Recent Advances in Pulmonary Hypertension

Pathophysiology and Treatment of

High-Altitude Pulmonary Vascular Disease
Martin R. Wilkins, MD; Hossein-Ardeschir Ghofrani, MD; Norbert Weissmann, PhD;
Almaz Aldashev, PhD; Lan Zhao, MD, PhD

I t is estimated that >140 million people live above 2500 m in

various regions of the world.1 There are many challenges to
living at high altitude, but chronic exposure to alveolar hypoxia
with ventilation. A fall in alveolar Po2 is the main stimu-
lus for HPV, but a reduction in mixed venous and bronchial
arterial Po2 may also contribute.9 Ventilation of intact lungs
is prominent among them. Inspired Po2 falls from ≈150 mm Hg with a hypoxic gaseous mixture (eg, fraction of inspired oxy-
at sea level to ≈100 mm Hg at 3000 m and 43 mm Hg on the gen=0.10) leads to acute pulmonary vasoconstriction through-
summit of Everest (8400 m).2,3 The body responds by hyperven- out the pulmonary vascular bed, including nonmuscular
tilating, increasing resting heart rate, and stimulating red cell arterioles, capillaries, and veins, but is most pronounced in
production in an attempt to maintain the oxygen content of arte- small pulmonary arterioles.10–13 That said, HPV is not distrib-
rial blood at or above sea level values.2 However, hypoxic pulmo- uted evenly throughout the lung and lung perfusion is inhomo-
nary vasoconstriction (HPV) and vascular remodeling, together geneous during hypoxia.14
with increased erythropoiesis, place an increased pressure load HPV has at least 2 phases (Figure 1A). An initial constrictor
on the right ventricle (RV). How well healthy humans adapt to response that starts within seconds and reaches a maximum
hypoxia depends on their rate of ascent to altitude, the severity within minutes is followed by a sustained phase, which devel-
and duration of their exposure, and their genetic background. ops after 30 to 120 minutes.9 A transient phase of vasodilation
may be observed linking the two, and a third phase of even
Pathophysiology of Acclimatization to Hypoxia more pronounced vasoconstriction can occur after 120 min-
utes. The phases are regulated, at least in part, by different
Pulmonary Vascular Response to Hypoxia signaling pathways.15 In vivo, factors such as neurohumoral
For most mammals, including humans, a rise in pulmonary mediators, red blood cells, and lung innervation may influence
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artery pressure (PAP) is an early and inevitable consequence of the response.16

ascent to high altitude. Resting mean PAP increases along a par- Alveolar capillaries have been proposed as a site for oxygen
abolic curve from 15 mm Hg at 2000 m to ≈30 mm Hg at 4500 sensing with propagation of the hypoxic signal by endothe-
m.4 The exceptions and interindividual variation in the magni- lial membrane depolarization to upstream arterioles in a con-
tude of response offer a natural experiment that might provide nexin 40-dependent manner.17 However, the recapitulation of
insight into fundamental underlying mechanisms (vide infra). contraction to hypoxia in cultured pulmonary artery smooth
The initial rise in PAP on exposure to hypoxia is attributed muscle cells, the effector cells, indicates that an oxygen-sens-
to HPV. With chronic hypoxia, other mechanisms that likely ing mechanism is intrinsic to these cells.18 Both mitochondria
drive vascular remodeling soon contribute to the elevated and nicotinamide adenine dinucleotide (phosphate) oxidases
pressure (Figure 1A). After 2 or 3 weeks of hypoxia, there is have been suggested as oxygen sensors. A change in the lev-
little response to rebreathing 100% oxygen, indicating a struc- els of reactive oxygen species is thought to be important, but
tural resistance to pulmonary blood flow rather than one based there is a lack of agreement regarding whether the signal is an
solely on increased vasomotor tone.6 A fall in PAP on re-expo- increase or decrease in reactive oxygen species (Figure 2).19–
sure to a normal oxygen environment is evident in rats moni- 21
Differences in techniques used contribute to the different
tored by telemetry over days after removal from a hypoxic observations, but the spatial distribution of reactive oxygen
chamber7 (Figure 1B) and is also documented in humans.4,8 species signaling may also be significant.22
The second phase of HPV is influenced by endothelial
Pulmonary Arteriolar Vasoconstriction Dominates cell function. The endothelium releases a variety of vasoac-
the Acute Pulmonary Vascular Response to Hypoxia tive mediators, such as endothelin 1, prostacyclin, and nitric
Oxygen tension is a major regulator of pulmonary vascular oxide (NO; Figure 3),9,16 and their production is perturbed
tone and a physiological mechanism for matching perfusion by hypoxia. For example, oxygen is a substrate for NO

From Experimental Medicine, Imperial College London, Hammersmith Hospital, United Kingdom (M.R.W., H.-A.G., L.Z.); Excellence Cluster
Cardio-Pulmonary System, Universities of Giessen, Germany (M.R.W., H.-A.G., N.W., L.Z.); University of Giessen Marburg Lung Center, Justus-Liebig-
University, Germany (M.R.W., H.-A.G., N.W., L.Z.); Kerckhoff Clinic, Bad Nauheim, Germany (H.-A.G.); Institute of Molecular Biology and Medicine,
Bishkek, Kyrgyzstan (A.A.).
Correspondence to Martin R. Wilkins, MD, NIHR Imperial Clinical Research Facility, Imperial College London, Hammersmith Hospital, Du Cane Road,
London W12 0NN, United Kingdom. E-mail m.wilkins@imperial.ac.uk
(Circulation. 2015;131:582-590. DOI: 10.1161/CIRCULATIONAHA.114.006977.)
© 2015 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.006977

582
 Wilkins et al   High-Altitude Pulmonary Vascular Response   583

A 5
although some species seem resistant.31 All of the layers of the
normoxic ventilation (21% O2)
hypoxic ventilation (3% O2)
vascular wall, including fibroblasts, are involved in the remod-
4 exchange of eling (Figure 4),32,33 but the hallmark of the vascular response
ΔPAP (mmHg)

perfusate
3 to chronic hypoxia is increased muscularization of distal ves-
2 sels with extension of muscle into previously unmuscularized
arterioles.28,30
1
Hypoxia leads to changes in endothelial cell membrane
0 normoxic control properties that compromise barrier function, resulting in an
p < 0.05
-3
-10 0 30 60 90 120 150 180
influx of plasma proteins that may activate vascular wall
Time (min) proteases.34 In addition, mechanical stress, blood-borne and
B 70 hypoxia
locally produced factors, and the recruitment of circulating
60
cells act collectively to drive the vascular remodeling of small
and large pulmonary vessels, with increasing recognition of
PAP (mmHg)

50 normoxia normoxia
the role of inflammation (Figure 4).35–37 Rapid expansion of
40
the adventitial vasa vasorum serves to facilitate the arrival of
30
these cells.33
20
HIFs and nuclear factor-κB are key transcriptional regu-
10
lators of the proliferative and inflammatory responses to
0
0 5 10 15 20 25 30 35 40 45
hypoxia. Pulmonary hypertension in hypoxic mice haploin-
Time (days) sufficient for HIF-1α (Hif1α+/-) or HIF-2α (Hif2α+/-) is
attenuated.38,39 Conversely, gain-of-function mutations in HIF-
Figure 1. Contribution of hypoxic pulmonary vasoconstriction
(HPV) and vascular remodeling to the rise in pulmonary artery pres- 2α are associated with the development of pulmonary hyper-
sure (PAP) in chronic hypoxia. A, The initial rise in PAP in hypoxia tension in mice and humans.40–42
is driven by HPV. The pressor response to hypoxia does not return Although in part caused by and adaptive to the increase in
to baseline on return to normoxia in isolated perfused rabbit lungs,
even if the perfusate is replaced to remove hypoxia-stimulated
hemodynamic stress, the vascular remodeling contributes to
circulating vasoactive factors. Modified from Weissmann et al.5 B, and sustains the elevated PAP. Indeed, the structural changes
Elevated PAP in a telemetered rat takes days to return to baseline take a considerable time to resolve on return to a sea-level
after removal from 2 weeks in a hypoxic chamber. oxygen environment and may persist in some form.43 The
extent to which the structural changes in pulmonary resis-
synthases, and NO bioavailability is reduced by hypoxia.23
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tance vessels infringe on the lumen and contribute a physical

In addition, sustained HPV has been shown to depend on obstruction to blood flow (ie, the argument being that vascular
glucose level.24 growth is outward rather than inward) and the extent of vas-
In addition to changes in intracellular Ca2+ levels, changes in cular rarefaction in response to chronic hypoxia are unclear.44
pulmonary artery smooth muscle cell myofilament sensitivity These may vary between species.
to Ca2+ arising from inhibition of myosin light chain phospha- Mechanisms other than narrowing of the vessel lumen are
tase via RhoA/Rho kinase or protein kinase C or a decreased relevant to this discussion, specifically the contribution of
activation of myosin light chain phosphatase by decreased NO changes in vascular compliance.45 Changes in the stiffness of
signaling9 also contribute to sustained HPV. A recent observa- proximal vessels leads to changes in the propagation of high-
tion that still has to be reconciled with the effects of global energy pulsatile waves. These are transmitted to the micro-
hypoxia-inducible factor (HIF)-1α haploinsufficiency on the circulation, where they might perpetuate or potentially even
pulmonary vasculature is that HIF-1α levels in pulmonary cause the microcirculatory changes, as well as contribute to
artery smooth muscle cells maintain low pulmonary vascular the burden on the RV.46
tone by decreasing myosin light chain phosphorylation.25
Rho kinase inhibitors are very effective at preventing and Cardiac Response to Chronic Hypoxia
attenuating HPV, underlying the importance of the RhoA/Rho Studies of healthy subjects exposed to hypoxia report an increase
kinase signaling pathway in regulating pulmonary vascular in resting heart rate and an initial increase in cardiac output in
tone. Acute administration of a Rho kinase inhibitor signifi- an attempt to maintain oxygen delivery to tissues.47 After 2 to
cantly reduces pulmonary vascular resistance in chronically 3 days of hypoxia, stroke volume falls. Heart rate remains ele-
hypoxic rats,26 advancing the argument that vasoconstriction vated, and so cardiac output remains at or just below sea level.
is an important pathophysiological mechanism in high-alti- Oxygen delivery to tissues is maintained by increased oxygen
tude pulmonary hypertension (HAPH), perhaps as important extraction. The roles of activation of the sympathetic nervous
or more important than vascular remodeling.27 system, hypovolemia (from hyperventilation and increased
diuresis), hypocapnia (from hyperventilation), and myocardial
Vascular Remodeling Contributes to and Sustains contractility in this response are difficult to discern.47 On the
the Chronic Pulmonary Vascular Response to whole, myocardial contractility is preserved, although reversible
Hypoxia reductions in cardiac mass and myocardial phosphocreatine/
Chronic global alveolar hypoxia is accompanied by structural ATP have been documented in healthy volunteers after a 17-day
remodeling of pulmonary vessels. This has been described trek to 5300 m.48 Right heart failure is a risk in some previously
in a number of species, including rat,28 cow,29 and humans,30 healthy individuals, precipitated by more extreme pulmonary
 584  Circulation  February 10, 2015

Figure 2. Signaling mechanisms underlying acute hypoxic pulmonary vasoconstriction (HPV). Pathways activated by hypoxia are depicted
in blue; those inhibited by hypoxia are depicted in red. Both mitochondria and nicotinamide adenine dinucleotide (phosphate) oxidases
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have been suggested as oxygen sensors. A reduction in the cytosolic redox state could inhibit voltage-dependent potassium channels,
subsequent membrane depolarization of PASMCs, opening of l-type calcium channels and Ca2+ influx.20 By contrast, increased cytosolic
ROS levels can result in Ca2+ release from the SR, possibly through the oxidation of cysteine residues in RyRs and the opening of
IP3-gated calcium stores.19 Increased ROS could also provoke an influx of extracellular Ca2+ or Na+ through transient receptor potential
channels (TRPC6).21 In this scenario, the increase of acute hypoxia-induced ROS triggers an accumulation of DAG, resulting from the acti-
vation of phospholipase C or phospholipase D or inhibition of DAG-degrading DAG kinases. Another proposal assumes that acute hypoxia
leads to inhibition of the respiratory chain and a subtle decrease in ATP production, which does not affect energy state, but rather acts as
a mediator and alters the cellular AMP/ATP ratio. An increase in the AMP/ATP ratio activates AMPK, followed by an increase in cADPR
that triggers the release of [Ca2+]i through RyR of SR.9 The level of ROS could be relevant through ROS-dependent alteration of function of
AMPK and cADPR. AMPK indicates AMP–activated protein kinase; Ca2+, calcium; cADPR, cyclic ADP–ribose; DAG, diacylglycerol; DGK,
DAG kinases; Em, membrane potential; GSH, glutathione; GSSG, glutathione disulfide; IP3, inositol trisphosphate; IP3R, inositol trisphos-
phate receptor; K+, potassium; Kv, voltage-dependent potassium channels; Na+, sodium; NAD+, nicotinamide adenine dinucleotide; NADH,
reduced form of NAD; NAD(P)H, nicotinamide adenine dinucleotide (phosphate) oxidase; O2, oxygen; PASMC, pulmonary arterial smooth
muscle cell; ROS, reactive oxygen species; RyR, ryanodine receptors; SR, sarcoplasmic reticulum; TRPC6, transient receptor potential
cation channel 6; and VOCC, voltage–dependent calcium channels (includes l-type calcium channels).

vascular responses to hypoxia, and also in the context of chronic from direct measurements of RV function at altitude are few,
mountain sickness (CMS), from pronounced erythrocytosis and and not all are convinced that the improvement in exercise
fluid retention (from relatively higher Pco2). capacity at altitude reported with some pulmonary vasodila-
tors is attributed to a reduction in RV afterload.50
Exercise
Exercise capacity is reduced at altitude, even after acclimati- Erythropoietic Response to Hypoxia
zation, but the contribution of pulmonary hypertension is con- Exposure to hypoxia leads to changes in blood-O2 affinity and
troversial.49,50 PAP increases more sharply with the increase stimulates red cell production in an attempt to improve tissue
in cardiac output on exercise at altitude than at sea level.51 oxygenation. Increased red cell 2,3 diphosphoglycerate levels
This augmented rise in PAP with exercise can persist for some have an allosteric effect on hemoglobin, reducing its affinity
time in acclimatized highlanders on descent to sea level, most for O2 and facilitating its release to tissues, although this is at
likely reflecting structural remodeling of the pulmonary vas- the expense of impairing O2 capture as blood passes through
culature with chronic exposure.5,8 The increase in PAP may the lungs. Increasing red cell mass also has its downside, as it
impair gas exchange from interstitial and alveolar edema and increases blood viscosity. Little attention has been paid to the
reduce maximal cardiac output, leading to a reduction in oxy- contribution of increased blood viscosity to PAP, because the
gen transport to exercising muscles.49 However, definitive data increase in PAP precedes the rise in hemoglobin, and patients
 Wilkins et al   High-Altitude Pulmonary Vascular Response   585

at altitude with high-altitude pulmonary edema (HAPE)

or over weeks, months, and years with right heart failure
secondary to severe pulmonary hypertension or excessive
erythrocytosis.

High-Altitude Pulmonary Edema

The pathognomonic clinical feature is breathlessness accom-
panied by cough, initially dry but later productive of white
and then pink frothy sputum.3,56 Tachycardia, mild pyrexia,
and sometimes cyanosis are also evident. The chest radio-
graph shows pulmonary edema. The condition develops in
susceptible individuals within the first 2 to 4 days of arrival
at altitudes above 2500 m. It is precipitated by rapid ascent
and exercise and is potentially lethal if not treated. The inci-
dence is variously recorded, depending on the subject popula-
tion, rapidity of ascent, and final altitude; everyone is at risk
of HAPE if they ascend fast and high enough. It is caused
by exaggerated and uneven HPV leading to high capillary
pressures in regions of the lung and an exudation that might
invoke a secondary inflammatory response.57–59 Susceptible
individuals exhibit a marked rise in PAP on exposure to
hypoxia mediated by pulmonary arteriolar vasoconstriction
and a greater rise in PAP on exercise in a normal oxygen envi-
ronment, indicating a hyperactive pulmonary circulation.56
The emphasis in management is on prevention. Travelers
Figure 3. Signaling mechanisms underlying sustained hypoxic should manage their rate of ascent to 300 to 500 m per day along
pulmonary vasoconstriction (HPV). The endothelium releases a with a day of rest every 3 to 4 days when traveling above 3000
variety of vasoactive mediators, such as endothelin 1, prostacy-
clin, and nitric oxide (NO),9,16 and their production is perturbed m.56 Pharmacologic measures that have been evaluated and dem-
onstrated efficacy in reducing the incidence of HAPE include
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by hypoxia. In addition to changes in intracellular Ca2+ levels,

changes in PASMC myofilament sensitivity to Ca2+, arising from slow-release nifedipine (30 mg BID),60 the phosphodiesterase
inhibition of MLCP via RhoA/Rho kinase or protein kinase C
type 5 inhibitor tadalafil (10 mg BID), and dexamethasone
(PKC), or a decreased activation of MLCP by decreased NO
signaling,9 also contributes to sustained HVP. ADMA indicates (8 mg BID).61 The β2-agonist salmeterol (125 μg BID) by
asymmetrical dimethylarginine; cGMP, cyclic guanosine mono- inhalation appears to be less effective.62
phosphate; DDAH, dimethylarginine dimethylaminohydrolase; When treatment is required, consideration should be given
DMA, dimethylamine; ET-1, endothelin 1; EC, endothelial cell;
MLC20, regulatory myosin light chain; MLCP, myosin light chain to descent to a lower altitude coupled with supplemental
phosphatase; NO, nitric oxide; NOS, nitric oxide synthase; O2, oxygen (2–4 L/min) where possible.56,63 Nifedine is the stan-
oxygen; PASMC, pulmonary arterial smooth muscle cell; PGI2, dard treatment. A phosphodiesterase type 5 inhibitor may be
prostacyclin; Rho, Ras homolog gene family; ROS, reactive oxy-
gen species; and sGC, soluble guanylyl cyclase. Phosphorylated
helpful but has not been formally trialed. There is no role for
proteins are indicated by a white “P” in a blue circle. diuretics. A fully conscious person with mild-to-moderate
HAPE may be managed at altitude if the appropriate expertise
with polycythemia at sea level do not have pulmonary hyper- and facilities are available.
tension. A recent re-evaluation of the effect of increased blood
viscosity on PAP measurements at altitude suggests that some HAPH and Heart Failure
correction for hematocrit is important.52,53 By convention, the definition of HAPH is a resting mean PAP
>30 mm Hg.64 This needs revisiting and reconciling with inter-
Clinical Presentations From national guidelines for the definition of pulmonary hyperten-
Maladaptation to Hypoxia sion, which is a resting mean PAP >25 mm Hg.53,65
Data on the prevalence of HAPH are sparse. Prevalence will
Variation in Susceptibility to High-Altitude vary according to altitude and ethnic background, but some
Pulmonary Vascular Disease 14% of Kyrgyz highlanders have been found to have ECG
The rise in PAP in chronic hypoxia is generally modest, evidence of right ventricular hypertrophy.66 A much smaller
certainly compared with that seen in idiopathic pulmonary percentage progress to and present with heart failure.
arterial hypertension, and is compatible with a normal life The RV generally copes well with a pressure load, and
at high altitude. However, variation in the pulmonary vas- there is doubt as to whether pressure load itself is sufficient to
cular response to hypoxia is well recognized, both between cause heart failure, suggesting that other factors, such as myo-
and within species,16,31,54,55 and in humans the magnitude cardial hypoxia and neurohumoral factors, are important.67
of HPV can vary ≈5-fold among individuals.16,55 Extreme Nonetheless, pulmonary hypertension progressing to fatal
responders are at highest risk of presenting acutely on arrival right heart failure, recognized as infantile subacute mountain
 586  Circulation  February 10, 2015

Figure 4. Mechanisms of vascular remodeling in chronic hypoxia. The vascular remodeling in response to chronic hypoxia involves
all 3 layers of the vascular wall–intima, media, and adventitia.32 Endothelial cell dysfunction and intimal proliferation are evident and
prominent in some species, such as the rat, exposed to moderately severe hypoxia.34 However, the hallmark of HAPH is increased
muscularization of distal vessels with extension of muscle into previously unmuscularized arterioles.28,30 There is thickening of the
media of large and medium pulmonary arteries, which, in large mammals (including humans), is attributable mainly to the prolifera-
tion of smooth muscle cells, along with increased collagen and elastin deposition.32 The medial layer of proximal vessels contains
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a heterogeneous population of smooth muscle cells, which includes a reservoir of cells that can divide when exposed to hypoxia
and could contribute to vascular hyperplasia.32 Medial smooth muscle cells from distal resistance pulmonary arterioles have a lower
capacity for proliferation. Remodeling in the distal vasculature may depend on the presence of cells from other vascular com-
partments, including circulating inflammatory cells and peripheral blood hematopoietic cells, that might stimulate proliferation or
transdifferentiate into smooth muscle-like cells. Increasing recognition is given to an adventitial reaction mediated by the fibroblast
in response to hypoxia and vascular wall stress.33 In addition, an inflammatory cell infiltrate, composed of monocytes, dendritic
cells, and T cells, is evident.35 Evidence for epigenetic regulation of pulmonary vascular remodeling comes from experiments with
HDACs. Class I HDAC inhibitors markedly decreased cytokine/chemokine mRNA expression levels in these cells proliferating adven-
titial fibroblasts and their ability to induce monocyte migration and inflammation.36 This in part may be attributed to modulation
of microRNA-124 expression.37 ECAM indicates endothelial cell adhesion molecule; FGF, fibroblast growth factor; HDAC, histone
deacetylase; GM-CSF, granulocyte macrophage colony stimulating factor; HIF, hypoxia-inducible factor; ICAM, intercellular adhesion
molecule; IL-1β, interleukin 6; IL-6, interleukin 6; NO-sGC-cGMP, nitric oxide-soluble guanylate cyclase-cyclic GMP; PDGF, platelet-
derived growth factor; PGI2, prostacyclin; ROS, reactive oxygen species; TRPC6, transient receptor potential cation channel 6; and
VCAM, vascular cell adhesion molecule.

sickness, has been described in infants of Chinese Han origin Chronic Mountain Sickness
who are born at low altitude and taken to high altitudes.68 They The defining feature of chronic mountain sickness (CMS) is
develop heart failure within a few weeks or months and the excessive erythrocytosis accompanied by neurologic symp-
pathology reveals extreme medial hypertrophy of the small toms, such as headache, dizziness, and fatigue.64 By con-
pulmonary arteries accompanied by hypertrophy and dilata- sensus, the hemoglobin should exceed ≥21g/dL in men and
tion of the RV. Heart failure has also been described in Indian ≥19 g/dL in women. Hypoventilation leading to hypoxemia
soldiers posted at the high-altitude borders in China69 and may stimulate red cell production,4 but an alternative possi-
occasionally in previously healthy travelers,70 and HAPH is bility is that polycythemia is the primary abnormality, which,
thought to be the major factor.71 by reducing Pco2 drive, leads to hypoventilation. Pulmonary
Descent to lower altitude is life saving for severe cases of hypertension may accompany the polycythemia but is not a
heart failure. There are a number of potential pharmacologic prerequisite.
treatments for managing less severe disease, but few have been Descent to low altitudes is the best treatment but may not be
formally trialed in HAPH. Phosphodiesterase type 5 inhibitors acceptable to patients for personal reasons. An alternative to
appear effective at reducing pulmonary vascular resistance,72 phlebotomy is acetazolamide. Acetazolamide (250 mg daily)
and acetazolamide73 and the Rho-kinase inhibitor, fasudil74, has been shown to reduce hematocrit, increase Pao2 and oxy-
are promising. The benefits of endothelin receptor antagonists gen saturation, and decrease in Paco2 in CMS, most likely
are less clear.75,76 via metabolic acidosis stimulating ventilation.73 Pulmonary
 Wilkins et al   High-Altitude Pulmonary Vascular Response   587

vascular resistance was also reduced and cardiac output other Asian and European populations studied at the same
increased without a change in pulmonary pressure. altitude.96 It is likely that the Andean and Tibetan populations
have developed different genetic adaptations to high-altitude
Insights From Humans Adapted to Hypoxia hypoxia, although pathways may converge. In the case of
Tibetans, one source of adaptation is likely to be attributed to
Variation in Susceptibility to High-Altitude
the introduction of genetic variants from archaic Denisovan-
Pulmonary Vascular Disease
like individuals into the ancestral Tibetan gene pool.97
The variation in pulmonary vascular response has a strong
Aside from HIF, genes encoding downstream components
genetic basis, which provides the substrate for environmen-
of the HIF pathway remain a priori candidates for natu-
tal selection pressures and adaptation to high-altitude liv-
ral selection to hypoxia. A recent study of single nucleotide
ing. Tibetans appear less susceptible than recent migrants to
polymorphisms in 5 Ethiopian populations at altitude suggest
HAPH77,78 and CMS,79 most likely the result of living above
positive selection for BHLHE41, a gene transcriptionally reg-
3000 m for thousands of years. Data are few, but PAP mea-
ulated by HIF-1α and with a major regulatory role in the same
surements in ethnic Tibetans living over 3600 m are in the
hypoxia-sensing pathway described in Tibetans, indicative
range typical of healthy adults at sea level,77,78 and postmortem
of convergent evolution.95 Other pathways may emerge from
studies show little vascular remodeling.78,80 A blunted pulmo-
unbiased genome-wide studies in larger population cohorts.
nary vascular pressor response to acute and sustained hypoxia
Evidence for adaptation outside the HIF family comes from
is retained by Tibetans at sea level.81
a study of Eurasians exposed to mild-to-moderate hypoxia,
where the strongest adaptive signal came from the μ-opioid
Recent Genomic Studies in Humans receptor-encoding gene (OPRM1, 2.54_10_9).98
A number of attempts have been made to understand adap-
Whole-genome sequencing of Andean highlanders, 10
tation to high-altitude life based on differences in candidate
with and 10 without CMS, followed by expression studies
pathways, such as the ability of Tibetans to preserve NO pro-
in fibroblasts identified 2 genes, SENP1 and ANP32D, that
duction at altitude82 and candidate genes,66,83 but this approach
exhibit a higher transcription response to hypoxia in CMS
is selective and the data come from small subject numbers. The
subjects.99 Downregulation of the orthologs of these genes in
advent of high-throughput genome sequencing has enabled a
flies enhanced their survival rates in a hypoxic environment.
less-biased strategy for investigating gene associations. The
SENP1 is known to regulate erythropoiesis and SENP1-/- mice
priority to date has been to compare the genetic architecture
die early because of anemia, lending biological plausibility to
of people living at high altitude with that of lowlanders or
this gene as a candidate for a role in CMS. There is widely
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recent migrants (genome-wide selection scans) rather than to

compare well-phenotyped populations with and without pul- believed to be a genetic predisposition to HAPE, but to date
monary vascular disease at altitude (genome-wide association only candidate genes have been examined with no consensus
studies). observations.100
Seven genome-wide selection scans of Tibetan DNA have
been reported. All have shown evidence of natural selection Conclusions
for noncoding variants in and around 2 HIF pathway genes, Humans can live a normal life at high altitudes given sufficient
EPAS1 (HIF-2α) and EGNL1 (HIF prolyl 4-hydroxylase time to acclimatize. People who exhibit a marked pulmonary
2).84–90 Key to the interpretation of genetic data is robust phe- vascular or erythropoietic response to hypoxia identify them-
notyping. Tibetans average ≥1 g/dL and as much as 3.5 g/ selves as at risk of heart failure. Studies in Tibetan people
dL (ie, ≈10% to 20%) lower hemoglobin concentration com- adapted genetically to high altitude highlight the importance
pared with acclimatized lowlanders. At first sight, a paradox, of the HIF pathway in determining the magnitude of response,
a lower red cell mass by reducing blood viscosity may be an but other pathways may emerge from studies of Tibetan
important factor enabling the cardiopulmonary circulation to cohorts better phenotyped for pulmonary hemodynamics, as
adapt to high-altitude life. Significantly, the polymorphisms well as studies of other ethnic groups. Considerable progress
in EPAS1 and EGLN1 in Tibetans correlate with hemoglobin has been made in understanding the pathology of HAPH, but
concentration.84,86–88,90 A high-frequency missense mutation few drugs studied in animal models have been formally trialed
has recently been identified in EGLN1 that encodes a variant in humans.
prolyl 4-hydroxylase 2 with increased hydroxylase activity
under hypoxic conditions that would contribute to this adap- Acknowledgments
tive response.91 We thank Dr Oleg Pak for his assistance with the figures.
A genome study in Andeans has found evidence of posi-
tive selection for EGLN1 but not EPAS1.92 Neither were Sources of Funding
candidates in reported studies in Ethiopian highlanders.93–95 Drs Wilkins and Zhao are funded by the British Heart Foundation.
Moreover, Andeans exhibit a robust erythropoietic response to Drs Weissmann and Ghofrani are funded by the German Research
altitude and polymorphisms identified in EGLN1 in Andeans, Foundation, Excellence Cluster Cardio-Pulmonary System (EXC
albeit different from those in Tibetans, did not associate with 147).
hemoglobin level. Analysis of other quantitative traits, such
as resting ventilation, hypoxic ventilator response, and oxy- Disclosures
gen saturation, also show differences between Tibetans and None.
 588  Circulation  February 10, 2015

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