemoglobin phenotype that is characteristic of Tibetans at high altitude but did not associate with the dampened response among Amhara from Ethiopia or the vigorous elevation of hemoglobin concentration among Andean highlanders. Future work will likely develop understanding of the integrative biology leading from genotype to phenotype to population in all highland areas.

Surviving Birth Height Altitude

Introduction: In the 16. Century, Potosi (3976m) was one of the most important cities in the world, because of the Silvermountains. The Spaniard chronic report about 100% mortality in newborns from Spaniard parents at that time, so that women used to migrate to lower altitude cities to give birth. Since that time more and more children from not high altitude natives survive. Pregnancy at high altitude is associated with a reduction in birth weight of ∼100 g/1000 m of ascent in mothers without high altitude ancestry.

Thyroid Hormone levels in Highlanders- A Comparison Between Residents of Two Altitudes in Nepal

The endocrine changes related to altitude adaptation in human have attracted physiologists around the globe for long. A number of high altitude studies to detect the physiological changes have been performed now and then. But, the study to see the hormonal changes to compare populations residing at different high altitudes is a scarce. Hence, we have performed a study in native populations of different high altitude comparing changes in thyroid hormones in western Nepal. The Jharkot population included in this study is at altitude of 3760 m and Jomsom population at 2800 m height from sea bed. The study is to compare changes in thyroid hormones at two different high altitude natives. To compare thyroid status between high altitude natives at two different altitudes a cross sectional study is performed by random sampling method. The blood sample was collected in a vacutainer from fifty eight individuals after obtaining the informed consent of participants. The blood collected from antecubital vein was centrifuged in an hour and the serum obtained was used for biochemical analysis of free triiodothyronine, free thyroxine and thyroid stimulating hormone. Mean free thyroxine (fT₄) of Jharkot population is significantly larger (p = 0.001) than Jomsom population. Mean thyroid stimulating hormone (TSH) with p = 0.597, does not indicate the difference between this two population. There is no significant difference between mean free triiodothyronine (fT₃) of Jharkot and Jomsom population (p = 0.345). The rise in free thyroid hormone at high altitude is not dependent on the thyroid stimulating hormone released from anterior pituitary. The rise in free thyroxine is found at higher altitude and no difference in fT₃ level is detected in population studied at high altitudes.

Cerebral blood flow at high altitude.

This brief review traces the last 50 years of research related to cerebral blood flow (CBF) in humans exposed to high altitude. The increase in CBF within the first 12 hours at high altitude and its return to near sea level values after 3-5 days of acclimatization was first documented with use of the Kety-Schmidt technique in 1964. The degree of change in CBF at high altitude is influenced by many variables, including arterial oxygen and carbon dioxide tensions, oxygen content, cerebral spinal fluid pH, and hematocrit, but can be collectively summarized in terms of the relative strengths of four key integrated reflexes: 1) hypoxic cerebral vasodilatation; 2) hypocapnic cerebral vasoconstriction; 3) hypoxic ventilatory response; and 4) hypercapnic ventilatory response. Understanding the mechanisms underlying these reflexes and their interactions with one another is critical to advance our understanding of global and regional CBF regulation. Whether high altitude populations exhibit cerebrovascular adaptations to chronic levels of hypoxia or if changes in CBF are related to the development of acute mountain sickness are currently unknown; yet overall, the integrated CBF response to high altitude appears to be sufficient to meet the brain's large and consistent demand for oxygen. This short review is organized as follows: An historical overview of the earliest CBF measurements collected at high altitude introduces a summary of reported CBF changes at altitude over the last 50 years in both lowlanders and high-altitude natives. The most tenable candidate mechanism(s) regulating CBF at altitude are summarized with a focus on available data in humans, and a role for these mechanisms in the pathophysiology of AMS is considered. Finally, suggestions for future directions are provided.

Differences in Cardiovascular and Hypothalamic-Pituitary-Adrenal Axis Functions between High-Altitude Visitors and Natives during a Trek on the Annapurna Circuit

Objective: Differences in the cardiovascular and hypothalamic-pituitary-adrenal (HPA) axis functions at high altitudes (HAs) between visitors to and natives of HA were examined. Methods: The cardiovascular functions and peripheral oxygen saturation (SPO₂) were monitored, and the cortisol awakening response (CAR) and nighttime cortisol concentration (NCC), as indices of the HPA axis function, were determined in 25 trekkers and 21 Sherpas during an Annapurna circuit trek. Results: SPO₂ decreased less in the Sherpas than in the trekkers at HAs (3,540, 3,800, and 4,800 m). Blood pressure and heart rate in the Sherpas changed concurrently during the trek; however, a tachycardic response occurred without changes in blood pressure in the trekkers at HAs. The CAR and NCC at HAs in the trekkers differed from those observed at 1,100 m and those observed at HAs in the Sherpas. The trekkers exhibited an elevated morning cortisol level at 3,540 and 3,800 m, a heightened CAR at 4,800 m, and an elevated NCC at 3,800 m. Alteration of the CAR resulted in an increase in the integrated volume of cortisol released within the first hour after awakening (CARauc) in the trekkers. The changes in SPO₂ occurred concurrently with the changes in the CARauc and the heart rate in the trekkers. Conclusions: The alterations of CAR occurred at HAs where blood pressure levels reached a peak plateau, which is associated with an increase in heart rate at HAs in the trekkers. The CAR was unaltered in the Sherpas during the trek.

Oxidative stress at high altitude: genotype&amp;ndash;phenotype correlations

Oxidative stress at high altitude: genotype&ndash;phenotype correlations Priyanka Pandey,1,2 MA Qadar Pasha1,2 1CSIR-Institute of Genomics and Integrative Biology, Delhi, India; 2Department of Biotechnology, University of Pune, Ganeshkhind, Pune, India Abstract: It has been well-documented that the hypobaric hypoxic environment at high altitude (HA) causes stress to both the permanent residents of HA and the sojourners. This oxidative stress primarily disturbs the oxygen-sensing and vascular homeostasis pathways, thereby upsetting normal human physiology, especially in sojourners. These environmental challenges have caused dynamic evolutionary changes within natives of HA, allowing them to develop adaptive plasticity. This review focuses on the genomic and biochemical features of the molecules involved in the oxygen-sensing and vascular homeostasis pathways with respect to HA pulmonary edema (HAPE) and adaptation. We review the role of genetic markers such as HIF-prolyl hydroxylase 2, endothelial PAS domain-containing protein 1, endothelial nitric oxide synthase, endothelin 1, cytochrome b-245 alpha polypeptide, and glutathione S-transferase pi 1, as well as three circulatory biomarkers (nitric oxide, endothelin 1, and 8-iso-prostaglandin F2&alpha;), by highlighting approaches such as candidate gene and genome-wide, adopted in deciphering the pathways. A disagreement between the two approaches has also been highlighted. In addition, we discuss that an overrepresentation of wild-type alleles in HA natives and mutant alleles of same polymorphisms in HAPE patients implies that the allelic variants at the same locus are involved in adaptation and HAPE, respectively. Moreover, healthy sojourners present a number of genomic features similar to HA natives, further strengthening the concept of genetic predisposition. A trend in correlation between protective and risk alleles and altered levels of circulatory markers clearly documents the phenomenon of genotype&ndash;phenotype correlations. We conclude that the genetic and biochemical markers discussed here both could prove to be potential targets for future diagnostic and therapeutic interventions. Keywords: high altitude, oxidative stress, pulmonary edema, sojourners, natives