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).