YPOXIA-INDUCED PULMOnary hypertensive disorders are a major cause of morbidity and mortality in respiratory and cardiac diseases and at high altitude. [1][2][3][4] Hypoxia causes pulmonary hypertension through hypoxic pulmonary vasoconstriction and vascular remodeling. 1 Convergent discoveries in the biochemistry of oxygen sensing and in cardiopulmonary physiology have recently established the importance of the hypoxia-inducible factor (HIF) family of transcription factors in regulating these processes. [5][6][7][8][9][10][11][12] Hypoxia-inducible factor controls an extensive range of transcriptional responses to hypoxia throughout the body. 5,6 Emerging evidence supports a role for HIF in regulating systemic responses to hypoxia across the principal organ systems responsible for oxygen delivery to cells, encompassing erythropoiesis as well as pulmo-See also Patient Page.

-Andean highaltitude (HA) natives have a low (blunted) hypoxic ventilatory response (HVR), lower effective alveolar ventilation, and lower ventilation (VE) at rest and during exercise compared with acclimatized newcomers to HA. Despite blunted chemosensitivity and hypoventilation, Andeans maintain comparable arterial O 2 saturation (SaO 2 ). This study was designed to evaluate the influence of ancestry on these trait differences. At sea level, we measured the HVR in both acute (HVR-A) and sustained (HVR-S) hypoxia in a sample of 32 male Peruvians of mainly Quechua and Spanish origins who were born and raised at sea level. We also measured resting and exercise VE after 10 -12 h of exposure to altitude at 4,338 m. Native American ancestry proportion (NAAP) was assessed for each individual using a panel of 80 ancestry-informative molecular markers (AIMs). NAAP was inversely related to HVR-S after 10 min of isocapnic hypoxia (r ϭ Ϫ0.36, P ϭ 0.04) but was not associated with HVR-A. In addition, NAAP was inversely related to exercise VE (r ϭ Ϫ0.50, P ϭ 0.005) and ventilatory equivalent (VE/V O2, r ϭ Ϫ0.51, P ϭ 0.004) measured at 4,338 m. Thus Quechua ancestry may partly explain the wellknown blunted HVR (10,35,36,57,62) at least to sustained hypoxia, and the relative exercise hypoventilation at altitude of Andeans compared with European controls. Lower HVR-S and exercise VE could reflect improved gas exchange and/or attenuated chemoreflex sensitivity with increasing NAAP. On the basis of these ancestry associations and on the fact that developmental effects were completely controlled by study design, we suggest both a genetic basis and an evolutionary origin for these traits in Quechua. genetic markers; admixture; arterial saturation; Andes THE HYPOXIC VENTILATORY RESPONSE (HVR) is the increase in ventilation (VE) that occurs when arterial blood oxygen partial pressure PO 2 decreases (60). Typically, on acute exposure to hypoxia, VE increases to a peak in the first few minutes and thereafter declines somewhat to a level higher than control depending on the level of hypoxia (13,49). This attenuation of VE has been termed the hypoxic ventilatory decline (HVD), and it is usually assessed by protocols that give a sustained hypoxic exposure greater than ϳ10 min. The sustained vs. acute response has not been systematically evaluated in Andean highland natives, but groups from this region appear to have a lower or "blunted" acute HVR and a lower effective alveolar ventilation compared with high altitude (HA)-acclimatized control groups from the lowlands (10,35,36,43,57,61,62). Andeans also have lower VE during exercise at HA compared with acclimatized lowland controls (7,32,55,66). These traits may be unique to Andeans, as many studies show normal HVR and higher VE in natives of the Himalayan plateau (2,21,25,29,75). However, little is known about the underlying genetic and/or environmental basis for ventilatory trait differences between populations. One possibility is that there are genes at which allele frequencies differ ...

Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores. (Blood. 2012;119(3):857-860) IntroductionDietary iron absorption was shown in the 1950s to be under the dual regulation of body iron stores and the prevailing rate of erythropoiesis, giving rise to the concept of the "store regulator" and the "erythroid regulator" in iron homeostasis. 1,2 The downstream mediator of both regulators was later shown to be the iron-regulatory hormone hepcidin, 3 which opposes iron absorption and recycling by binding and internalizing the cellular iron exporter ferroportin. 4 The molecular mechanisms of hepcidin regulation are not completely understood. Oral iron loading stimulates hepcidin production in healthy humans. 5,6 This may result in part from the binding of serum holotransferrin to transferrin receptor 1 in the liver, releasing the non-classical MHC class 1 molecule hereditary hemochromatosis protein (HFE) to interact with a holotransferrintransferrin receptor 2 (TfR2) complex that up-regulates hepcidin expression. [7][8][9] There is also evidence of a role for the membranebound protein hemojuvelin in the response to iron loading, 5,10 and mutations in HFE, TfR2, or hemojuvelin can all cause hemochromatosis via inadequate hepcidin production. 11 The signal linking erythropoiesis to hepcidin suppression remains unknown. Candidates include erythropoietin (EPO) itself, soluble transferrin receptor (sTfR), and growth differentiation factor-15 (GDF15), which is released by maturing erythroblasts and reduces hepcidin mRNA expression in cultured hepatocytes. 12 Excessive serum GDF15 appears to underlie the paradoxical iron overload seen in patients with ␤-thalassemia. 12 It is now known that hepcidin expression is also suppressed by hypoxia, but the mechanism is controversial. In mice, hypoxiainducible factor was reported to regulate hepcidin expression via direct transcriptional suppression, 13 but this finding has not been replicated in isolated hepatocytes. 14 Hypoxia-inducible factor may, however, contribute to hepcidin suppression indirectly via effects on the breakdown of hemojuvelin. 15,16 In vivo, hypoxia could also suppress hepcidin indirectly through erythropoiesis and enhanced iron use. Recently, a decrease in hepcidin was...

Orthostatic tolerance is a measure of the ability to prevent hypotension during gravitational stress. It is known to be dependent on the degree of vasoconstriction and the magnitude of plasma volume, but the possible influence of packed cell volume (PCV) is unknown. High altitude residents have high haematocrits and probably high packed cell volumes. However, it is not known whether plasma volume and blood volume are affected, or whether their orthostatic tolerance is different from low altitude residents. In this study we determined plasma volume, PCV and orthostatic tolerance in a group of high altitude dwellers (HA), including a subgroup of highland dwellers with chronic mountain sickness (CMS) and extreme polycythaemia. Plasma volume and PCV were determined using Evans Blue dye dilution and peripheral haematocrit. Orthostatic tolerance was assessed as the time to presyncope in a test of head-up tilting and lower body suction. All studies were performed at 4338 m. Results showed that plasma volumes were not significantly different between CMS and HA, or in highland dwellers compared to those seen previously in lowlanders. PCV and haematocrit were greater in CMS than in HA. Orthostatic tolerance was high in both CMS and HA, although the heart rate responses to orthostasis were smaller in CMS than HA. Orthostatic tolerance was correlated with haematocrit (r = 0.57, P < 0.01) and PCV (r = 0.54, P < 0.01). This investigation has shown that although high altitude residents have large PCV, their plasma volumes were similar to lowland dwellers. The group with CMS have a particularly large PCV and also have a very high orthostatic tolerance, despite smaller heart rate responses. These results are compatible with the view that PCV is of importance in determining orthostatic tolerance.

Bigham, Abigail W., Melisa Kiyamu, Fabiola León-Verlarde, Esteban J. Parra, Maria Rivera-Ch, Mark D. Shriver, and Tom D. Brutsaert. Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua. High Alt. Med. Biol. 9:167-178, 2008.-The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n ϭ 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (Sa O 2 ) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on Sa O 2 is mediated by the isocapnic hypoxic ventilatory response (HVR, l/min Ϫ1 /%Sa O 2 Ϫ1 ). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (Ͻ24 h) and BHA subjects (born at HA) who were lifelong residents of HA. To control for the possibility of population stratification, Native American ancestry proportion (NAAP) was estimated as a covariate for each individual using a panel of 70 ancestry-informative molecular markers (AIMS). At HA, resting and exercise Sa O 2 was strongly associated with the ACE genotype, p ϭ 0.008 with ϳ4% of the total variance in Sa O 2 attributed to ACE genotype. Moreover, I/I individuals maintained ϳ2.3 percentage point higher Sa O 2 compared to I/D and D/D. This I-allele effect was evident in both BLA and BHA groups, suggesting that acclimatization state has little influence on the phenotypic expression of the ACE gene. Finally, ACE genotype was not associated with the isocapnic HVR, although HVR had a strong independent effect on Sa O 2 (p ϭ 0.001). This suggests that the I-allele effect on Sa O 2 is not mediated by the peripheral control of breathing, but rather by some other central cardiopulmonary effect of the ACE gene on the renin-angiotensin-aldosterone system (RAAS).