High Altitude Evidence

Question 1

Semenza and Wang (1992)

Discovery of the hypoxic regulator

Answer 1

Isolated a 50-nucleotide DNA sequence from the human EPO gene that drove hypoxia-inducible transcription in Hep3B cells; mutations of that sequence abolished the hypoxic response, leading to the discovery of HIF-1.

Question 2

Gruber et al (2007)

Establishing the role of Hif isoforms

Answer 2

Used tamoxifen-inducible, ubiquitous Cre to delete HIF-2α or HIF-1α postnatally in mice; only HIF-2α deletion caused anemia responsive to EPO and blunted renal EPO induction, demonstrating HIF-2’s in vivo role in erythropoiesis.

Question 3

Dorrington et al (1997)

Characterising the pulmonary response

Answer 3

Measured pulmonary vascular resistance with a balloon-tipped catheter in 8 men during 8 h isocapnic hypoxia, 3 h euxia, then re-hypoxia; PVR rose and fell in parallel with inspired PO₂, characterizing dynamic HPV.

Question 4

Smith, Talbot et al (2009)

Effect of iron on pulmonary arterial pressure

Answer 4

In 22 healthy lowlanders at 4340 m, gave IV iron vs placebo on day 3 and measured PASP by echo: iron reduced PASP by 6 mmHg, placebo did not; in CMS highlanders, venesection–induced iron deficiency increased PASP by 9 mmHg, showing iron/HIF-dependence.

Question 5

Santer et al (2020)

Effect of iron on phsyiological outcomes

Answer 5

Randomized 48 non-anemic COPD patients to ferric carboxymaltose vs placebo; after 1 week measured SpO₂, 6MWD, breathlessness, QoL: iron improved 6MWD and breathlessness but not SpO₂ or QoL.

Question 6

Forster et al (1971)

Ventilatory responses in acclimatised and adapted individuals

Answer 6

Tracked ventilatory responses to CO₂ and O₂ in lowlanders over 6 weeks at altitude, altitude-residing lowlanders, and natives: lowlanders’ CO₂ sensitivity rose progressively; natives had blunted hypoxic response,

Question 7

Busch et al (1985)

Peripheral driver of acclimatisation

Answer 7

In goats with one carotid body perfused extracorporeally, perfused hypoxic blood for 6 h under isocapnia: ventilation progressively rose and persisted after normoxia, proving carotid-body hypoxia alone drives acclimatization.

Question 8

Hodson et al (2016)

Role of PHD2 and Hif in the ventilatory response

Answer 8

Used tamoxifen-inducible knockouts of PHD2, HIF-1α, and HIF-2α to test hypoxic ventilatory response and carotid-body proliferation in mice: PHD2 KO increased HVR; HIF-2α deletion (not HIF-1α) blocked the enhanced HVR and CB proliferation, identifying PHD2–HIF-2α as key.

Question 9

Beall et al (1998)

Hct in high altitude populaions

Answer 9

Compared hemoglobin in Tibetans and Aymara at high altitude: Tibetans showed no marked Hb increase whereas Aymara did, revealing a blunted erythropoietic response in Tibetans due to genetic adaptation.

Question 10

Beall et al (2010)

Natural selection in high altitude populations

Answer 10

GWAS in Tibetans vs Han Chinese identified EPAS1 under strong selection; EPAS1 genotype was associated with ∼1 g/dL lower Hb in homozygotes, replicated at 4300 m, implicating EPAS1 in Tibetan adaptation.

Question 11

Petousi et al (2014)

Natural selection in high altitude populations

Answer 11

Assessed associations of compound EPAS1 and PHD1 variants with hemoglobin in highlanders.
Some studies showed lower Hb in homozygous patients for the compound variant, others showed lower Hb only when the PHD2 variants were associated with positively selected HIF2alpha variants

Question 12

Moore et al (2021)

CMS in high altitude populations

Answer 12

Surveyed prevalence of chronic mountain sickness in Tibetans, Europeans, Han, and Andeans: Tibetans had the lowest CMS rate, linked to lower Hb and blunted pulmonary hypertensive response, underscoring durable adaptation.

Question 13

Groves et al (1985)

Pulmonary response in Tibetans

Answer 13

Measured pulmonary artery pressure and resistance at rest and during maximal exercise in 5 Tibetans at 3658 m: values were within sea-level norms and little changed when subjects breathed a hypoxic gas mixture. Near maximal exercise increased CO three-fold but did not elevate PVR.

Question 14

Singh et al (1969)

Early recorded cases of HACE

Answer 14

Reported LP opening pressures in 24 Indian soldiers moving between sea level and high altitude: indicative of increased ICP; one of the earliest recorded cases of HACE

Question 15

Housten and Dickenson (1975)

Establishing HACE as a distinct condition

Answer 15

Described 12 severe altitude‐illness cases dominated by neurological signs; necropsy in 2 fatalities showed widespread petechiae and hemorrhage, establishing HACE as distinct from AMS.

Question 16

Hackett et al (1998)

Clinical feature of HACE

Answer 16

Used T2-weighted MRI in 9 HACE patients vs 6 controls at high altitude: intense white-matter signal in HACE revealed vasogenic edema, especially in the splenium of the corpus callosum.

Question 17

Kallenberg et al (2008)

Clinical distinguisher of HACE

Answer 17

Applied susceptibility-weighted 3 T MRI in 3 HACE and 3 AMS patients: HACE patients showed extensive microbleeds not seen in AMS, indicating distinct microvascular pathology.

Question 18

Hackett et al (2019)

Long term effect of HACE

Answer 18

Followed 8 HACE patients with MRI over months–years: persistent and coalescing microbleeds in white matter demonstrated long-term sequelae of cerebral edema; also observed evidence of cytotoxic oedema

Question 19

Maggiorini et al (2001)

PCP and HAPE

Answer 19

Exposed 30 non-acclimatized mountaineers (16 HAPE history) to controlled hypoxia; measured pulmonary capillary pressure (PCP): PCP ≥ 19 mmHg predicted HAPE, linking elevated PCP to risk.

Question 20

Dehnert et al (2015)

HPV and HAPE

Answer 20

Screened > 400 lowlanders for exaggerated HPV; selected high-HPV and control groups for 48 h at 4559 m: only 13% of high-HPV subjects developed HAPE, showing exaggerated HPV is an imperfect surrogate.

Question 21

Bush et al (2001)

NO bioavailability and HAPE

Answer 21

Measured exhaled NO over 4 h of hypoxic exposure in HAPE-susceptible vs controls: susceptible individuals had lower NO, implicating reduced NO bioavailability in HAPE vulnerability.

Question 22

Swenson et al (2002)

NO bioavailability in HAPE

Answer 22

Assayed BAL nitrate/nitrite in mountaineers who did or did not develop HAPE: HAPE-susceptible had lower NO metabolites, supporting a role for impaired NO signaling in HAPE pathogenesis.

Question 23

Gong et al (2018)

Animal model in HACE research

Answer 23

Ganglioside GM1, which is known to alleviate brain injury, protects HACE in rats by muting inflammatory cytokines

Question 24

Viault (1890)

Initial characterisation of erythrocytosis

Answer 24

Expedition to the Peruvian Andes; identified elevated RBC numbers as an acute physiologic response rather than an inherited condition.

Question 25

Derstine et al (2023) | Gender-specific effects in altitude pathology

Answer 25

literature review that concluded there is very limited data on female-specific findings regarding AMS and HACE so in the context of Housten and Dickenson's recommendation, it hasn't been conclusively ascertained whether the pre-menstrual phase is a risk factor for HACE

Question 26

Song et al (2020) | The Tibetan PHD2 mutation

Answer 26

Mice with Tibetan PHD2 showed augmented HVR; mice that were Tib/Tib for Phd2 but +/- for HIF-α had ameliorated pulmonary hypertension ;suggests the Tibetan Phd2 is a loss-of-function mutation