The development of systemic hypertension is influenced by genetic, racial, geographic, and environmental determinants, including high-altitude (H-ALT). The cut-point to define H-ALT has generally been defined as >2500 meters above sea level (mASL; ≈8200 ft).1 According to a recent estimation, ≈83 million people live at >2500 mASL,2 including populations mainly from South America, Central Asia, and Eastern Africa. These highlanders are chronically exposed to relative hypoxia, which has important consequences on the cardiovascular system and on blood pressure (BP) regulation.

Several recent studies have focused on the acute and subacute hemodynamic changes in lowlanders who are suddenly exposed to H-ALT. However, little is known about the precise pathophysiologic mechanisms of chronic hypertension at H-ALT, differences in the characteristics of chronic hypertension between various H-ALT settings, or the efficacy of antihypertensive agents in chronic highlanders. People living in low-income countries, such as the majority of highlanders, demonstrate higher prevalence of noncommunicable diseases, including hypertension.3 Even though the World Health Organization considers the current extent of hypertension as a global public health issue,4 the real burden of hypertension and its complications in H-ALT locations worldwide remains to be well defined. Given the large number of highlanders around the world, and the well-established role of hypertension in cardiovascular risk, hypertension at H-ALT is a highly relevant clinical and public health problem that requires increased awareness and study.

In this review, we aim to summarize and integrate our current knowledge about the association between H-ALT and hypertension, the cardiovascular phenotypes observed at H-ALT, the effects of H-ALT on the cardiovascular system, and major biological pathways of BP regulation, as well as their potential therapeutic implications. Although mechanisms of acute and chronic H-ALT sometimes overlap, we attempt to make clear distinctions between acute and chronic vascular effects of H-ALT where appropriate.

Known Effects of H-ALT on the Cardiovascular System

Altitude constitutes a hypobaric hypoxic environment, in which lower atmospheric pressure determines a lower driving pressure for gas exchange in the lungs; therefore, lower oxygen is available for physiological metabolic processes, which determines different oxygen tensions at various anatomic levels (Figure 1). Chronic mountain sickness is an exaggerated response to chronic hypoxemia characterized by a markedly increased production of red blood cells as an attempt to overcome the reduced oxygen delivery to tissues. This exerts deleterious effects on blood viscosity, ventilation, and acid-base balance.6 Chronic hypoxia also triggers pulmonary hypertension and right-sided heart failure because of sustained hypoxic pulmonary vasoconstriction.6

Figure 1.
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Figure 1. The oxygen transport cascade. The partial pressure of oxygen gradually decreases from inspired air, to venous level, at sea level and high-altitude (H-ALT). Overall, oxygen tension is lower at H-ALT. mASL indicates meters above sea level. Adapted from Hurtado5 with permission. Copyright © 2005, John Wiley and Sons.

Studies about H-ALT adaptations have elucidated that adaptive mechanisms vary between the 2 most representative H-ALT populations, Andean highlanders (AN-HLs) and Tibetan highlanders (TIB-HLs), suggesting the existence of distinct evolutionary courses in response to chronic hypoxia. Compared with TIB-HLs, AN-HLs (in whom the prevalence of chronic mountain sickness ranges from 6.8% to 33.7%)6 demonstrate higher pulmonary arterial pressures, arterial oxygen content, oxygen saturation, and hemoglobin concentration.7 In contrast, TIB-HLs exhibit greater endothelial nitric oxide (NO) production in pulmonary arteries, higher peripheral capillary density,7 and a chronic mountain sickness prevalence of 1.2% (Table).6 These data clearly indicate the presence of unique phenotypes in different H-ALT populations, which may have resulted from the fact that Tibetans settled at H-ALT lands much earlier (≈25 000 years ago) than Andeans (≈11 000 years ago).7

Table. Summary of Main Differences in the Vascular Function Between Lowlanders and Highlanders
Physiological Factors Vascular Variables Lowlanders During Acute H-ALT Exposure Andean Highlanders Tibetan Highlanders
Altitude adaptations CMS prevalence … 6.8%–33.7% 1.2%
Pulmonary arterial pressures … Higher Lower
NO production in pulmonary arteries … Lower Higher
Arterial oxygen content … Higher Lower
Vascular changes Peripheral capillary density Unknown Lower Higher
Circulation NO levels Unknown High High
cIMT Unknown Unknown Decreased*
Common carotid artery diameter Increased† Unknown Increased*
Brachial artery diameter Unknown Unknown Increased*
Carotid-femoral PWV Increased† Unknown Not changed or Increased*
Augmentation index Increased† Unknown Not changed*
Endothelial function FMD Decreased† Unknown Decreased*
NTG Decreased† Unknown Increased*
Oxidative stress LOOH Increased† Unknown Unknown
Nitrites Increased† Unknown Unknown
F(2)-isoprostane Increased† Unknown Unknown
8-iso-PGF2α Increased† Increased* Increased‡
Blood pressure Blood pressure Increased† Lower Higher
CBF CBF Increased† Decreased* Increased*

Impact of Ethnicity on the Association Between H-ALT and Systemic Hypertension

White lowlanders acutely exposed to H-ALT demonstrate a BP increase during the initial days.8–10 The underlying mechanisms of this response include activation of the adrenergic system, increased arterial stiffness, endothelin (ET) release, and reduced vasodilatory responses (Figure 2).11,12 Additional mechanisms for this acute surge of BP will be reviewed in the following sections. Conversely, the only study that investigated changes of BP in white lowlanders exposed to H-ALT for >2 years demonstrated a reduction in systolic and diastolic BPs.13

Figure 2.
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Figure 2. Pathways that may regulate blood pressure (BP) and cerebral blood flow (CBF) during acute and subacute high-altitude (H-ALT) exposure. The figure represents the complexity of the mechanisms linked to acute/subacute H-ALT exposure and increased BP, which is mediated by augmentation of the renin-angiotensin-aldosterone system, sympathetic hyperactivity (and various effects on adrenergic receptors), increased oxidative stress, and endothelial dysfunction, leading to an acute increase in large artery stiffness. The role of CBF (which is influenced by BP, nitric oxide [NO], and cerebral vascular changes) in maintaining brain oxygen delivery is also represented. Blue arrows indicate stimulation, red lines indicate inhibition. *Desensitization/downregulation. ACE indicates angiotensin-converting enzyme; ALD, aldosterone; ARs, adrenergic receptors; AT-I, angiotensin-I; AT-II, angiotensin-II; DD ACE genotype frequency, deletion of repeat element in ACE gene; ET-1, endothelin 1; and NE, norepinephrine.

Different results have been described in highlanders. The prevalence of hypertension at different H-ALT locations ranges from 8.6%14 to 55.9%,15 however, various factors, such as geographical location, ethnicity, and sample population, must be taken into consideration when comparing different prevalence of hypertension. A retrospective study that included 16 913 TIB-HLs reported a significant correlation between altitude and the prevalence of hypertension with a 2% increase for every ≈100 m (≈330 ft)-increase in altitude above 3000 mASL (≈9800 ft).16 Nonetheless, this study was limited by the use of different definitions of hypertension and a lack of adjustment for demographic, metabolic, and anthropomorphic factors. A subsequent retrospective analysis that included a multiethnic sample of 40 854 subjects living at >2400 mASL (≈7900 ft) showed that in TIB-HLs, for every 1000-m (≈3300 ft) increase in altitude, BP increased by ≈17/9.5 mm Hg.17 However, in non-Tibetans (mainly AN-HLs), the same increase in altitude was not significantly associated with changes in BP.17 Similarly, an earlier cross-sectional study demonstrated a lower prevalence of hypertension among AN-HLs, as compared with Andean lowlanders.18

Taken together, available data suggest a positive association between altitude and hypertension in TIB-HLs, in contrast to AN-HLs, among whom a neutral to negative correlation seems to be present (Table). However, available studies are limited because they do not account for potential confounders, including environmental and lifestyle factors. Even though TIB-HLs seem to have higher BP levels than AN-HLs, TIB-HLs exhibit higher capillary density than AN-HLs.7 In addition, higher circulating NO levels have been observed in both AN-HLs19 and TIB-HLs,20 as compared with lowlanders, but in TIB-HLs, these increased levels have been associated with greater oxygen delivery (Figure 3).21 Therefore, the underlying correlates of BP may be different between AN-HLs and TIB-HLs. Further population-specific data are required to fully characterize the biological mechanisms linking H-ALT and hypertension, and the precise association between H-ALT and hypertension risk, while accounting for environmental, geographical, racial, lifestyle, and socioeconomic factors. Important pathways that may mediate the relationship between H-ALT and increased BP (as occurs in TIB-HLs) are summarized in Figure 3.

Figure 3.
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Figure 3. Pathways that may mediate increased blood pressure (BP) in chronic highlanders (as reported in Tibetan populations). Increased concentrations of hypoxia-inducible factors (HIFs), and subsequently erythropoietin (EPO), exert various effects on vascular mechanisms of BP maintenance, including increased production of endothelin-1 (ET-1), vascular neointima formation, polycythemia, and decreased responsiveness to vasodilators, all of which may contribute to increased BP. The relationships between arterial stiffness, endothelial dysfunction, changes in capillary density, increased NO bioavailability, and BP are also represented. Blue arrows indicate stimulation, red lines indicate inhibition. *DD ACE genotype is associated with hypertension in female Tibetan highlanders. ACE indicates angiotensin-converting enzyme; AT-II, angiotensin-II; ATR1, angiotensin receptor type 1; DD ACE genotype frequency, deletion of repeat element in ACE gene; NO, nitric oxide; PDGF-BB, platelet-derived growth factor BB; PHD, propyl-hydroxylase domain enzyme; and PPARγ, peroxisome proliferator-activated receptor-γ.

An important limitation of available studies is the lack of standardized well-validated measurements of BP. Furthermore, available studies tended to focus on office BP, whereas the importance of ambulatory and home BP and the circadian patterns of BP variability is increasingly recognized. It is essential that methodological issues on BP monitoring, hypertension diagnosis, and the use of validated devices22 be taken into account in the design of future studies of H-ALT. Whereas H-ALT may not affect the performance of oscillometric or mercury BP monitors,23 general considerations about device validity and methods of office, home, and ambulatory measurements will need to be adequately considered.

Vascular Structure and Function at H-ALT

Acute/Subacute Exposure

Compared with sea-level measurements, acute (3 days) H-ALT exposure in white lowlanders has been associated with reduced flow-mediated brachial artery dilation (a marker of endothelium-dependent vascular function) and nitroglycerin-dependent dilation (a marker of endothelium-independent vascular smooth muscle function), both of which persist after subacute (12–14 days) H-ALT exposure (Figure 2).24 Augmentation index (a marker of arterial wave reflections) has been shown to increase,25 whereas carotid-femoral pulse wave velocity (a measure of large artery stiffness) was unchanged (after 2 days)25 or increased (after 3–14 days)24 at H-ALT. White lowlanders demonstrate higher levels of lipid hydroperoxide (a marker of oxidative stress) and nitrite (NO2 −) after exposure to H-ALT (Figure 2).24 These vascular changes after acute/subacute exposure to H-ALT have been attributed at least partially to oxidative stress since lipid hydroperoxide levels correlated with the reduction in nitroglycerin-dependent dilation–mediated dilation (Figure 2).24

The role of circulating NO2 − in this setting is intriguing. On one hand, NO2 − can be a byproduct of NO metabolism, and thus a marker of production. On the other hand, NO2 − is a direct precursor of NO via the nitrate-NO2 −-NO pathway, and the reduction of NO2 − to NO occurs preferentially in hypoxic and acidotic environments (Figure 2).26 Increased NO bioavailability associated with acute H-ALT exposure has been described.21,24 Acute H-ALT–associated NO2 − rise may be an adaptive mechanism to maintain circulatory homeostasis via vasodilation.27 The physiological response to altitude manifests as blood redistribution toward the brain to protect this organ from the deleterious effects of hypoxia.24 In experimental models, hypoxia has been associated with increased NO bioavailability, which resulted in increased cerebral blood flow (CBF; Figure 2).28 Interestingly, inorganic nitrate (which increased NO2 − levels) does not produce important cerebral vasodilation at sea level,29 but this phenomenon may be different at H-ALT given the differences in cerebral microvascular Po 2. This issue requires further research.

Chronic Exposure

Compared with white lowlanders at sea level, TIB-HLs demonstrate lower carotid intima media thickness,30 higher common carotid artery diameters,24,30 higher brachial artery diameters (after adjustment for body surface area),30 higher nitroglycerin-dependent dilation–mediated dilation, lower flow-mediated dilation,30 and lower carotid pulse pressure, with similar augmentation index (Figure 3).30 Discordant findings have been reported for carotid-femoral pulse wave velocity.24,30 Overall, these results indicate that, in contrast to the adverse changes in pulsatile hemodynamics and arterial stiffness associated with acute hypobaric hypoxia among chronic lowlanders, arterial remodeling in chronic highlanders involve eccentric conduit artery remodeling, with or without increased arterial stiffness. Key differences in physiological and clinical parameters between lowlanders acutely exposed to H-ALT and chronic highlanders are summarized in the Table.

Pathways of BP Regulation at H-ALT

Adrenergic Nervous System

Acute/Subacute Exposure

There is a close relationship between acute hypobaric hypoxia and the activation of the sympathetic nervous system (SNS). Acute exposure to H-ALT and subsequent hypoxemia are followed by the activation of peripheral arterial chemoreceptors that stimulate the adrenergic center in the medulla, increasing adrenergic activity (Figure 2).31 Plasma and urine catecholamine concentrations (especially norepinephrine) remain unchanged within the first 1 to 2 days of acute H-ALT exposure but increase thereafter.8,32 Sympathetic hyperactivity has been reported during acute (4 days)33 and prolonged (50 days)34 H-ALT exposure among white lowlanders (Figure 2).

During acute H-ALT exposure, daytime mean arterial pressure is not suppressed with propranolol administration.8 Among white lowlanders acutely exposed to H-ALT, carvedilol and nebivolol reduced systolic BP at H-ALT compared with placebo, but they were unable to completely suppress the BP rise at H-ALT compared with sea level9; however, subjects receiving nebivolol showed better exercise performance than those receiving carvedilol, at H-ALT.35 Similarly, prazosin in women acutely exposed to H-ALT failed to block the rise in BP at H-ALT compared with sea level.10

The limited response to antiadrenergic drugs during acute H-ALT exposure may be related to changes in adrenergic receptor density at H-ALT (Figure 2). A decrease in β-adrenergic receptor density in the left ventricle after exposure to simulated H-ALT has been shown in rats,36 which may be prevented by low doses of propranolol before H-ALT exposure.37 Similarly, subacute H-ALT exposure has been shown to reduce α1-adrenergic receptor density in adult sheep common carotid and cerebral arteries.38 Downregulation of α2-adrenergic receptors has also been reported, which seems to play an important role in SNS hyperactivity during prolonged H-ALT exposure (≈50 days).39

Therefore, even though H-ALT exposure is associated with an ongoing activation of the SNS, it is also associated with downregulation of adrenergic receptors (possibly as a result of increased receptor occupancy).37 Additional factors, including uncoupling of cardiac β-adrenergic receptor s,40 decreased presynaptic uptake of norepinephrine in cardiac adrenergic synapses41 (which may increase β-adrenergic receptors desensitization), and higher levels of Gi-protein (inhibitory) of cardiac β-adrenergic receptors, may also be at play (Figure 2).41 Similarly, whether the downregulation of α2-adrenergic receptors at H-ALT39 affects the therapeutic efficacy of α methyldopa (an α2-adrenergic receptor agonist predominantly used for the treatment of hypertension in pregnancy) is unknown. Overall, the implications of these effects on the potential efficacy of adrenoreceptor blockers for the treatment of chronic hypertension at H-ALT require further research.

There may exist a complex relationship between H-ALT, changes in adrenergic receptors of cerebral arteries, changes in CBF, and BP (Figure 2). A decreased contractile response to norepinephrine after H-ALT exposure has been shown in sheep.42 The impairment of arterial cerebral autoregulation during acute H-ALT exposure43 is accompanied by an increase in CBF, which reaches a peak after 3 days, gradually decreasing to normal levels thereafter.44 This response seems to exert a preferential maintenance of CBF to the brain stem to maintain oxygen delivery to the cardiorespiratory centers.43 The effects of SNS activation on the regulation of CBF at H-ALT remain unclear.44 Nonetheless, it has been postulated that in the presence of impaired arterial cerebral autoregulation at H-ALT, the rise of BP may result in a pressure-passive increase in CBF.44 A recent study showed that when a conflict exist between maintaining brain O2 delivery and controlling CBF to prevent brain damage from overperfusion-pressure, priority is given to brain O2 delivery.45 In this regard, the rise of BP during acute H-ALT exposure may help maintain brain oxygenation and metabolism (Figure 2). Importantly, limited data indicate the presence of reversible and irreversible brain abnormalities on magnetic resonance imaging in mountain climbers.46,47 Given these considerations, care should be taken when assessing the risk/benefit ratio of using short-term antihypertensive regimens to blunt acute BP responses to H-ALT among chronic lowlanders because the latter may provide protection against hypoxic brain damage.

Chronic Exposure

Sympathetic hyperactivity has been described in native AN-HLs33,34; however, they demonstrate lower CBF than lowlanders, whereas TIB-HLs seem to exhibit higher CBF than lowlanders (Table).43 Differences in brain metabolism (such as decreased brain glucose metabolic uptake among AN-HLs),48 and increased NO bioavailability with greater oxygen delivery in TIB-HLs, may be related to CBF differences between these groups.43 To our knowledge, no data on the efficacy of adrenergic blocking agents in hypertensive chronic highlanders are currently available.

Renin-Angiotensin-Aldosterone System

Acute/Subacute Exposure

Acute H-ALT exposure transiently suppresses the renin-angiotensin-aldosterone system. The HIGHCARE-HIMALAYA study (High Altitude Cardiovascular Research) demonstrated an initial reduction of plasma renin, angiotensin, and aldosterone concentrations in white lowlanders at H-ALT, followed by an increase of these values after 12 days (Figure 2).49 Men demonstrate more profound falls of plasma renin level at H-ALT.50 Compared with placebo, telmisartan decreased BP in healthy white lowlanders acutely exposed to 3400 mASL (≈11 200 ft) but failed to do so at 5400 mASL (≈17 700 ft).49 The loss of antihypertensive properties of telmisartan at 5400 mASL could be explained not only by the effects of higher altitude on BP dysregulation but also by the timing of ascent in this study since the participants stayed for 3 days at 3400 mASL and arrived after 5 additional days to 5400 mASL, allowing time for the progressive recovery of renin-angiotensin-aldosterone system activity after H-ALT exposure.49 This interesting observation reminds us that the rate of ascent to H-ALT should also be taken into consideration in studies assessing the effects of antihypertensive agents in lowlanders acutely exposed to H-ALT.

Chronic Exposure

Data on plasma angiotensin-I–converting enzyme (ACE) levels at H-ALT are conflicting,51 but there is growing interest on ACE gene polymorphisms, which seem to play a role in vascular adaptations to H-ALT. The insertion (I)/deletion (D) ACE polymorphism describes the insertion or deletion of a DNA repeat element in intron 16 of the ACE gene.52 Subjects with the DD, ID, and II genotypes demonstrate higher, intermediate, and lower levels of plasma ACE, respectively.52 Higher DD genotype frequencies have been found in lowlanders that developed increased BP during subacute (30 days) H-ALT exposure, demonstrating the combination of environmental and preexisting genetic factors in the development of subacute hypertensive responses at H-ALT (Figure 2).53 A meta-analysis showed that the frequency of the DD genotype in highlanders (including Andeans and Tibetans) is lower than in lowlanders54; however, the DD genotype was associated with hypertension in female TIB-HLs (Figure 3).55 Whether these genetic differences impact the efficacy of ACE inhibitors at H-ALT is unknown.

A randomized trial assessed the antihypertensive efficacy of valsartan compared with enalapril among 142 mild hypertensives living at different altitudes (100 mASL or ≈330 ft, 1538 mASL or ≈5000 ft, and 2600 mASL or ≈8500 ft) during a 4-week period.56 Both medications demonstrated similar efficacy (on office BP) independent of altitude, with valsartan having a better safety profile.

Little data are available about the role of plasma aldosterone in chronic H-ALT. Concentrations in TIB-HLs have been shown to be higher than in healthy lowlanders,20 but to our knowledge, no data are available in this regard among AN-HLs. The relationship between plasma aldosterone and BP during chronic exposure to HA or the potential role of aldosterone receptor blockade in H-ALT in chronic highlanders is unknown.

Carbonic Anhydrase

Acute/Subacute Exposure

Although carbonic anhydrase (CA) inhibitors are mainly used for the prevention and treatment of acute mountain sickness, they can impact BP via effects on the peripheral vasculature, the heart, and the nervous system.57 Acetazolamide has shown to significantly blunt the rise of systolic BP, diastolic BP, and augmentation index in white lowlanders acutely exposed to H-ALT.25 Mechanistic studies involving CA inhibition on lowering BP at H-ALT have not been performed. Nonetheless, indirect mechanisms may explain the effect of CA inhibitors. CA demonstrates NO2 − anhydrase activity, which promotes NO generation from NO2 −, particularly at low pH, and acetazolamide has shown augment (rather than inhibit) the NO2 − anhydrase of CA, which may mediate the vasodilatory properties of this drug.58 In addition, acetazolamide seems to counteract the SNS activation at H-ALT via lowering the sensitivity of peripheral chemoreceptors59 through direct inhibition of CA in type I cells of the carotid body and other vascular mechanisms independent of CA inhibition.60

Chronic Exposure

The role of CA and the effects of CA inhibition on hypertensive highlanders have not been studied.

Endothelin-1

ET is a bioactive peptide whose subtypes, ET-1, ET-2, and ET-3, have different physiological effects.61 ET-1 binds to 2 different receptor subtypes, ETA (ET type A receptor) and ETB receptors (ET type B receptor), which are predominant in cardiac muscle cells and vascular smooth cells, and produce a potent vasopressor response.61 ET type B receptor (also expressed in the vascular endothelium) is of special interest because it also generates a vasodilatory response, mediated by endothelial NO release,62 which indicates a balanced interaction between ligands and receptors in the ET system.

Acute/Subacute Exposure

Increased ET type A receptor and ET type B receptor mRNA levels in the lung, heart, and thoracic aorta, as well as selective ET-1 upregulation in the pulmonary arteries and plasma, have been reported in rats exposed to subacute (28 days) normobaric hypoxia.63 In healthy humans, plasma and urine ET-1 levels increase during acute H-ALT exposure (Figure 2),64 which may be because of hypoxia-related decreased activity of endopeptidases that degrade ET-1.64 During acute H-ALT exposure, administration of bosentan (ET-1 antagonist) did not show significant effects on the systemic arterial BP; however, it significantly reduced systolic pulmonary artery pressure and mildly increased arterial oxygen saturation, as compared with placebo.65

Chronic Exposure

ET-1 levels in TIB-HLs are lower than in Indian lowlanders,66 suggesting that ET-1 downregulation could represent an adaptive mechanism for chronic hypobaric hypoxia in these populations. However, a recent study found that ET-1 levels are significantly higher in Tibetan males compared with Han males living at H-ALT and are associated with a higher baseline brachial artery diameters and reduced brachial artery flow-mediated dilation.67 These apparently paradoxical observations illustrate a common important problem with the interpretation of data from phenotypic comparison studies between lowlander and highlanders, which can be substantially confounded by genetic, ethnic, lifestyle, and other factors.

Currently, there are no available data on ET-1 variations in AN-HLs or the use of ET-1 antagonist agents for the treatment of hypertension in highlanders. The role of the ET system at H-ALT, including the complex interactions between H-ALT, ET type B receptor allele expression, adaptive mechanisms in different H-ALT populations, and the hypoxia-inducible factor (HIF) pathway, still needs to be elucidated.68

Calcium Channels

Ca2+ plays a key role in the vascular response elicited by ET-1. This response involves an initial increase of Ca2+ from intracellular stores, followed by sustained Ca2+ increase because of influx from the extracellular space.69 Because the rise of Ca2+ also augments the synthesis of ET-1,70 it is possible that inhibition of voltage-dependent Ca2+ influx using calcium channel blockers (CCB) blunts the deleterious effects of ET-1 on vascular function in hypertension.69 Lacidipine71 and nifedipine72 have shown to improve endothelial function in patients with hypertension, which may be related to higher NO availability.73 Chronic oral treatment with nifedipine reduces the vasoconstriction response induced by ET-1 and phenylephrine.72 It remains unclear whether H-ALT could alter these mechanisms in humans.

Acute/Subacute Exposure

Even though CCBs are widely used for the treatment and prevention of H-ALT-pulmonary edema,6 no study has evaluated the effects of a CCB agent alone during acute H-ALT exposure. The concomitant use of slow-release CCB nifedipine gastrointestinal therapeutic system plus telmisartan in Peruvian hypertensive lowlanders acutely exposed to H-ALT resulted in lower 24-hour systolic BP and diastolic BP, with acceptable treatment tolerance rates.74

Available data in animals indicate that prolonged exposure to H-ALT (110 days) does not affect sensitivity to nifedipine in sheep coronary arteries.75 After the same period of exposure to H-ALT, increased activity (more sensitive to activation and higher affinity for Ca2+) of large-conductance Ca2+-activated K+ channels was found in basilar arteries of ovine adults.76 This behavior of cerebral arteries could favor an increased CBF during H-ALT exposure76 because in vascular smooth muscle cells, large-conductance Ca2+-activated K+ channel opening favors K+ efflux and hyperpolarization, with subsequent closure of voltage-dependent Ca2+ channels, decreased intracellular Ca2+, and vasodilation.77

Chronic Exposure

The effect of chronic HA on Ca2+ channels and the effects of CCBs on hypertension in chronic highlanders requires further study. The INTERVENCION Trial (ClinicalTrials.gov Identifier NCT02373163) will provide data on the efficacy of amlodipine (compared with telmisartan and hydrochlorothiazide) for the treatment of hypertension at 3 different altitudes above sea level.

Erythropoietin

Erythropoietin (EPO) is the main hormone involved in erythropoiesis. The effects of EPO on BP are well described and include mechanisms other than the increase of hematocrit. EPO regulates the production of endothelium-derived modulators of vascular tone, including vasodilators (eg, NO) and vasoconstrictors (eg, ET-1; Figure 3).78

Acute/Subacute Exposure

In lowlanders, plasma EPO increases after short-term (11 days) H-ALT exposure.79 This initial increase in EPO levels has been observed as early as 16 hours after H-ALT exposure and is followed by a significant decrease in both serum ferritin and hepcidin levels, suggesting that acute hypobaric hypoxia induces a marked suppression of hepcidin which may be the result of increased EPO and acute iron depletion, possibly because of the acute shift of iron toward the bone marrow.80 The administration of exogenous EPO increases BP in healthy subjects, and this seems to be independent of its effects on red blood cell volume.81 These effects could involve a dose-dependent increase of ET-1 release and activation of ET type A receptors, as demonstrated in hypertensive rats.82 EPO also accelerates smooth muscle cell–rich neointima formation in rats, which is mediated release of platelet-derived growth factor-BB from endothelial cells.83 Other proposed mechanisms of EPO-induced hypertension include changes in the sensitivity to vasopressors, dysregulation of production or responsiveness to endogenous vasodilators, and direct vasopressor effects of EPO (Figure 3).84

Chronic Exposure

Increased EPO levels have been reported in lowlanders chronically (6 months to 2 years) exposed to H-ALT and are comparable to those observed in highlanders.79 Polycythemia has been identified as an independent correlate of hypertension at H-ALT in AN-HLs.85 In addition, there is a close relationship between EPO and angiotensin-II (AT-II). Among AN-HLs with altitude-polycythemia and 24-hour urinary protein excretion >150 mg, administration of low doses of enalapril for 2 years was associated with a reduction in hemoglobin concentration and proteinuria despite stable levels of BP.85 In humans, the administration of AT-II increases EPO concentrations (even as early as 6 hours after AT-II) and effect mediated by AT-II type 1 receptors.86 Whether hypobaric hypoxia and other adaptive mechanisms at H-ALT enhance the vascular effects of AT-II and its deleterious consequences on BP via increased compensatory erythropoiesis is still unknown. The INTERVENCION trial will provide data on the antihypertensive efficacy of angiotensin receptor blockade for chronic hypertension at H-ALT.

Hypoxia-Inducible Factors

HIFs are transcription factors that bind to specific DNA sequences and modulate the expression of various genes involved in hypoxic adaptations.87 HIF-α subunits (HIF-1α and HIF-2α) are hydroxylated by propyl-hydroxylase domain enzyme in the presence of oxygen, which enhances the binding of the von Hippel-Lindau protein to HIF-α subunits, promoting their degradation.88 Cellular hypoxia reduces propyl-hydroxylase domain activity, which is associated with accumulation of HIF-α subunits that heterodimerize with HIF-β and augment the transcription of target genes (Figure 3).88 These genes encode proteins associated with energy utilization, anaerobic metabolism, angiogenesis, erythropoiesis, cardiovascular development, endothelial function, vasomotor regulation, and catecholamine metabolism.87,88

Acute Exposure

No data on the effect of acute H-ALT exposure on HIFs are available.

Chronic Exposure

HIFs seem to play a key role on chronic adaptation mechanisms in highlanders.87 HIFs interact with various pathways known to mediate systemic BP regulation (Figure 3). Some pathways related to HIFs may promote hypertension at H-ALT. The close relationship between HIFs and EPO production is widely recognized. HIF-1 also promotes expression of ET-1 in human endothelial cells, but this response involves additional binding factors.89 AT-II upregulates renal VEGF (vascular endothelial growth factor) expression by a mechanism that involves HIF-1 activation.90

However, HIF-1α may also exert antihypertensive effects. Deletion of HIF-1α from vascular smooth muscle cells in mice (smooth muscle cell-HIF-1α-knockout) reduced peroxisome proliferator-activated receptor-γ expression, which in turn increased AT-II type 1 receptor expression in mesenteric arteries ex vivo.91 This had no effects on circulating AT-II levels but was associated with increased BP in smooth muscle cell-HIF-1α-knockout mice, which was reversible by telmisartan, supporting the importance of the vascular HIF-1α-peroxisome proliferator-activated receptor-γ-AT-II type 1 receptor axis for BP homeostasis (Figure 3).91 No data are available on the effects of pharmacological manipulation of HIFs on chronic hypertension at H-ALT in humans.

Oxidative Stress, Altitude, and Hypertension

Acute Exposure

Lowlanders acutely exposed to H-ALT show increased levels of lipid peroxidation biomarkers, such as urinary F(2)-isoprostane and 8-iso-PGF2α (prostaglandin-F) and plasma thiobarbituric acid reactive substances (small increase), and also increased glutathione (antioxidant; Figure 2).92 As previously stated, increased levels of lipid hydroperoxide in lowlanders acutely exposed to H-ALT correlate with the degree of vascular dysfunction in these subjects.24

Chronic Exposure

Compared with lowlanders at sea level, AN-HLs demonstrate higher levels of urine 8-iso-PGF2α, plasma thiobarbituric acid reactive substances, but also of plasma glutathione (perhaps as a compensatory mechanism).92 TIB-HLs show higher levels of plasma 8-iso-PGF2α compared with lowlanders exposed to H-ALT (Figure 3).20 BP correlates positively with 8-iso-PGF2α levels, in both lowlanders and highlanders of Indian origin.93 However, the causal role of oxidative stress biomarkers, such as 8-iso-PGF2α, on the development of hypertension needs to be clarified because 8-iso-PGF2α may exert vasoconstrictive94 or vasodilatory95 effects on different arterial vessels.

It has been proposed that H-ALT may weaken the antioxidant systems and that oxidative stress damage at H-ALT resembles that of reperfusion injury.96 Higher superoxide dismutase (antioxidant enzyme) activity and lower catalase, glutathione peroxidase, and glutathione reductase activities have been described among TIB-HLs, as compared with lowlanders exposed to H-ALT for 4 weeks, suggesting that lifelong exposure to H-ALT is associated with protective adaptive effects on the antioxidant system, at least in TIB-HLs (Figure 3).97 In AN-HLs, oxidative stress is increased, but its deleterious effects on the vascular function are seen on maladapted individuals (those with chronic mountain sickness) unlike well-adapted natives,98 which may indicate that adequate H-ALT adaptation involves protection of the vascular system against oxidative stress, as seen on TIB-HLs.

Renal Function, Altitude, and Hypertension

Acute/Subacute Exposure

Important acute effects of H-ALT on the kidney and volume regulation are decreased plasma sodium and bicarbonate, increased diuresis and natriuresis (because of increased atrial natriuretic peptide and suppressed antidiuretic hormone), and increased insensible fluid loses, all of which lead to plasma volume reduction.99 The data on renal plasma flow and glomerular filtration rate during acute H-ALT exposure remain conflicting.99

Chronic Exposure

Chronic effects of H-ALT include reduced glomerular filtration rate, effective renal plasma and blood flow, as well as augmented filtration fraction.100 Even nondiabetic, nonhypertensive AN-HLs demonstrate lower glomerular filtration rate and more proteinuria than Andean lowlanders, indicating a previously unrecognized higher prevalence of chronic kidney disease in AN-HLs.101 A proposed mechanism for worsening renal function at H-ALT is the development of excessive erythrocytosis because of chronic hypoxia. Increased red blood cell volume reduces renal plasma flow, resulting in a higher filtration fraction, which tends to initially preserve the glomerular filtration rate at the expense of chronic hyperfiltration with subsequent glomerular damage.101 In addition, as previously stated, HIFs are key regulators of the response to hypoxia, and they have been involved in the pathogenesis of chronic kidney disease through a mechanism involving chronic renal (tubulo-interstitial) hypoxia.102 H-ALT exposure has also been associated with glomerular hypertrophy.103 To date, no study has compared the prevalence of chronic kidney disease in AH-HLs versus TIB-HLs and their association with hypertension as to determine the degree of renal adaptation between these H-ALT populations.

Some highlanders develop a clinical syndrome known as H-ALT renal syndrome,104 whose clinical features include preserved glomerular function, polycythemia, hyperuricemia, microalbuminuria, and hypertension.104 Hyperuricemia seems to be a key feature in this syndrome, and the mechanisms explaining its presence at H-ALT include increased production of urate because of hypoxia (reduced ATP levels with increased nucleotide turnover), decreased renal excretion of uric acid (secondary to increased lactate because of hypoxia), and excessive erythrocytosis that increases urate concentrations because of increased cell turnover.105 Even though uric acid acts as an antioxidant, it may also stimulate oxidative stress in various cells, causing endothelial dysfunction that may contribute to systemic hypertension.101 There are no data on the prevalence of H-ALT renal syndrome in TIB-HLs; however, the prevalence of hyperuricemia is increased and is associated with systemic hypertension and microalbuminuria.106 Hyperuricemia may also induce glomerular hypertrophy because of activation of the renin-angiotensin-aldosterone system and stimulation of glomerular hypertension.105 ACE inhibitors seem to be more beneficial than other first-line antihypertensive agents in H-ALT renal syndrome.85,104

Treatment of Chronic Hypertension at H-ALT

Little data exist on optimal therapeutic approaches for the chronic hypertensive patient living at H-ALT. Current clinical practice guidelines for the diagnosis and management of hypertension do not take into consideration H-ALT as a potential modifier of the effects or choice of antihypertensive agents in highlanders. Multiple studies, as previously reviewed, have addressed the effect of antihypertensive agents in hypertensive or normotensive subjects at sea level acutely and temporally exposed to H-ALT.9,25,35,49,74 Clinical trials and therapeutic recommendations for hypertensives at sea level planning to ascend to H-ALT have recently been published and take into consideration medication options for certain altitudes.107 In contrast, data are extremely scarce on the best therapeutic approaches and the effects of specific antihypertensive agents among hypertensive chronic highlanders. These trials may inform not only about optimal approaches for chronic hypertension at H-ALT but may also yield significant biological insights into BP regulation in general. The INTERVENCION Trial should provide the first data on the efficacy of common antihypertensive agents in hypertensive highlanders living at 3 different altitude above sea level.

Conclusions

A large number of hypertensives live at H-ALT around the world. Despite the clear influence of H-ALT on biological pathways that regulate systemic BP, our understanding of mechanisms leading to or modifying the prevalence and clinical course of chronic hypertension at H-ALT is limited. There is a need for focused research on this problem. Important evolutionary responses exist for a successful cardiovascular adaptation to hypobaric hypoxia. These responses are likely to result in important differences in the pathogenesis of systemic hypertension in chronic highlanders and its response to standard antihypertensive medications. Mechanistic studies in humans and therapeutic randomized clinical trials at various levels of altitude are required to enhance our biological and clinical understanding of chronic hypertension at H-ALT.

Sources of Funding

J.A. Chirinos is supported by National Institutes of Health grant R01 HL 121510-01A1.

Disclosures

J.A. Chirinos has received consulting honoraria from Bristol-Myers Squibb, OPKO Healthcare, Fukuda-Denshi, Sanifit, Microsoft, Pfizer, Akros Pharma, Merck, and Bayer. He received research grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Bristol-Myers Squibb, Microsoft, and CVRx Inc and device loans from AtCor Medical. J.A. Chirinos is named as inventor in a University of Pennsylvania patent application for the use of inorganic nitrates/nitrites for the treatment of Heart Failure and Preserved Ejection Fraction. The other authors report no conflicts.

Footnotes

Correspondence to Julio A. Chirinos, University of Pennsylvania Perelman School of Medicine and Hospital of the University of Pennsylvania, S Tower, Room 11–138, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104. Email julio. [email protected] upenn.edu

References

  • 1. Leon-Velarde F, Reeves JT. International consensus group on chronic mountain sickness. Adv Exp Med Biol . 1999; 474:351–353.CrossrefMedlineGoogle Scholar
  • 2. Beall CM. Adaptation to high altitude: phenotypes and genotypes. Annu Review Anthropol . 2014; 43:251–272.CrossrefGoogle Scholar
  • 3. Islam SM, Purnat TD, Phuong NT, Mwingira U, Schacht K, Fröschl G. Non-communicable diseases (NCDs) in developing countries: a symposium report. Global Health . 2014; 10:81. doi: 10.1186/s12992-014-0081-9.CrossrefMedlineGoogle Scholar
  • 4. World Health Organization (WHO). A Global Brief on Hypertension: Silent Killer, Global Public Health Crisis.http://www.thehealthwell.info/node/466541. Accessed March 10, 2017.Google Scholar
  • 5. Hurtado A. Animals in high altitudes: resident man. Dill DB. In: Handbook of Physiology. Section 4. Adaptation to the Environment . Washington, DC: American Physiological Society; 1964:843–860.Google Scholar
  • 6. Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation . 2007; 115:1132–1146. doi: 10.1161/CIRCULATIONAHA.106.624544.LinkGoogle Scholar
  • 7. Beall CM. Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci USA . 2007; 104(suppl 1):8655–8660.CrossrefMedlineGoogle Scholar
  • 8. Wolfel EE, Selland MA, Mazzeo RS, Reeves JT. Systemic hypertension at 4,300 m is related to sympathoadrenal activity. J Appl Physiol (1985) . 1994; 76:1643–1650. doi: 10.1152/jappl.1994.76.4.1643.CrossrefMedlineGoogle Scholar
  • 9. Bilo G, Caldara G, Styczkiewicz K, Revera M, Lombardi C, Giglio A, Zambon A, Corrao G, Faini A, Valentini M, Mancia G, Parati G. Effects of selective and nonselective beta-blockade on 24-h ambulatory blood pressure under hypobaric hypoxia at altitude. J Hypertens . 2011; 29:380–387. doi: 10.1097/HJH.0b013e3283409014.CrossrefMedlineGoogle Scholar
  • 10. Mazzeo RS, Carroll JD, Butterfield GE, Braun B, Rock PB, Wolfel EE, Zamudio S, Moore LG. Catecholamine responses to alpha-adrenergic blockade during exercise in women acutely exposed to altitude. J Appl Physiol (1985) . 2001; 90:121–126. doi: 10.1152/jappl.2001.90.1.121.CrossrefMedlineGoogle Scholar
  • 11. Brook RD. The environment and blood pressure. Cardiol Clin . 2017; 35:213–221. doi: 10.1016/j.ccl.2016.12.003.CrossrefMedlineGoogle Scholar
  • 12. Calbet JA, Boushel R, Robach P, Hellsten Y, Saltin B, Lundby C. Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans. Acta Physiol (Oxf) . 2014; 211:574–584. doi: 10.1111/apha.12325.CrossrefMedlineGoogle Scholar
  • 13. Marticorena E, Ruiz L, Severino J, Galvez J, Peñaloza D. Systemic blood pressure in white men born at sea level: changes after long residence at high altitudes. Am J Cardiol . 1969; 23:364–368.CrossrefMedlineGoogle Scholar
  • 14. Hernández-Hernández R, Silva H, Velasco M, Pellegrini F, Macchia A, Escobedo J, Vinueza R, Schargrodsky H, Champagne B, Pramparo P, Wilson E; CARMELA Study Investigators. Hypertension in seven Latin American cities: the Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study. J Hypertens . 2010; 28:24–34. doi: 10.1097/HJH.0b013e328332c353.CrossrefMedlineGoogle Scholar
  • 15. Zhao X, Li S, Ba S, He F, Li N, Ke L, Li X, Lam C, Yan LL, Zhou Y, Wu Y. Prevalence, awareness, treatment, and control of hypertension among herdsmen living at 4,300 m in Tibet. Am J Hypertens . 2012; 25:583–589. doi: 10.1038/ajh.2012.9.CrossrefMedlineGoogle Scholar
  • 16. Mingji C, Onakpoya IJ, Perera R, Ward AM, Heneghan CJ. Relationship between altitude and the prevalence of hypertension in Tibet: a systematic review. Heart . 2015; 101:1054–1060. doi: 10.1136/heartjnl-2014-307158.CrossrefMedlineGoogle Scholar
  • 17. Aryal N, Weatherall M, Bhatta YK, Mann S. Blood pressure and hypertension in adults permanently living at high altitude: a systematic review and meta-analysis. High Alt Med Biol . 2016; 17:185–193. doi: 10.1089/ham.2015.0118.CrossrefMedlineGoogle Scholar
  • 18. Ruiz L, Penaloza D. Altitude and hypertension. Mayo Clin Proc . 1977; 52:442–445.MedlineGoogle Scholar
  • 19. Wang P, Ha AY, Kidd KK, Koehle MS, Rupert JL. A variant of the endothelial nitric oxide synthase gene (NOS3) associated with AMS susceptibility is less common in the Quechua, a high altitude native population. High Alt Med Biol . 2010; 11:27–30. doi: 10.1089/ham.2009.1054.CrossrefMedlineGoogle Scholar
  • 20. Ali Z, Mishra A, Kumar Ret al. . Interactions among vascular-tone modulators contribute to high altitude pulmonary edema and augmented vasoreactivity in highlanders. PLoS One . 2012; 7:e44049.CrossrefMedlineGoogle Scholar
  • 21. Beall CM, Laskowski D, Erzurum SC. Nitric oxide in adaptation to altitude. Free Radic Biol Med . 2012; 52:1123–1134. doi: 10.1016/j.freeradbiomed.2011.12.028.CrossrefMedlineGoogle Scholar
  • 22. Stergiou GS, Palatini P, Asmar Ret al. . Blood pressure monitoring: theory and practice. European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability Teaching Course Proceedings. Blood Press Monit . 2018; 23:1–8.MedlineGoogle Scholar
  • 23. Verberk WJ, Mieke S. Are blood pressure monitors affected by high altitude? Heart Asia . 2016; 8:52–53.CrossrefGoogle Scholar
  • 24. Lewis NC, Bailey DM, Dumanoir GR, Messinger L, Lucas SJ, Cotter JD, Donnelly J, McEneny J, Young IS, Stembridge M, Burgess KR, Basnet AS, Ainslie PN. Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation. J Physiol . 2014; 592:1009–1024. doi: 10.1113/jphysiol.2013.268615.CrossrefMedlineGoogle Scholar
  • 25. Parati G, Revera M, Giuliano A, Faini A, Bilo G, Gregorini F, Lisi E, Salerno S, Lombardi C, Ramos Becerra CG, Mancia G, Salvi P. Effects of acetazolamide on central blood pressure, peripheral blood pressure, and arterial distensibility at acute high altitude exposure. Eur Heart J . 2013; 34:759–766. doi: 10.1093/eurheartj/ehs140.CrossrefMedlineGoogle Scholar
  • 26. Chirinos JA, Zamani P. The nitrate-nitrite-NO pathway and its implications for heart failure and preserved ejection fraction. Curr Heart Fail Rep . 2016; 13:47–59. doi: 10.1007/s11897-016-0277-9.CrossrefMedlineGoogle Scholar
  • 27. Umbrello M, Dyson A, Feelisch M, Singer M. The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching. Antioxid Redox Signal . 2013; 19:1690–1710. doi: 10.1089/ars.2012.4979.CrossrefMedlineGoogle Scholar
  • 28. Rong Z, Cooper CE. Modeling hemoglobin nitrite reductase activity as a mechanism of hypoxic vasodilation? Adv Exp Med Biol . 2013; 789:361–368. doi: 10.1007/978-1-4614-7411-1_48.CrossrefMedlineGoogle Scholar
  • 29. Chirinos JA, Londono-Hoyos F, Zamani P, Beraun M, Haines P, Vasim I, Varakantam S, Phan TS, Cappola TP, Margulies KB, Townsend RR, Segers P. Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction. Eur J Heart Fail . 2017; 19:1507–1515. doi: 10.1002/ejhf.885.CrossrefMedlineGoogle Scholar
  • 30. Bruno RM, Cogo A, Ghiadoni L, Duo E, Pomidori L, Sharma R, Thapa GB, Basnyat B, Bartesaghi M, Picano E, Sicari R, Taddei S, Pratali L. Cardiovascular function in healthy Himalayan high-altitude dwellers. Atherosclerosis . 2014; 236:47–53. doi: 10.1016/j.atherosclerosis.2014.06.017.CrossrefMedlineGoogle Scholar
  • 31. Richalet JP. Physiological and clinical implications of adrenergic pathways at high altitude. Adv Exp Med Biol . 2016; 903:343–356. doi: 10.1007/978-1-4899-7678-9_23.CrossrefMedlineGoogle Scholar
  • 32. Rostrup M. Catecholamines, hypoxia and high altitude. Acta Physiol Scand . 1998; 162:389–399. doi: 10.1046/j.1365-201X.1998.00335.x.CrossrefMedlineGoogle Scholar
  • 33. Dedobbeleer C, Hadefi A, Pichon A, Villafuerte F, Naeije R, Unger P. Left ventricular adaptation to high altitude: speckle tracking echocardiography in lowlanders, healthy highlanders and highlanders with chronic mountain sickness. Int J Cardiovasc Imaging . 2015; 31:743–752. doi: 10.1007/s10554-015-0614-1.CrossrefMedlineGoogle Scholar
  • 34. Lundby C, Calbet J, van Hall G, Saltin B, Sander M. Sustained sympathetic activity in altitude acclimatizing lowlanders and high-altitude natives. Scand J Med Sci Sports . 2018; 28:854–861. doi: 10.1111/sms.12976.CrossrefMedlineGoogle Scholar
  • 35. Valentini M, Revera M, Bilo G, Caldara G, Savia G, Styczkiewicz K, Parati S, Gregorini F, Faini A, Branzi G, Malfatto G, Magrì D, Agostoni P, Parati G. Effects of beta-blockade on exercise performance at high altitude: a randomized, placebo-controlled trial comparing the efficacy of nebivolol versus carvedilol in healthy subjects. Cardiovasc Ther . 2012; 30:240–248. doi: 10.1111/j.1755-5922.2011.00261.x.CrossrefMedlineGoogle Scholar
  • 36. Kacimi R, Richalet JP, Corsin A, Abousahl I, Crozatier B. Hypoxia-induced downregulation of beta-adrenergic receptors in rat heart. J Appl Physiol (1985) . 1992; 73:1377–1382. doi: 10.1152/jappl.1992.73.4.1377.CrossrefMedlineGoogle Scholar
  • 37. Voelkel NF, Hegstrand L, Reeves JT, McMurty IF, Molinoff PB. Effects of hypoxia on density of beta-adrenergic receptors. J Appl Physiol Respir Environ Exerc Physiol . 1981; 50:363–366. doi: 10.1152/jappl.1981.50.2.363.CrossrefMedlineGoogle Scholar
  • 38. Ueno N, Zhao Y, Zhang L, Longo LD. High altitude-induced changes in alpha1-adrenergic receptors and Ins(1,4,5)P3 responses in cerebral arteries. Am J Physiol . 1997; 272(2pt 2):R669–R674. doi: 10.1152/ajpregu.1997.272.2.R669.MedlineGoogle Scholar
  • 39. Fischetti F, Fabris B, Zaccaria M, Biagi A, Calci M, Candido R, Bortoletto M, Caretta R. Effects of prolonged high-altitude exposure on peripheral adrenergic receptors in young healthy volunteers. Eur J Appl Physiol . 2000; 82:439–445. doi: 10.1007/s004210000239.CrossrefMedlineGoogle Scholar
  • 40. Kacimi R, Moalic JM, Aldashev A, Vatner DE, Richalet JP, Crozatier B. Differential regulation of G protein expression in rat hearts exposed to chronic hypoxia. Am J Physiol . 1995; 269(6pt 2):H1865–H1873. doi: 10.1152/ajpheart.1995.269.6.H1865.MedlineGoogle Scholar
  • 41. Mardon K, Merlet P, Syrota A, Mazière B. Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats. J Appl Physiol (1985) . 1998; 85:890–897. doi: 10.1152/jappl.1998.85.3.890.CrossrefMedlineGoogle Scholar
  • 42. Longo LD, Pearce WJ. High altitude, hypoxic-induced modulation of noradrenergic-mediated responses in fetal and adult cerebral arteries. Comp Biochem Physiol A Mol Integr Physiol . 1998; 119:683–694.CrossrefMedlineGoogle Scholar
  • 43. Ainslie PN, Subudhi AW. Cerebral blood flow at high altitude. High Alt Med Biol . 2014; 15:133–140. doi: 10.1089/ham.2013.1138.CrossrefMedlineGoogle Scholar
  • 44. Ainslie PN, Ogoh S. Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance. Exp Physiol . 2010; 95:251–262. doi: 10.1113/expphysiol.2008.045575.CrossrefMedlineGoogle Scholar
  • 45. Curtelin D, Morales-Alamo D, Torres-Peralta R, Rasmussen P, Martin-Rincon M, Perez-Valera M, Siebenmann C, Pérez-Suárez I, Cherouveim E, Sheel AW, Lundby C, Calbet JA. Cerebral blood flow, frontal lobe oxygenation and intra-arterial blood pressure during sprint exercise in normoxia and severe acute hypoxia in humans. J Cereb Blood Flow Metab . 2018; 38:136–150. doi: 10.1177/0271678X17691986.CrossrefMedlineGoogle Scholar
  • 46. Fayed N, Modrego PJ, Morales H. Evidence of brain damage after high-altitude climbing by means of magnetic resonance imaging. Am J Med . 2006; 119:168.e1–168.e6. doi: 10.1016/j.amjmed.2005.07.062.CrossrefGoogle Scholar
  • 47. Fan C, Zhao Y, Yu Q, Yin W, Liu H, Lin J, Yang T, Fan M, Gesang L, Zhang J. Reversible brain abnormalities in people without signs of mountain sickness during high-altitude exposure. Sci Rep . 2016; 6:33596. doi: 10.1038/srep33596.CrossrefMedlineGoogle Scholar
  • 48. Hochachka PW, Clark CM, Brown WD, Stanley C, Stone CK, Nickles RJ, Zhu GG, Allen PS, Holden JE. The brain at high altitude: hypometabolism as a defense against chronic hypoxia? J Cereb Blood Flow Metab . 1994; 14:671–679. doi: 10.1038/jcbfm.1994.84.CrossrefMedlineGoogle Scholar
  • 49. Parati G, Bilo G, Faini A, Bilo B, Revera M, Giuliano A, Lombardi C, Caldara G, Gregorini F, Styczkiewicz K, Zambon A, Piperno A, Modesti PA, Agostoni P, Mancia G. Changes in 24 h ambulatory blood pressure and effects of angiotensin II receptor blockade during acute and prolonged high-altitude exposure: a randomized clinical trial. Eur Heart J . 2014; 35:3113–3122. doi: 10.1093/eurheartj/ehu275.CrossrefMedlineGoogle Scholar
  • 50. Haditsch B, Roessler A, Krisper P, Frisch H, Hinghofer-Szalkay HG, Goswami N. Volume regulation and renal function at high altitude across gender. PLoS One . 2015; 10:e0118730. doi: 10.1371/journal.pone.0118730.CrossrefMedlineGoogle Scholar
  • 51. Kamikomaki N, Nishioka O. Serum angiotensin-converting enzyme (ACE) is altered at altitude. High Alt Med Biol . 2004; 5:465–466; discussion 466. doi: 10.1089/ham.2004.5.465.MedlineGoogle Scholar
  • 52. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest . 1990; 86:1343–1346. doi: 10.1172/JCI114844.CrossrefMedlineGoogle Scholar
  • 53. Kumar R, Qadar Pasha MA, Khan AP, Gupta V, Grover SK, Norboo T, Srivastava KK, Selvamurthy W, Brahamchari SK. Association of high-altitude systemic hypertension with the deletion allele-of the angiotensin-converting enzyme (ACE) gene. Int J Biometeorol . 2003; 48:10–14. doi: 10.1007/s00484-003-0172-4.CrossrefMedlineGoogle Scholar
  • 54. Wang Y, Lu H, Chen Y, Luo Y. The association of angiotensin-converting enzyme gene insertion/deletion polymorphisms with adaptation to high altitude: a meta-analysis. J Renin Angiotensin Aldosterone Syst . 2016; 17:1470320315627410. doi: 10.1177/1470320315627410.CrossrefGoogle Scholar
  • 55. Gesang L, Liu G, Cen W, Qiu C, Zhuoma C, Zhuang L, Ren D, Pincuo Z, Chan Y. Angiotensin-converting enzyme gene polymorphism and its association with essential hypertension in a Tibetan population. Hypertens Res . 2002; 25:481–485.CrossrefMedlineGoogle Scholar
  • 56. Botero R, Matiz H, María E, Orejarena H, Blanco M, Velez JR, Del Portillo H. Efficacy and safety of valsartan compared with enalapril at different altitudes. Int J Cardiol . 2000; 72:247–254.CrossrefMedlineGoogle Scholar
  • 57. Swenson ER. New insights into carbonic anhydrase inhibition, vasodilation, and treatment of hypertensive-related diseases. Curr Hypertens Rep . 2014; 16:467. doi: 10.1007/s11906-014-0467-3.CrossrefMedlineGoogle Scholar
  • 58. Aamand R, Dalsgaard T, Jensen FB, Simonsen U, Roepstorff A, Fago A. Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation. Am J Physiol Heart Circ Physiol . 2009; 297:H2068–H2074. doi: 10.1152/ajpheart.00525.2009.CrossrefMedlineGoogle Scholar
  • 59. Vovk A, Duffin J, Kowalchuk JM, Paterson DH, Cunningham DA. Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest. Exp Physiol . 2000; 85:847–856.MedlineGoogle Scholar
  • 60. Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol (1985) . 2007; 102:1313–1322. doi: 10.1152/japplphysiol.01572.2005.CrossrefMedlineGoogle Scholar
  • 61. Simonson MS. Endothelins: multifunctional renal peptides. Physiol Rev . 1993; 73:375–411. doi: 10.1152/physrev.1993.73.2.375.CrossrefMedlineGoogle Scholar
  • 62. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation . 1998; 97:752–756.LinkGoogle Scholar
  • 63. Li H, Chen SJ, Chen YF, Meng QC, Durand J, Oparil S, Elton TS. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol (1985) . 1994; 77:1451–1459. doi: 10.1152/jappl.1994.77.3.1451.CrossrefMedlineGoogle Scholar
  • 64. Morganti A, Giussani M, Sala C, Gazzano G, Marana I, Pierini A, Savoia MT, Ghio F, Cogo A, Zanchetti A. Effects of exposure to high altitude on plasma endothelin-1 levels in normal subjects. J Hypertens . 1995; 13:859–865.CrossrefMedlineGoogle Scholar
  • 65. Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF, Parati G. Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation . 2006; 114:1410–1416. doi: 10.1161/CIRCULATIONAHA.105.605527.LinkGoogle Scholar
  • 66. Rajput C, Najib S, Norboo T, Afrin F, Qadar Pasha MA. Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high-altitude natives. Biochem Biophys Res Commun . 2006; 341:1218–1224. doi: 10.1016/j.bbrc.2006.01.086.CrossrefMedlineGoogle Scholar
  • 67. Yang B, Zhao H, Zhang J, Jiang B, Li CW, Cao YK, Cao F. Racial differences of endothelial function and plasma endothelin 1 level in preclinical Tibetan and Han male population. Eur Rev Med Pharmacol Sci . 2016; 20:3238–3243.MedlineGoogle Scholar
  • 68. Prchal JT. Genetic selection by high altitude: beware of experiments at ambient conditions. Proc Natl Acad Sci USA . 2015; 112:10080–10081. doi: 10.1073/pnas.1512899112.CrossrefMedlineGoogle Scholar
  • 69. Tykocki NR, Watts SW. The interdependence of endothelin-1 and calcium: a review. Clin Sci (Lond) . 2010; 119:361–372. doi: 10.1042/CS20100145.CrossrefMedlineGoogle Scholar
  • 70. Strait KA, Stricklett PK, Kohan JL, Miller MB, Kohan DE. Calcium regulation of endothelin-1 synthesis in rat inner medullary collecting duct. Am J Physiol Renal Physiol . 2007; 293:F601–F606. doi: 10.1152/ajprenal.00085.2007.CrossrefMedlineGoogle Scholar
  • 71. Taddei S, Virdis A, Ghiadoni L, Uleri S, Magagna A, Salvetti A. Lacidipine restores endothelium-dependent vasodilation in essential hypertensive patients. Hypertension . 1997; 30:1606–1612.CrossrefMedlineGoogle Scholar
  • 72. Sudano I, Virdis A, Taddei S, Spieker L, Corti R, Noll G, Salvetti A, Luscher TF. Chronic treatment with long-acting nifedipine reduces vasoconstriction to endothelin-1 in essential hypertension. Hypertension . 2007; 49:285–290. doi: 10.1161/01.HYP.0000254645.33321.a3.LinkGoogle Scholar
  • 73. Berkels R, Egink G, Marsen TA, Bartels H, Roesen R, Klaus W. Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms. Hypertension . 2001; 37:240–245.CrossrefMedlineGoogle Scholar
  • 74. Bilo G, Villafuerte FC, Faini Aet al. . Ambulatory blood pressure in untreated and treated hypertensive patients at high altitude: the High Altitude Cardiovascular Research-Andes study. Hypertension . 2015; 65:1266–1272. doi: 10.1161/HYPERTENSIONAHA.114.05003.LinkGoogle Scholar
  • 75. Kono S, Stiffel VM, Gilbert RD. Effects of long-term, high-altitude hypoxia on tension and intracellular calcium responses in coronary arteries of fetal and adult sheep. J Soc Gynecol Investig . 2006; 13:11–18. doi: 10.1016/j.jsgi.2005.09.006.CrossrefMedlineGoogle Scholar
  • 76. Tao X, Lin MT, Thorington GU, Wilson SM, Longo LD, Hessinger DA. Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle. Am J Physiol Heart Circ Physiol . 2015; 308:H707–H722. doi: 10.1152/ajpheart.00564.2014.CrossrefMedlineGoogle Scholar
  • 77. Carvalho-de-Souza JL, Varanda WA, Tostes RC, Chignalia AZ. BK channels in cardiovascular diseases and aging. Aging and Disease . 2013; 4:38–49.MedlineGoogle Scholar
  • 78. Jelkmann W, Elliott S. Erythropoietin and the vascular wall: the controversy continues. Nutr Metab Cardiovasc Dis . 2013; 23(suppl 1):S37–S43. doi: 10.1016/j.numecd.2012.04.002.CrossrefMedlineGoogle Scholar
  • 79. Basu M, Malhotra AS, Pal K, Prasad R, Kumar R, Prasad BA, Sawhney RC. Erythropoietin levels in lowlanders and high-altitude natives at 3450 m. Aviat Space Environ Med . 2007; 78:963–967.CrossrefMedlineGoogle Scholar
  • 80. Piperno A, Galimberti S, Mariani Ret al. ; HIGHCARE Investigators. Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project. Blood . 2011; 117:2953–2959. doi: 10.1182/blood-2010-08-299859.CrossrefMedlineGoogle Scholar
  • 81. Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol . 2009; 4:470–480. doi: 10.2215/CJN.05040908.CrossrefMedlineGoogle Scholar
  • 82. Tojo A, Doumoto M, Oka K, Numabe A, Kimura K, Yagi S. Endothelin-mediated effect of erythropoietin on blood pressure and renal hemodynamics in hypertensive rats. Am J Physiol . 1996; 270(4pt 2):R744–R748. doi: 10.1152/ajpregu.1996.270.4.R744.MedlineGoogle Scholar
  • 83. Janmaat ML, Heerkens JL, de Bruin AM, Klous A, de Waard V, de Vries CJ. Erythropoietin accelerates smooth muscle cell-rich vascular lesion formation in mice through endothelial cell activation involving enhanced PDGF-BB release. Blood . 2010; 115:1453–1460. doi: 10.1182/blood-2009-07-230870.CrossrefMedlineGoogle Scholar
  • 84. Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis . 1999; 33:821–828.CrossrefMedlineGoogle Scholar
  • 85. Plata R, Cornejo A, Arratia C, Anabaya A, Perna A, Dimitrov BD, Remuzzi G, Ruggenenti P; Commission on Global Advancement of Nephrology (COMGAN), Research Subcommittee of the International Society of Nephrology. Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial. Lancet . 2002; 359:663–666.CrossrefMedlineGoogle Scholar
  • 86. Gossmann J, Burkhardt R, Harder S, Lenz T, Sedlmeyer A, Klinkhardt U, Geiger H, Scheuermann EH. Angiotensin II infusion increases plasma erythropoietin levels via an angiotensin II type 1 receptor-dependent pathway. Kidney Int . 2001; 60:83–86. doi: 10.1046/j.1523-1755.2001.00773.x.CrossrefMedlineGoogle Scholar
  • 87. West JB. High-altitude medicine. Am J Respir Crit Care Med . 2012; 186:1229–1237. doi: 10.1164/rccm.201207-1323CI.CrossrefMedlineGoogle Scholar
  • 88. Bishop T, Ratcliffe PJ. HIF hydroxylase pathways in cardiovascular physiology and medicine. Circ Res . 2015; 117:65–79. doi: 10.1161/CIRCRESAHA.117.305109.LinkGoogle Scholar
  • 89. Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA. Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem . 2001; 276:12645–12653. doi: 10.1074/jbc.M011344200.CrossrefMedlineGoogle Scholar
  • 90. Sánchez-López E, López AF, Esteban V, Yagüe S, Egido J, Ruiz-Ortega M, Alvarez-Arroyo MV. Angiotensin II regulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha induction and redox mechanisms in the kidney. Antioxid Redox Signal . 2005; 7:1275–1284. doi: 10.1089/ars.2005.7.1275.CrossrefMedlineGoogle Scholar
  • 91. Huang Y, Di Lorenzo A, Jiang W, Cantalupo A, Sessa WC, Giordano FJ. Hypoxia-inducible factor-1α in vascular smooth muscle regulates blood pressure homeostasis through a peroxisome proliferator-activated receptor-γ-angiotensin II receptor type 1 axis. Hypertension . 2013; 62:634–640. doi: 10.1161/HYPERTENSIONAHA.111.00160.LinkGoogle Scholar
  • 92. Jefferson JA, Simoni J, Escudero E, Hurtado ME, Swenson ER, Wesson DE, Schreiner GF, Schoene RB, Johnson RJ, Hurtado A. Increased oxidative stress following acute and chronic high altitude exposure. High Alt Med Biol . 2004; 5:61–69. doi: 10.1089/152702904322963690.CrossrefMedlineGoogle Scholar
  • 93. Kumar R, Kohli S, Ali Z, Duhan K, Ram R, Gupta M, Tyagi S, Mohammad G, Pasha MQ. CYBA (p22phox) variants associate with blood pressure and oxidative stress markers in hypertension: a replication study in populations of diverse altitudes. Hypertens Res . 2015; 38:498–506. doi: 10.1038/hr.2015.31.CrossrefMedlineGoogle Scholar
  • 94. Lahaie I, Hardy P, Hou X, Hasséssian H, Asselin P, Lachapelle P, Almazan G, Varma DR, Morrow JD, Roberts LJ, Chemtob S. A novel mechanism for vasoconstrictor action of 8-isoprostaglandin F2 alpha on retinal vessels. Am J Physiol . 1998; 274(5pt 2):R1406–R1416.MedlineGoogle Scholar
  • 95. Jourdan KB, Evans TW, Curzen NP, Mitchell JA. Evidence for a dilator function of 8-iso prostaglandin F2 alpha in rat pulmonary artery. Br J Pharmacol . 1997; 120:1280–1285. doi: 10.1038/sj.bjp.0701052.CrossrefMedlineGoogle Scholar
  • 96. Dosek A, Ohno H, Acs Z, Taylor AW, Radak Z. High altitude and oxidative stress. Respir Physiol Neurobiol . 2007; 158:128–131. doi: 10.1016/j.resp.2007.03.013.CrossrefMedlineGoogle Scholar
  • 97. Sinha S, Ray US, Tomar OS, Singh SN. Different adaptation patterns of antioxidant system in natives and sojourners at high altitude. Respir Physiol Neurobiol . 2009; 167:255–260. doi: 10.1016/j.resp.2009.05.003.CrossrefMedlineGoogle Scholar
  • 98. Bailey DM, Rimoldi SF, Rexhaj E, Pratali L, Salinas Salmòn C, Villena M, McEneny J, Young IS, Nicod P, Allemann Y, Scherrer U, Sartori C. Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia. Chest . 2013; 143:444–451. doi: 10.1378/chest.12-0728.CrossrefMedlineGoogle Scholar
  • 99. Goldfarb-Rumyantzev AS, Alper SL. Short-term responses of the kidney to high altitude in mountain climbers. Nephrol Dial Transplant . 2014; 29:497–506. doi: 10.1093/ndt/gft051.CrossrefMedlineGoogle Scholar
  • 100. Lozano R, Monge C. Renal function in high-altitude natives and in natives with chronic mountain sickness. J Appl Physiol . 1965; 20:1026–1027. doi: 10.1152/jappl.1965.20.5.1026.CrossrefMedlineGoogle Scholar
  • 101. Hurtado-Arestegui A, Plata-Cornejo R, Cornejo A, Mas G, Carbajal L, Sharma S, Swenson ER, Johnson RJ, Pando J. Higher prevalence of unrecognized kidney disease at high altitude. J Nephrol . 2018; 31:263–269. doi: 10.1007/s40620-017-0456-0.CrossrefMedlineGoogle Scholar
  • 102. Shoji K, Tanaka T, Nangaku M. Role of hypoxia in progressive chronic kidney disease and implications for therapy. Curr Opin Nephrol Hypertens . 2014; 23:161–168. doi: 10.1097/01.mnh.0000441049.98664.6c.CrossrefMedlineGoogle Scholar
  • 103. Naeye RL. Children at high altitude: pulmonary and renal abnormalities. Circ Res . 1965; 16:33–38.CrossrefMedlineGoogle Scholar
  • 104. Arestegui AH, Fuquay R, Sirota J, Swenson ER, Schoene RB, Jefferson JA, Chen W, Yu XQ, Kelly JP, Johnson RJ, Escudero E. High altitude renal syndrome (HARS). J Am Soc Nephrol . 2011; 22:1963–1968. doi: 10.1681/ASN.2010121316.CrossrefMedlineGoogle Scholar
  • 105. Hurtado A, Escudero E, Pando J, Sharma S, Johnson RJ. Cardiovascular and renal effects of chronic exposure to high altitude. Nephrol Dial Transplant . 2012; 27(suppl 4):iv11–iv16.CrossrefMedlineGoogle Scholar
  • 106. Chen W, Liu Q, Wang H, Chen W, Johnson RJ, Dong X, Li H, Ba S, Tan J, Luo N, Liu T, He H, Yu X. Prevalence and risk factors of chronic kidney disease: a population study in the Tibetan population. Nephrol Dial Transplant . 2011; 26:1592–1599. doi: 10.1093/ndt/gfq608.CrossrefMedlineGoogle Scholar
  • 107. Parati G, Agostoni P, Basnyat Bet al. . Clinical recommendations for high altitude exposure of individuals with pre-existing cardiovascular conditions: a joint statement by the European Society of Cardiology, the Council on Hypertension of the European Society of Cardiology, the European Society of Hypertension, the International Society of Mountain Medicine, the Italian Society of Hypertension and the Italian Society of Mountain Medicine. Eur Heart J . 2018; 39:1546–1554.MedlineGoogle Scholar

Source: https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.118.11140

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