Human Adaptation to High Altitude

Study aim A: Red cell mass and hypoxia:

Various forms of altitude training have been used to increase in particular endurance performance of elite athletes. The most commonly used approaches is either to live and train at altitude (Live high - train high; LHTH) or to live at high altitude while training at sea level (Live high - train low; LHTL). While it is generally accepted that the potential performance enhancing effects of LHTH and LHTL are mediated through a hypoxia dependent increase in red cell mass (1), this has never been demonstrated experimentally. In 2010 the investigators conducted the first placebo controlled double blinded LHTL study (supported with BASPO funding) with the clear aim to identify the mechanism(s) responsible for the performance enchantment following LHTL. In brief, for this reason 16 elite athletes (average VO2max ≈ 70 ml.kg.min) resided for 16 hours/day in either normoxia or at the stimulated altitude of 3000 m for four weeks. This protocol was chosen based on recent reviews by experts within the field (2). Despite this supposedly optimal setting the investigators did not find a single positive change induced by LHTL. To our big surprise and despite having measured VO2max, time trial performance, red cell mass, markers of erythropoiesis at a much higher frequency than in any other previous LHTL study they all remained unaffected by LHTL. Based on our experience within altitude physiology and studies including erythropoietin injections in humans, the investigators have begun to speculate if even 3 weeks of continuous altitude exposure is sufficient stimulus to increases red cell mass which is the cornerstone assumption for LHTL (1, 3). If this is not the case, then the scientific rationale to perform LHTL vanishes.

The initial determination of red cell mass at altitude dates 100 years back when Douglas (4) reported that 6 weeks of exposure to 2300 m altitude on the Gran Canaries did not increase red cell mass whereas htc did increase. Some 50 years later Lawrence (5) concluded that a true increase in red cell mass required several weeks (8) of altitude exposure (3800 m), whereas the decrease in plasma volume begins upon arrival. It should here be noted that they used a superb method to determine red cell mass: autologous red cells tagged with radioactive phosphorous, something that is not possible today. In 1964 Hannon (6) conducted his now classic study when he exposed 8 female and 8 males to 4300 m altitude for 9 full weeks. During the first month there was no increase in red cell mass, and over the next 5 weeks red cell mass only increased by 5% despite of continued iron supplementation. The method used in this particular study was autologous chromium-51-labbeled red cells, i.e. gold standard. Even at the severely high altitude of 5450 m (with no relevance for elite sport), Reynafarje (7) reported that 6 weeks are required for an increase in red cell volume. To follow up on all previous altitude studies is impossible here, but in a recent review Grover and Bärtsch (8) summarized these by stating that "True polycythemia develops when residence at high altitude (3800-4500m) extends over months to years". Thus, as compared to the altitude research done in the past in regards to red cell mass, mostly conducted with the use of techniques by far superior to those used today and at higher latitudes than applied in LHTL protocols, the proposal that LHTL should increase red cell mass seems at odds. It should be kept in mind however, that in most altitude studies it is difficult to isolate the effects to hypoxia, and also changes in temperature, nutritional intake and physical activity level are often a confounding factor.

Levine and Stray-Gundersen (3) were the first to report an increase in red cell mass following LHTL. After 3 weeks of LHTL at 2500 m they calculated RCV to be increased by 8% based on changes in plasma volume as derived by Evens Blue. Evens blue is a poor measure for changes in RCV since it rapidly leaks from the circulation, and the data should be taken with some caution. It is also interesting that an increase in RCV was only observed in 50% of the LHTL subjects. This does not exclude that the observed changes were simply not just the result of biological variation (9). In the 10 years following the first positive LHTL results the data could not be replicated. Especially the Australian research group lead by Chris Gore made huge efforts in this period but could not confirm that 3 weeks of LHTH or normobaric LHTL caused RCV to increase (10-16). From 2006 and onwards positive effects of LHTL have been reported on RCV, but the data are far from convincing. The research group of J.P. Richalet conducted a series of experiments in Premanon, and found red cell mass to increase in one study (17), but unchanged in another two studies (18, 19). J Wehrlin from the Bundesamt für Sport found three weeks of LHTL to increase RCV (20), but the study design is not clean as subjects from different disciplines served as control and treatment subjects. This is a problem since they were at different stages in their training season and it cannot be excluded that this does not affect RCV. Since the subjects were elite athletes competing at the international level it is also a pity that no anti-doping samples were collected in this subject's population. Chris Gore has for the last few years applied an unusual statistical approach and thereby reported what they call "marginal" increases in RCV following LHTL (21). This conclusion however cannot be drawn if using a standard accepted statistical approach. Thus, although it is generally accepted that LHTL may increase RCV, the picture is not as clear as expected, and the investigators argue that it is rather unlikely when comparing with the above mentioned chronic altitude exposure studies.

The main aim with this present study is to determine in a large study population (n=16) if continuous exposure to 3450 m altitude for four weeks increases red cell mass or not. The investigators have chosen this altitude because 1) In populations living permanently at this altitude, an elevated red cell volume has been reported as compared to their countrymen living near sea level, 2) If the investigators choose a lower altitude, and the investigators observe no increase in red cell mass the investigators would not be able to determine whether this was the consequence of a too low altitude or a too short exposure duration, 3) Exposure to much higher elevations may not be suitable for athletes.