Populations living at high altitude
Accurate up-to-date data are difficult to come by but a commonly used
statistic reports that roughly 7% of the world’s population live above
1500m with some 140 million highlanders above 2,500m (Moore, Niermeyer
& Zamudio, 1998) (Figure 1). Barometric pressure and the fraction of
inspired oxygen (FiO2) fall with increasing altitude,
leading to hypobaric hypoxia (Imray et al). At 2,500 m above the sea
level, barometric pressure falls from 101 Pa at sea level to 75 Pa and
FiO2 from 21% to 15%. For reference, on Mount Everest
(summit 8,848 m), barometric pressure is 36 Pa and FiO27% (Hopfl, Ogunshola & Gassmann, 2003). Of note, the air’s oxygen
concentration remains at 21% even at that high altitude.
The extent to which HAPH is a health problem for residents at altitude
is a relevant question. Most non-natives that ascend to these altitudes
experience health problems in the early days, from breathlessness and
headaches, to HAPE and high altitude cerebral oedema (HACE) in more
severe cases. CMS is recognised among high altitude dwellers. A recent
meta-analysis has provided a more complete picture of the prevalence of
HAPH among highlanders than obtained from single reports. The analysis
identified 12 studies that had collected echocardiographic estimations
of PAP from a total of 834 high-altitude residents; all but one study
was performed between 3,600m and 4,350m (Soria, Egger, Scherrer, Bender
& Rimoldi, 2016). Mean systolic PAP was approximately 7 mmHg higher
than recorded at low altitudes. It is noted, however, that HAPH was
rare, with <1% of those studied recording a mean systolic PAP
above 27.1 mmHg.
Nonetheless, PAP does increase with ascent and high-altitude regions
offer a natural laboratory for investigating hypoxic response mechanisms
in humans. Of particular interest is relating genotype to phenotype.
Given that environmental hypoxia is a potent selection pressure,
particularly at birth, individuals that exhibit the lowest PAPs at
altitude might be expected to host genetic variants associated with
adaptive molecular pathways. As genetic variants linked to phenotype
offer a powerful strategy for defining critical molecular pathways,
studying the genetic basis of adaptive responses to hypoxia provide an
important approach to elucidating major drivers of HAPH.
The high-altitude populations for which most data are available are
Tibetans, Andeans, Ethiopians and, somewhat less, the Kyrgyz (Figure 1).
Humans have occupied the Tibetan plateau for over 25,000yrs, and those
we refer to as Tibetans today split from Han Chinese, the usual control
group in comparator studies, around 2750 ~ 5500 years
ago (Yang et al., 2017). Human inhabitation of the Andean Altiplano
began around 11,000yrs ago, the Semian Plateau in Ethiopia around
5,000yrs ago and the Tien-Shen mountains in Kyrgyzstan only in the last
1,000yrs. Given their longer history at altitude, Tibetans have had more
time to adapt.
The most robustly quantitative traits studied at altitude are
haemoglobin (Gassmann et al., 2019) and O2-carrying
capacity, and here there is agreement. Tibetans have a higher resting
ventilation but lower arterial O2 content than Andean or
Han Chinese migrants and are arguably the most hypoxic of the
high-altitude populations commonly studied. They also run lower
haemoglobin concentrations, by around 1g/dl compared to Han Chinese at
the same elevation. Han Chinese at the same altitude.
Accurate cardiopulmonary phenotyping in the field is more challenging. A
widely held view is that Tibetans are more resistant to HAPH and there
is a small but persuasive body of data in support of this. An early
study of 5 Tibetans who underwent direct cardiac catherization at ≥3600
m reported PAP measurements in the same range as those measured in
populations at sea level and minimal change in PVR when those subjects
exposed to greater hypoxia (Groves et al., 1993). Related to this,
histology of lung specimens from deceased Himalayan residents show no
remodelling of small pulmonary arteries (Gupta, Rao, Anand, Banerjee &
Boparai, 1992). More recent studies of ethnic Tibetans in a UK
laboratory using Doppler echocardiography found a blunted pulmonary
vascular response to both acute (minutes) and sustained (8 h) hypoxia
compared to Han Chinese (Petousi et al., 2014). Also supportive is the
low prevalence of chronic mountain sickness in Tibetans compared to Han
Chinese or Peruvian Quechuas. At odds with these observations is the
previously mentioned meta-analysis where the echocardiography derived
PAP pressures in Tibetans living between 3,600 and 4,350 m were similar
to those of Andeans and Caucasians at the same elevation (Soria, Egger,
Scherrer, Bender & Rimoldi, 2016). That Tibetans maintain a similar
resting PAP to, say, Andeans despite lower arterial oxygen levels
supports the concept that they are more resistant, but the marked
overlap in distribution of measurements in the different populations
puts that concept in context. The relative resistance of the Tibetan
pulmonary vascular bed to a hypoxia-induced rise in PAP may be more
pronounced at higher altitudes (e.g. >5,000 m), but here
there are few data. It is worth noting that the measurements of PAP at
altitude show a wider distribution than those taken at lower altitude
and comparing extremes of response within a population can be
informative (Wilkins et al., 2014).