AltitudeOmics: Rapid Hemoglobin Mass Alterations with Early Acclimatization to and De-Acclimatization from 5260 m in Healthy Humans

<div><p>It is classically thought that increases in hemoglobin mass (Hbmass) take several weeks to develop upon ascent to high altitude and are lost gradually following descent. However, the early time course of these erythropoietic adaptations has not been thoroughly investigated and data are lacking at elevations greater than 5000 m, where the hypoxic stimulus is dramatically increased. As part of the AltitudeOmics project, we examined Hbmass in healthy men and women at sea level (SL) and 5260 m following 1, 7, and 16 days of high altitude exposure (ALT1/ALT7/ALT16). Subjects were also studied upon return to 5260 m following descent to 1525 m for either 7 or 21 days. Compared to SL, absolute Hbmass was not different at ALT1 but increased by 3.7±5.8% (mean ± SD; n = 20; p<0.01) at ALT7 and 7.6±6.6% (n = 21; p<0.001) at ALT16. Following descent to 1525 m, Hbmass was reduced compared to ALT16 (−6.0±3.7%; n = 20; p = 0.001) and not different compared to SL, with no difference in the loss in Hbmass between groups that descended for 7 (−6.3±3.0%; n = 13) versus 21 days (−5.7±5.0; n = 7). The loss in Hbmass following 7 days at 1525 m was correlated with an increase in serum ferritin (r = −0.64; n = 13; p<0.05), suggesting increased red blood cell destruction. Our novel findings demonstrate that Hbmass increases within 7 days of ascent to 5260 m but that the altitude-induced Hbmass adaptation is lost within 7 days of descent to 1525 m. The rapid time course of these adaptations contrasts with the classical dogma, suggesting the need to further examine mechanisms responsible for Hbmass adaptations in response to severe hypoxia.</p></div

Hemoglobin mass in men and women during 16 days high altitude acclimatization.

<p>A) Time course of changes in absolute Hbmass. Data are presented as mean ± SD, with the number of men and women tested at each time indicated below the x-axis. †Significantly different from sea level (p<0.05; main effect of time). The percent changes were not significantly different between men and women (p>0.05). B) Relationship between serum ferritin level upon arrival at high altitude and the percent change in absolute Hbmass following 16 days at high altitude. Two subjects had missing ferritin data at ALT1 and their Hbmass data were excluded from this graph. There was no correlation between initial ferritin level upon arrival at altitude and the percent change in absolute Hbmass during high altitude acclimatization (r = 0.33; n = 19; p = 0.16).</p

Hematological adaptations during 16 days high altitude acclimatization in healthy men and women.

<p>Data are presented as mean ± SD with the number of subjects indicated in parentheses. Linear mixed model statistical analyses were performed to examine the effects of sex, time (with SL as the reference) and a sex × time interaction. Paired t-tests were performed to compare ALT7 with ALT16. Effects were accepted as significant when p≤0.05.</p><p>Hematological adaptations during 16 days high altitude acclimatization in healthy men and women.</p

Estimate of the increase in hemoglobin mass produced during 16 days high altitude acclimatization determined from the measured Hbmass increase above sea level baseline plus the calculated Hbmass loss due to blood sampling.

<p>Panel A represents the absolute increase in Hbmass (g) produced. Panel B represents the percent increase in Hbmass produced. Data are presented as mean ± SD. Upward SD bars represent the SD of the increase in Hbmass measured above baseline and the downward SD bars represent the SD of calculated Hbmass loss due to blood sampling.</p

Hematological parameters at sea level and the first day of exposure to 5260 m.

<p>Data are presented as mean ± SD with the number of subjects (M,W) indicated in parentheses. This table only includes data for subjects with measures at both time points so that the effect of acute altitude on Hbmass and BV parameters can be distinguished from the inter-individual variation. Paired t-tests were performed for each parameter and none of the differences were statistically significant (all p>0.05).</p><p>Hematological parameters at sea level and the first day of exposure to 5260 m.</p

Change in hemoglobin mass following descent from high altitude to low altitude.

<p>Subjects were tested at high altitude at the end of a 16 day acclimatization period and upon return to high altitude after descent to low altitude (1525 m) for either 7 (POST7; n = 13) or 21 days (POST21; n = 7). Data are presented as mean ± SD. A) Changes in Hbmass. † Significantly different from POST (p<0.05; main effect of time). There were no significant differences between the POST7 and POST21 groups or between POST and SL (p>0.05). B) Relationship between changes in Hbmass following 16 days high altitude acclimatization and changes in Hbmass following descent to low altitude. C) Relationship between changes in Hbmass and changes in serum ferritin following descent to low altitude for 7 days.</p

AltitudeOmics: The Integrative Physiology of Human Acclimatization to Hypobaric Hypoxia and Its Retention upon Reascent

<div><p>An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1) to describe a phenotype for successful acclimatization and assess its retention and 2) use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS), cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (n = 14) or 21 (n = 7) days at 1525 m. At 16 days at 5260 m we observed: 1) increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO₂ rose 9±4 mmHg to 45±4 while PaCO₂ dropped a further 6±3 mmHg to 21±3, and [Hb] rose 1.8±0.7 g/dL to 16±2 g/dL; 2) no AMS; 3) improved cognitive function; and 4) improved exercise performance by 8±8% (all changes p<0.01). Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention.</p></div

Timeline for AltitudeOmics Studies.

<p>Each subject completed this study timeline, with n = 14 staying at low altitude for POST7 and n = 7 staying at low altitude for POST21. Subjects flew from the USA to Bolivia aboard commercial aircraft with no recording of barometric pressure during the flight; the profile for travel in the figure is therefore approximate.</p

Neurocognitive Function During Acclimatization and Upon Reascent.

<p>Five tests of cognitive function revealed marked decrements in performance from SL to ALT1, and improvement back to sea level values by ALT16. Code Substitution—Simultaneous and Match to Sample retained levels found at ALT16 on POST7, while Simple Reaction Time-1, Simple Reaction Time-2, and Procedural Reaction Time essentially reflected a loss of during acclimatization upon reascent at POST7. None of the cognitive function tests showed any retention of acclimatization at POST21. (tp  =  throughput  =  mean number of correct responses made within one min). *Significantly different than SL (p<0.01); ^†significantly different vs. ALT1 (p<0.01); ^‡significantly different vs. ALT16 (p<0.01).</p

General Subject Characteristics.

<p>Height (HT); Weight (WT); Body Mass Index (BMI).</p