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Padhy, Gayatri, Anamika Gangwar, Manish Sharma, Kalpana Bhargava, and Niroj Kumar Sethy. Plasma proteomics of Ladakhi natives reveal functional regulation between renin-angiotensin system and eNOS-cGMP pathway. High Alt Med Biol. 18:27-36, 2017.-Humans have been living in high altitudes for more than 25,000 years but the molecular pathways promoting survival and performance in these extreme environments are not well elucidated. In an attempt to understand human adaptation to high altitudes, we used two-dimensional gel electrophoresis combined with MALDI-TOF/TOF to identify plasma proteins and associated pathways of ethnic Ladakhi natives residing at 3520 m. This resulted in the identification of 36 differential proteins compared with sea-level individuals. Proteins belonging to coagulation cascade and complement activation were found to be less abundant in Ladakhi natives. Interestingly, we observed lower abundance of angiotensinogen (ANGT) and subsequent analysis also revealed lower levels of both ANGT and angiotensin II (Ang II) in Ladakhi natives. Concomitantly, we observed elevated levels of eNOS, phosphorylated eNOS (Ser1177), and plasma biomarkers for nitric oxide (NO) production (nitrate and nitrite) and availability (cGMP). These results suggest that functional interplay between renin-angiotensin system and NO-cGMP pathway contributes to the hypoxia adaptation in Ladakhi natives. These findings will augment the present understanding of higher NO and NO-derived metabolite availability during human adaptation to high altitude.

The aim of this study was to evaluate the prevalence of acute mountain sickness (AMS) among trekkers on Mount Kilimanjaro during the winter season of 2006-2007. A A total of 130 Finnish trekkers at Marungu route were asked to complete daily a Lake Louise self-report and clinical assessment score questionnaire with the help of a trainee Finnish guide during their trek to Kilimanjaro. A Lake Louise questionnaire score>or=3 indicated AMS. Altogether 112 mountaineers or travelers [54 men, 58 women, mean age 51+/-10 (SD) years] were studied. Fifty-nine travelers (53%) reached Gillman's Point or Uhuru Peak. The incidence of AMS among Finnish Kilimanjaro trekkers was 75%. The most common high altitude symptoms were headache, followed by sleeping problems and fatigue or weakness. The incidence of AMS is high among trekkers climbing Mount Kilimanjaro.The main reason for this seems to be rapid ascent. Kilimanjaro treks normally have a fixed timetable, and for commercial reasons there is little opportunity to spend extra days for acclimatization in the camps. Some contributing factors are preventable, so we recommend an educational program for all the trekking agencies that guide on this peak and, in particular, the Tanzania-based guiding agencies, which, typically, are driving these very fast ascent rates.

Since the beginning of the Himalayan climbing era, the anecdotal extraordinary physical performance at high altitude of Sherpas and Tibetans has intrigued scientists interested in altitude adaptation. These ethnic groups may have been living at high altitude for longer than any other population, and the hypothesis of a possible evolutionary genetic adaptation to altitude makes sense. Reviewed here is the evidence as to whether Tibetans are indeed better adapted for life and work at high altitude as compared to other populations and, if so, whether this better adaptation might be inborn. Tibetans, compared to lowlanders, maintain higher arterial oxygen saturation at rest and during exercise and show less loss of aerobic performance with increasing altitude. Tibetans have greater hypoxic and hypercapnic ventilatory responsiveness, larger lungs, better lung function, and greater lung diffusing capacity than lowlanders. Blood hemoglobin concentration is lower in Tibetans than in lowlanders or Andeans living at similar altitudes. Tibetans develop only minimal hypoxic pulmonary hypertension and have higher levels of exhaled nitric oxide than lowlanders or Andeans. Tibetans' sleep quality at altitude is better and they desaturate less at night. Several of these findings are also found in Tibetans born at low altitude when exposed for the first time to high altitude once adult. In conclusion, Tibetans indeed seem better adapted to life and work at high altitude, and this superior adaptation may very well be inborn, even though its exact genetic basis remains to be elucidated.

For the male inhabitants of La Paz, Bolivia (3200-4100 m), and other high altitude regions in America and Asia, chronic mountain sickness (CMS) is a major health problem. Since CMS was first described by Carlos Monge in the Peruvian Andes in 1925, numerous research papers have been devoted to this topic, but many unanswered questions still exist with respect to the beginning of the disease and its cause(s). The experience with CMS has shown that an excessively high hemoglobin concentration is not favorable for high altitude acclimatization, and the hypothesis of theoretically "optimal" hematocrit and "optimal" hemoglobin has been made. The calculated optimal hemoglobin concentration of 14.7 g/dL for resting men in the Andes is discussed as theoretical and not applicable in real life. The most frequent congenital and acquired heart diseases are discussed, such as patent ductus, atrial septum defect, ventricle septum defect among congenital heart diseases and the still very frequent rheumatic valve cardiopathies and Chagas disease as acquired cardiopathies. Among the typical acquired heart diseases of the high altitude dweller, special attention is given to chronic cor pulmonale as a consequence of severe CMS with pulmonary hypertension.

Highland population (HA) from the Andes, living above 3000 m, have a blunted ventilatory response to increasing hypoxia, breathe less compared to acclimatized newcomers, but more, compared to sea-level natives at sea level. Subjects with chronic mountain sickness (CMS) breathe like sea-level natives and have excessive erythrocytosis (EE). The respiratory stimulation that arises through the peripheral chemoreflex is modestly less in the CMS group when compared with the HA group at the same P(ET(O2)). With regard to CO(2) sensitivity, CMS subjects seem to have reset their central CO(2) chemoreceptors to operate around the sea-level resting P(ET(CO2)). Acetazolamide, an acidifying drug that increases the chemosensitivity of regions in the brain stem that contain CO(2)/H(+) sensitive neurons, partially reverses this phenomenon, thus, providing CMS subjects with the possibility to have high CO(2) changes, despite small changes in ventilation. However, the same type of adjustments of the breathing pattern established for Andeans has not been found necessarily in Asian humans and/or domestic animals nor in the various high altitude species studied. The differing time frames of exposure to hypoxia among the populations, as well as the reversibility of the different components of the respiratory process at sea level, provide key concepts concerning the importance of time at high altitude in the evolution of an appropriate breathing pattern.