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La ascendencia andina de gran altitud no protege contra el mal agudo de montana ni la hipoxemia arterial inducida por la altitud.

ASCENDENCIA ANDINA DE ALTA ALTITUDE NAO PROTEGER DA MAL AGUDO DE MONTANHA E HIPOXEMIA ARTERIAL INDUCIDA PELA ALTITUDE

ANDEAN HIGH-ALTITUDE ANCESTRY DOES NOT PROTECT FROM ACUTE MOUNTAIN SICKNESS AND ALTITUDE-INDUCED ARTERIAL HYPOXEMIA

Introduction

High altitude hypoxia represents a unique environmental stressor that in altitude populations may lead to adaptive changes which attenuate altitude-induced alterations of homeostasis and confer protection against altitude-induced diseases (Beall, 2006; Maclnnis et. al, 2010). In high-altitude populations, this ability to adapt could be related genetic factors acquired during evolutionary adaptation and/or to changes ocurred during foetal development and growth (Brutsaert et. al, 2004). Travel to high-altitude destinations above 2500masl for recreational motifs exposes several hundred thousands of non-acclimatized tourists to arterial hypoxemia and related medical risks. Acute mountain sickness (AMS), a syndrome of nonspecific symptoms including headache, fatigue, anorexia and nausea, dizziness, and sleep disturbance, is by far the most frequent problem (Imray et. al., 2010). While there is general agreement that speed of ascent, absolute altitude, and prior acclimatization are determinants of AMS susceptibility, genetic factors may also play an important role (MacInnis et. al, 2010).

We speculated that adaptive mechanisms protect Aymara children and adolescents against AMS and altitude-induced hypoxemia compared to non-Aymara children and adolescents. To eliminate the potentially important confounding protective effects related to developmental changes induced by being born and/or living at high altitude, we studied children and adolescents of highland ancestry who were born and had been permanently living at sea level. In a prospective and controlled study, we assessed the prevalence of AMS and measured arterial oxygen saturation during the first 48h after rapid ascent by bus from sea level to 3500masl in non-acclimatized Aymara and nonAymara children and adolescents born and permanently living at sea level.

Materials and Methods

Study group

Between March and August 2012, we studied 91 healthy Chilean children and adolescents who were born and had been permanently living at sea level. Of the participants, 37 were Aymaras (13.9-17.7 years old, 18 girls and 19 boys) and 54 were nonAymaras (13.7-17.5 years old, 26 girls and 28 boys). Participants were considered Aymaras if both grandfathers and both grandmothers had family names of Aymara origin, as Fuentes et. al. (2014) have shown, based on ancestry-informative marker (AIM) estimates, that individuals with two Aymara surnames in our study region (Arica-Parinacota region in Northern Chile) harbor on average 99.68 [+ or -] 0.49% of American genetic background. None of the participants had slept at high altitude (>2500m) during the last six months prior to the study, and none was taking any medication during the study. The experimental protocol was approved by the review board on human investigation of the University of Tarapaca and all parents provided written informed consent.

Based on data published by Moraga et. al. (2008) assuming that a difference of 50% in the prevalence of AMS between Aymara and non-Aymara participants would be clinically relevant, and considering an alpha error of 5% and a desired statistical power of 90%, we calculated that the minimal sample size of each group should be n=30 to test our hypothesis. With regard to arterial oxygen saturation (Sa02) assuming an Sa02 of 82.2 [+ or -] 3.2% on the day of arrival in non-Aymara and a 3% higher value in Aymaras to be clinically significant, and considering an alpha error of 5% and a desired statistical power of 90%, we calculated that the minimal sample size of each group should be n=25 to test our hypothesis.

The participants ascended in mixed groups (n=10-50) of Aymaras and non-Aymaras with a 2.5h bus ride that took them from sea level (Arica, Chile) to the high-altitude research station at 3500masl (Putre, Chile), where they arrived in the early afternoon. They then spent two days and two nights at the research station. During the stay, all participants received the same diet and care was taken to assure an adequate fluid intake. Physical activity was standardized. On the day of arrival, the participants rested quietly and visited the village of Putre. On the second day, participants were offered the possibility to participate in recreational activities of moderate physical intensity. On the morning before descent the participants remained within the research station.

Evaluation for acute mountain sickness (AMS)

The presence of AMS was assessed on the evening of the day of arrival and on the two following mornings (i.e. 6, 18 and 42h after arrival at high altitude) with a Spanish version of the Lake Louise self-assessment questionnaire (Imray et. al., 2010) under the supervision of a trained examiner, as described previously (Bloch et. al., 2009; Rexhaj et. al., 2011). Briefly, for each of the five items (headache, gastrointestinal symptoms, fatigue, dizziness and sleep disturbance), the participants noted a score between 0 and 3, with 0 indicating the absence of the symptom; 1, mild symptoms; 2, moderate symptoms; and 3, severe, incapacitating symptoms. Participants were considered suffering from AMS if they were experiencing headache (score [greater than or equal to] 1), the condition sine qua non for the diagnosis of AMS, and the total score on the self-assessment questionnaire was [greater than or equal to] 3, the maximal score for the questionnaire being 15 (Imray et. ai, 2010). After the assessment, participants with AMS suffering from headache were treated with acetaminophen, if needed.

Measurement, of arterial oxygen saturation

Trans-cutaneous arterial saturation and heart rate were measured at a fingertip with a pulse oxymeter (OxiMax[R]N-595, Nellcor, Pleasantn, CA) before each evaluation for AMS.

Statistical analysis

Statistical analysis was done with the Graphpad Prism 5 software package (GraphPad Software Inc, San Diego, CA, USA). Unpaired 2-tailed t tests were used for group comparisons of continuous variables. For comparisons of categorical variables the Fischer exact test was used. Data are expressed as mean with standard devia tion (SD). A p value <0.05 was considered to indicate statistical significance.

Results

All participants completed the daily AMS questionnaires. Table I shows the mean and standard deviation (SD) of the age, weight, height and body mass index (BMI) of the participants. It can be seen that there are no significant differences between the Aymaras and non-Aymaras children and adolescents in the study.

At low altitude, the AMS score was equal to 0 in all participants.

Figure 1 shows that in both Aymaras and non-Aymaras, the large majority of cases (roughly 80%) of AMS developed during the first 6h at high altitude and that the total prevalence of AMS, as well its prevalence at the three time points of the study, was not statistically different (all p's >0.09) between Aymaras and non-Aymaras. On the evening of the day of arrival (i.e. 6h after arrival at high altitude), 18 of the 37 Aymaras (49%) and 31 of the 54 nonAymaras (57%) (p=0.52, Aymaras vs non-Aymaras) suffered from headache (the conditio sine qua non for the diagnosis of AMS) and had a symptom score greater or equal to 3 (range 3 to 9). On the morning of the next day (18h after arrival at high altitude) AMS had resolved for 10 of the 18 Aymaras and for 11 of the 31 non-Aymaras suffering from AMS on the evening of the first day, and new AMS developed in 4 Aymaras and 8 non-Aymaras (range of scores 3 to 9), resulting in 12 Aymaras (32%) and 28 non-Aymaras (52%) suffering from AMS at this time point. During the next 24h at high altitude, the prevalence of AMS decreased markedly in both groups, such that on the morning of the third day at high altitude (42h after arrival), only 7 (19%) Aymaras and 12 (23%) non-Aymaras had symptoms of AMS (range of scores 3 to 7).

The overall prevalence of AMS among the participants was 67% (61/91). In 50% (30 of 61) of the participants suffering from AMS, the symptoms lasted for less than 24h. In 46 subjects the symptoms disappeared spontaneously, whereas the remaining 15 were given acetaminophen for headache. Of the 15 participants receiving drug treatment, 13 (6 Aymaras, 7 non-Aymaras) were treated 6h after arrival at high altitude. The symptoms responded rapidly to this symptomatic treatment.

Throughout the study, arterial oxygen saturation was similar in Aymaras and nonAymaras (Table II) it was also not different between the participants who suffered from AMS and those who did not: 6h (82.8 (SD 4.9) vs 82.7% (4.5), p=0.97), 18h (86.9 (4.1) vs 87.6% (3.1), p=0.41) and 42h (89.3 (3.40) vs 89.9% (2.5), p=0.41).

Among the participants who suffered from AMS, the disease was mild and comparable in the two groups; for a theoretically maximal score of 15, the mean Lake Louise score was 4.7 (SD 1.8) in Aymaras and 4.6 (1.7) in non-Aymaras (p=0.72 Aymaras vs nonAymaras). There was no difference in the severity of the symptoms between the two genders (mean Lake Louise score 4.6 (1.7) in girls, and 4.7 (1.5) in boys, p= 0.84 girls vs boys) and there existed no significant differences in the frequency of the symptoms making up for AMS between Aymaras and non-Aymaras.

Discussion

AMS is a major health problem typically occurring shortly after arrival at high altitude (Hackett and Roach, 2001; Bloch et al., 2009). While speed of ascent and absolute altitude are established determinants of its occurrence (Hackett and Roach, 2001; Imray et al., 2010), high altitude ancestry, by protecting against this problem, has also been suggested to play a role (Beall, 2000; MacInnis et al., 2010), but there is no information from controlled studies. This is the first controlled prospective study to examine the effects of adaptive changes related to Andean high altitude ancestry per se, on altitude-induced arterial hypoxemia and the prevalence, time-course and severity of AMS. The main new finding was that both the prevalence and severity of AMS, and the altitude-induced arterial hypoxemia during the first 3 days after rapid ascent to 3500m, were not different between non-acclimatized Aymara and non-Aymara children and adolescents who were born and had been permanently living at sea level. These findings strongly suggest that Andean high altitude ancestry does not confer important protection against altitude-induced hypoxemia and AMS, the most frequent altitude related medical problem.

An important feature of the present study was that all participants were born and had been permanently living at low altitude. This allowed to rule out the potentially important confounding protective effects conferred by developmental changes induced by being born and/or by living at high altitude, and to study exclusively the protective effects conferred by adaptive changes related to high altitude ancestry. We found that Aymara high altitude ancestry had no significant effect on AMS prevalence or severity at any of the three time points of the study. Recent controlled studies of the prevalence and severity of AMS in non-acclimatized European children in the Alps (Bloch et al., 2009; Rexhaj et al., 2011) using similar speed of ascent, absolute altitude and time of observation allow some additional comparisons. First, the prevalence of AMS (total prevalence between 15 and 38%) in European children of similar age was similar (or tended to be lower) to the one observed in Aymara children in the present study, strengthening the interpretation that Aymaras do not appear to be protected from this problem. Second, the overall and day-today prevalence of AMS in these European children was significantly lower than the one observed in non-Aymara children in the present study, indicating that the inability to demonstrate a protective effect of Aymara ancestry against AMS in the present studies does not appear to be related to an unexpectedly low prevalence of this problem in the non-Aymara controls. Third, this controlled study allowed to exclude the influence of confounding factors known to facilitate AMS, such as exercise (Roach et al., 2000). Taken together, these comparisons further strengthen the conclusion that Aymara high altitude ancestry per se does not confer protection against AMS. In line with this interpretation, we found that Aymara ancestry also did not attenuate the altitude-induced decrease of arterial oxygenation, since arterial oxygen saturation was comparable in the two groups. Finally, it is likely that the present findings in Aymaras also are valid for Quechuas, the other Andean high altitude population, since there is evidence that genes facilitating high altitude adaptation are better preserved in the former (GayaVidal et al., 2011). Further study is needed to examine whether Tibetan or Ethiopian high-altitude ancestry that may have resulted in adaptive changes distinct from those in Andean high altitude populations (Beall, 2000; MacInnis et al., 2010) also does not confer such protection. Observational data comparing AMS prevalence in adult Tibetans and Han Chinese suggest that in adults, Tibetan ancestry may have a protective effect (Li et al., 2011).

The time course of AMS was also comparable in the two groups, and, as in previous studies (Bloch et al., 2009; Rexhaj et al., 2011), the majority of cases of AMS developed during the first 6h after arrival at high altitude. Moreover, in line with previous findings in children at a similar study altitude in the Alps (Bloch et al., 2009; Rexhaj et al., 2011) the disease was relatively mild (mean symptom score 4.7 and 4.6, of a theoretical maximum of 15, in Aymaras and Europeans respectively) and symptoms resolved rapidly, in the majority of cases spontaneously, in the remaining after administration of symptomatic treatment. None of the participants needed to be evacuated to low altitude and in none AMS progressed to life-threatening high-altitude cerebral or pulmonary oedema (Hackett and Roach, 2001; Sartori et al., 2010; Scherrer et al., 2010). Collectively, these observations suggest that rapid ascent of non-acclimatized healthy young persons to this study altitude appears to be safe, since it rarely induces these life-threatening medical complications.

In the present study, we used surname analysis of both grand-parents as a proxy of genetic ancestry in Aymara participants and did not assess potential European admixture by assessing genetic markers. Recent data using ancestry informative markers to estimate individual genetic ancestry suggest that in northern Chile altitude ancestral assessment based on Aymara surnames appears surprisingly reliable (Fuentes et al., 2014; Rothhammer et al., 2015). In line with these observations, in Peruvian Quechuas born at sea level, European admixture assessed by ancestry-informative genetic markers was low (<10%) and had no detectable effect on the exercise phenotype during acute high altitude exposure (Brutsaert et al., 2004); most interestingly, this study found that Quechuas born and raised at high altitude had better exercise performances than their sea level counterparts, emphasizing the importance of environmental developmental adaptation to high altitude rather than evolutionary genetic adaptation in this setting.

Conclusion

In conclusion, here we show for the very first time that evolutionary adaptive changes related to Aymara high-altitude ancestry per se do not confer protection against acute mountain sickness and altitude-induced arterial hypoxemia during rapid exposure to 3500masl.

Disclosures

Funding sources: Universidad de Tarapaca (Project No. 4712/12), Swiss National Science Foundation and Placide Nicod Foundation. Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. Conflict of Interest: The authors have no conflict of interest to disclose.

ACKNOWLEDGMENT S

The authors are indebted to the study participants, to the Chilean Army for providing the facilities in Putre, to the Principals of Liceo A1, Liceo B4 and Liceo Politecnico and the Biology Teachers Lizette Melendez and Lucia Castro for helping with the recruitment of participants, and to CONADI (National Corporation for Indigenous Development) for help with the identification of Aymara surnames.

REFERENCES

Beall CM (2000) Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Human Biol. 72: 201-228.

Beall CM (2006) Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Integr. Comp. Biol. 46: 18-24. Bloch J, Duplain H, Rimoldi SF, Stuber T, Kriemler S, Allemann Y, Sartori C , Scherrer U (2009) Prevalence and time course of acute mountain sickness in older children and adolescents after rapid ascent to 3450 meters. Pediatrics 123: 1-5.

Brutsaert TD, Parra E, Shriver M, Gamboa A, Palacios JA, Rivera M, Rodriguez I, Leon-Velarde F (2004) Effects of birthplace and individual genetic admixture on lung volume and exercise phenotypes of Peruvian Quechua. Am. J. Phys. Anthropol. 123: 390-398.

Fuentes M, Pulgar I, Gallo C, Bortolini M-C, Canizales-Quinteros S, Bedoya G, GonzalezJose R, Ruiz-Linares A, Rothhammer F (2014) Gene geography of Chile. Regional distribution of American, European an African genetic contributions. Rev. Med. Chil. 142: 281-289.

Gaya Vidal M, Moral P, Saenz Ruales N, Gerbault P, Tonasso L, Villena M, Vasquez R, Bravi CM, Dugoujon JM (2011) mtDNA and Y-chromosome diversity in Aymaras and Quechuas from Bolivia: different stories and special genetic traits of the Andean Altiplano populations. Am. J. Phys. Anthropol. 145: 215-230.

Hackett PH, Roach RC (2001) High-altitude illness. N. Engl. J. Med. 345: 107-114.

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MacInnis MJ, Koehler MS, Rupert JL (2010) Evidence for a genetic basis for altitude illness: 2010 update. High Alt. Med. Biol. 11: 349-368.

Moraga FA, Pedreros CP, Rodriguez CE (2008) Acute mountain sickness in children and their parents after rapid ascent to 3500 m (Putre, Chile). Wildern. Environ. Med. 19: 287-292.

Rexhaj E, Garcin S, Rimoldi SF, Duplain H, Stuber T, Allemann

Y, Sartori C, Scherrer U (2011) Reproducibility of acute mountain sickness in children and adults: a prospective study. Pediatrics 127: 1445-1448.

Roach RC, Maes D, Sandoval D, Robergs RA, Icenogle M, Hinghofer-Szalkay H, Lium D, Loeppky JA (2000) Exercise exacerbates acute mountain sickness at simulated high altitude. J. Appl. Physiol. 88: 581-585.

Rothhammer F, Fuentes-Guajardo M, Chakraborty R, Bermejo J, Dittmar M (2015) Neonatal Variables, Altitude of Residence and Aymara Ancestry in Northen Chile. PLos One. 10(4): e0121834.

Sartori C, Rimoldi SF, Scherrer U (2010) Lung fluid movements in hypoxia. Prog. Cardiovasc. Dis. 52: 493-499.

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Received: 03/22/2016. Modified: 12/09/2016. Accepted: 12/12/2016.

Gertrudis Cabello. Doctor in Genetics and Cell Biology, Universidad Autonoma de Madrid, Spain. Professor, Universidad de Tarapaca, Chile. Addres: Departamento de Biologia, Facultad de Ciencias, Universidad de Tarapaca, Velasquez 1775 Arica, Chile. e-mail: gertrudis.cabello(r) gmail.com

Emilio Farina. Pharmaceutical Chemist, Universidad de Chile. Master in Biological Sciences, Universidad de Tarapaca, Arica, Chile.

Alejandro Jeldres. Physician, Universidad de Chile.

Stefano F. Rimoldi. Doctor of Medicine, University of Bern, Switzerland. Lecturer, Cardiology Hospital, Bern, Switzerland. Department of Cardiology and Clinical Research, Inselspital, University.

Urs Scherrer. Doctor of Medicine, University of Zurich, Switzerland. Professor, University of Lausanne and Bern University, Switzerland. Address: Department of Cardiology and Clinical Research, Inselspital, 3010 Bern. Switzerland, e-mail: urs.scherrer2@insel.ch
TABLE I
MEAN AND STANDARD DEVIATION (SD)
OF AGE, WEIGH AND BODY MASS INDEX (BMI)
OF THE PARTICIPANTS

                             Aymara           Non-Aymara      Sig. p
                        mean (SD) (n=37)   mean (SD) (n=54)

Age (years)                14.8 (0.7)         14.8 (0.6)       1.0
Weight (kg)               63.5 (11.9)        63.5 (14.8)       0.99
Stature (cm)              160.0 (7.8)         164 (8.3)        0.40
BMI (kg x [m.sup.2])       24.7 (3.7)         23.2 (4.0)       0.16

TABLE II
ARTERIAL OXYGEN SATURATION IN AYMARAS AND
NON-AYMARAS AT SEA LEVEL AND IN THE HEIGHT

Time    Height          Aymara            Non-Aymara
(h)     (masl)
                  n     SaO2 % (SD)    n      SaO2 % (SD)    Sig p

0          20     37    98.1 (1.5)     54     98.4 (0.6)     0.15
6        3500     37    82.9 (4.1)     54     82.5 (5.2)     0.73
18       3500     37    87.9 (3.2)     54     86.6 (4.2)     0.13
42       3500     36    89.7 (4.5)     53     89.3 (2.9)     0.64
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Title Annotation:texto en ingles
Author:Cabello, Gertrudis; Farina, Emilio; Jeldres, Alejandro; Rimoldi, Stefano F.; Scherrer, Urs
Publication:Interciencia
Date:Jan 1, 2017
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