Neonatal Oxygenation, Pulmonary Hypertension, and Evolutionary Adaptation to High Altitude (2013 Grover Conference series)

Abstract

Andeans and Tibetans have less altitude reduction in birth weight than do shorter-resident groups, but only Tibetans are protected from pulmonary hypertension and chronic mountain sickness (CMS). We hypothesized that differences in neonatal oxygenation were involved, with arterial O 2 saturation (SaO 2 ) being highest in Tibetans, intermediate in Andeans, and lowest in Han or Europeans, and that improved oxygenation in Andeans relative to Europeans was accompanied by a greater postnatal decline in systolic pulmonary arterial pressures (P pa sys ). We studied 41 healthy (36 Andeans, 5 Europeans) and 9 sick infants at 3,600 m in Bolivia. The SaO 2 in healthy babies was highest at 6-24 hours of postnatal age and then declined, whereas sick babies showed the opposite pattern. Compared to that of 30 Tibetan or Han infants studied previously at 3,600 m, SaO 2 was higher in Tibetans than in Han or Andeans during wakefulness and active or quiet sleep. Tibetans, as well as Andeans, had higher values than Han while feeding. The SaO 2 's of healthy Andeans and Europeans were similar and, like those of Tibetans, remained at 85% or above, whereas Han values dipped below 70%. Andean and European P pa sys values were above sea-level norms and higher in sick than in healthy babies, but right heart pressure decreased across 4-6 months in all groups. We concluded that Tibetans had better neonatal oxygenation than Andeans at 3,600 m but that, counter to our hypothesis, neither was SaO 2 higher nor P pa lower in Andean than in European infants. Further, longitudinal studies in these 4 groups are warranted to determine whether neonatal oxygenation influences susceptibility to high-altitude pulmonary hypertension and CMS later in life.Keywords: Andean, cardiopulmonary transition, Ethiopian, European, genetic adaptation, Han, hypoxia, Tibet. Studies at high altitude have long provided a useful model for persons interested in the pulmonary circulation. [1][2][3][4] While pulmonary arterial pressures (P pa 's) are generally elevated at high altitude, there is considerable population variation in both P pa and pulmonary circulation-related disorders such as chronic mountain sickness (CMS; Fig. 1A) 11,36 and subacute infantile mountain sickness. 37 Specifically, directly measured P pa and hypoxic pulmonary vasoconstrictor responses are lowest in Tibetans, intermediate in Andeans, and highest in European-derived residents of Colorado (Fig. 1B). Recent estimates using echocardiography also suggest intermediate values in Ethiopians. 15 While multiple factors contribute to the etiology of CMS and no well-controlled comparative epidemiological studies exist, a reduced prevalence among Tibetans is consistent with the lower hemoglobin levels seen in Tibetans, relative to Andeans, in multiple reports. [38][39][40] Tibetans are also protected, relative to Han, from subacute infantile mountain sickness, a syndrome characterized by severe pulmonary hypertension in 4-6-month-old infants that has also been reported in European-derived popul...

Altitude Adaptation: A Glimpse Through Various Lenses

“…Maternal adaptive gene copies of PRKAA1 are also associated with uterine artery diameter and metabolic homeostasis in Andeans due to a decrease in sleep-disordered breathing ( Julian et al, 2013), differences in ventilatory patterns , or other unexplored but possibly developmental and/ or genetically regulated phenomenon ). SaO 2 is also higher in Tibetan neonates compared to Andeans, who exhibit SaO 2 and pulmonary arterial pressures similar to European infants (Niermeyer et al, 2015). It remains to be seen if and how the ability to tolerate hypoxia during early developmental stages relates to distinct physiology in highland adults.…”

Human genetic adaptation to high altitudes: Current status and future prospects

“…Panel C presents data for the prevalence of chronic mountain sickness (CMS) as reported for persons of various ancestry groups residing at the altitudes shown. Figure is adapted from (Niermeyer et al, 2015) where the original references may be found.…”

Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans

“…Current physiological evidence suggests that selection in Andeans has targeted physiological systems other than the regulation of erythropoiesis. 28 For example, Andeans (as well as Tibetans) are protected from altitude-associated fetal growth restriction 29 partly because of the maintenance of high uterine artery blood flow, suggesting that vascular factors are likely to be part of the adaptive response in these populations. Another indication of the importance of vascular factors in altitude adaptation is the population variation in hypoxic pulmonary vasoconstrictor response.…”

“…Tibetans exhibit a minimal pressure rise in comparison with that present in lifelong Colorado high-altitude residents, and intermediate values are seen in Andeans and perhaps also Amhara Ethiopians. 29,30 Protection from hypoxic pulmonary hypertension is also evident in well-adapted high-altitude species such as the yak (Bos grunniens), llama (Lama glama), and viscacha (Lagidium peruanum), which in the case of bovine species, is most likely due to selection for EPAS1 variants that reduce HIF2a stability. 31 Several previous studies have analyzed genomic signals of high-altitude-related natural selection in Andeans as a means of investigating altitude adaptation.…”