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The Journal of Physiology logoLink to The Journal of Physiology
. 2015 Jun 25;593(Pt 14):3207–3218. doi: 10.1113/JP270518

Low haemoglobin concentration in Tibetan males is associated with greater high-altitude exercise capacity

T S Simonson 1,✉, G Wei 2, H E Wagner 1, T Wuren 2, G Qin 2, M Yan 2, P D Wagner 1, R L Ge 2
PMCID: PMC4532538  PMID: 25988759

Abstract

Tibetans living at high altitude have adapted genetically such that many display a low erythropoietic response, resulting in near sea-level haemoglobin (Hb) concentration. We hypothesized that absence of the erythropoietic response would be associated with greater exercise capacity compared to those with high [Hb] as a result of beneficial changes in oxygen transport. We measured, in 21 Tibetan males with [Hb] ranging from 15.2 g dl−1 to 22.9 g dl−1 (9.4 mmol l−1 to 14.2 mmol l−1), [Hb], ventilation, volumes of O2 and CO2 utilized at peak exercise (Inline graphic and Inline graphic), heart rate, cardiac output and arterial blood gas variables at peak exercise on a cycle ergometer at ∼4200 m. Lung and muscle O2 diffusional conductances were computed from these measurements. [Hb] was related (negatively) to Inline graphic kg–1 (r = −0.45, P< 0.05), cardiac output kg–1 (QT kg–1, r = −0.54, P < 0.02), and O2 diffusion capacity in muscle (DM kg–1, r = −0.44, P<0.05), but was unrelated to ventilation, arterial partial pressure of O2 (Inline graphic) or pulmonary diffusing capacity. Using multiple linear regression, variance in peak Inline graphic kg–1 was primarily attributed to QT, DM, and Inline graphic (R2 = 0.88). However, variance in pulmonary gas exchange played essentially no role in determining peak Inline graphic. These results (1) show higher exercise capacity in Tibetans without the erythropoietic response, supported mostly by cardiac and muscle O2 transport capacity and ventilation rather than pulmonary adaptations, and (2) support the emerging hypothesis that the polycythaemia of altitude, normally a beneficial response to low cellular Inline graphic, may become maladaptive if excessively elevated under chronic hypoxia. The cause and effect relationships among [Hb], QT, DM, and Inline graphic remain to be elucidated.

Key points

  • We hypothesized that sea-level range haemoglobin concentration ([Hb]) at altitude, previously linked with adaptive genetic factors in Tibetans, would be associated with greater exercise capacity, explained by changes in steps of the oxygen transport system in this population.

  • In 21 Tibetan and 9 Han Chinese males resident at 4200–4300 m, we measured [Hb], ventilation, volumes of O2 and CO2 utilized at peak exercise (Inline graphic and Inline graphic), heart rate, cardiac output and arterial blood gas variables at peak exercise on a cycle ergometer and determined oxygen (O2) diffusion capacity in lung and muscle.

  • Tibetans with low [Hb] exhibit greater peak Inline graphic kg–1, which was explained mostly by variation in cardiac output, ventilation and O2 diffusional conductances in muscle.

  • These results suggest that polycythaemia may be an excessive response to low Inline graphic at altitude.

Introduction

Humans have occupied the Tibetan highlands for hundreds of generations despite the unavoidable stress of high-altitude hypoxia and exhibit a set of unique physiological traits distinct from native highland counterparts and lowlanders at altitude (Moore, 2001; Beall, 2007; Petousi & Robbins, 2014). One such difference is that many Tibetans exhibit haemoglobin concentrations ([Hb]) within the range expected at sea level, also common among Amhara Ethiopians (Beall et al. 2002, 2006; Alkorta-Aranburu et al. 2012), while healthy sojourners and Andeans at high altitude exhibit polycythaemia (Winslow et al. 1989; Beall et al. 1998; Beall, 2000, 2007; Moore, 2001; Wu et al. 2005). Polycythaemia is thought to enhance oxygenation to tissues by carrying more O2 per millilitre of blood and thus might be expected to enhance O2 transport and support exercise capacity. However, acute experimental studies dispute this hypothesis (Calbet et al. 2002), and excessive [Hb] is associated with severe complications and disease such as chronic mountain sickness (CMS) (Monge, 1976; Monge et al. 1992; Vargas & Spielvogel, 2006b) suggesting excessive [Hb] at high altitude in response to high-altitude hypoxia may become maladaptive.

The physiological significance of a markedly low in many Tibetans has not been established, particularly with respect to exercise capacity and steps of the O2 transport system necessary to support exercise. Previous studies show that Tibetan natives, compared to other high-altitude residents, exhibit greater exercise capacity at high altitude (Sun et al. 1990; Ge et al. 1994; Ge, 1995; Niu et al. 1995; Chen et al. 1997, Moore et al. 1992), although this is not observed in all studies (Kayser et al. 1994). If and how these characteristics relate to [Hb] and/or genetic variation in Tibetans is unknown.

Progress in genomics suggests that several genes underlie Tibetan adaptation to high altitude (Simonson et al. 2012; Petousi & Robbins, 2014). Low, sea-level range, [Hb] among Tibetans at altitude is associated with adaptive changes in hypoxia-related genes (Beall et al. 2010; Simonson et al. 2010), suggesting that this reduction, at least in part, has a genetic basis. Whether [Hb] is secondary to other physiological changes at one or more steps of the O2 transport cascade or rather a direct target of adaptation (e.g. [Hb] is specifically targeted for reduction to ameliorate negative effects associated with high blood viscosity) is unknown (Moore, 2001; Beall et al. 2004; Leon-Velarde et al. 2005; Julian et al. 2007; Storz, 2010; Storz et al. 2010).

Considering that adaptive genetic factors in Tibetans are associated with non-elevated [Hb] at altitude, we challenged traditional thoughts that polycythaemia at altitude improves O2 availability and thus exercise capacity. By making use of the natural variation in their [Hb], we tested the hypothesis that this relatively low [Hb] in Tibetans is associated with higher exercise capacity at altitude, which, if found to be true, would imply that the usual polycythaemic response to altitude seen in most populations may be a consequence of the erythropoeitic system’s usual, and generally beneficial, response to cellular hypoxia, such as after blood loss. If the hypothesis is correct, then one or more steps of the O2 transport pathway must be of greater capacity in Tibetans with lower [Hb], which directed the focus of this study. Such differences in the O2 transport pathway may reflect a suite of sequential adaptive events in this population, some which are related to [Hb].

Methods

Subjects

Twenty-one healthy, non-athletic, but active, non-smoking Tibetan male subjects aged 18–40 who were permanent residents at elevations >4000 m and nine Han Chinese males who had been resident above 4000 m for more than 2 years were recruited for this study and another study (Table2; additional information is reported in Table2 of Simonson et al. 2014) and screened for exercise studies as previously described (Simonson et al. 2014). No subjects exhibited illness, including chronic mountain sickness, as only screened healthy subjects were eligible to participate. Subjects provided written informed consent, obtained by Chinese members of the project team who spoke the local dialect (health assessment and consent led by an established Chinese academic physician Ri-Li Ge), and the University of California San Diego and University of Qinghai Medical College review boards approved all studies, which conformed to the standards set by the Declarationof Helsinki.

Table 2.

Oxygen transport data collected from 21 Tibetan and 9 Han Chinese males at >4200 m during maximal exercise

Ethnicity Age Height (cm) Weight (cm) Inline graphic kg–1 Inline graphic kg–1 DL/VC A-a Inline graphic difference (mmHg) Base deficit QT kg–1 DM kg–1
Tibetan 23 ± 5 168 ± 7 61 ± 12 37.5 ± 7.0 1.92 ± 0.40 18.4 ± 3.3 16.3 ± 4.0 13 ± 3 0.26 ± 0.05 1.3 ± 0.4
Han Chinese 27 ± 10 173 ± 4 60 ± 9 36.8 ± 5.2 1.95 ± 0.38 15.5 ± 2.5 18.5 ± 2.8 13 ± 2 0.22 ± 0.05 1.3 ± 0.3
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Values are means ± SD.

See Simonson et al. 2014 for additional published variables including [Hb], Inline graphic, P50, arterial Inline graphic, Inline graphic, and pH;

individual values available upon request.)

Study design

Studies were performed in a hospital outpatient room in either of two neighbouring villages from which the subjects were recruited at an altitude between 4200 and 4300 m. After detailed explanations of the protocol and measurement procedures, spirometry was performed to determine vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), maximum mid-expiratory flow (FEF25-75), and peak expiratory flow (PEF). Individuals exhibiting signs of significant respiratory disease based on spirometry data were excluded from the study. None of the 30 subjects displayed any spirometric abnormalities.

Following spirometry, a forehead oximeter (Nellcor N-395 Louisville, KY, USA) probe was taped to the skin, and a 20-gauge radial arterial catheter was then placed percutaneously under local anaesthetic using sterile technique. Six electrodes were taped onto cleansed skin in customary regions (two each on the back, neck and chest) for impedance cardiography measurements (PhysioFlow Enduro, Paris, France). A tight-fitting facemask covering both nose and mouth was secured and connected to a Carefusion ‘Oxycon’ Inline graphic/Inline graphic measurement system.

Given the lack of familiarity of the subjects with research studies, a straightforward, simplified, incremental exercise protocol to exhaustion was adopted (Simonson et al. 2014). Subjects were seated on a cycle ergometer, resting until heart rate and respiratory rate were stable, at which point resting data were collected. Subjects were then asked to pedal at light exercise breathing room air as a warm-up, the load being varied according to each individual’s capacity. After 2 min, subjects were asked to pedal at a moderate workload intended to target about 70–90% of maximal power, as judged by both frequent questioning of each subject, as he pedalled, and heart rate. After 2 min at this work rate, further data collection was performed, and when completed, subjects then pedalled at maximal effort, the load again being varied to achieve exhaustion in 2–3 min. Towards the end of this period, data were again collected.

After removal of the arterial line, securing of haemostasis, and at least a 30 min rest, subjects repeated the exercise as above, but now breathing 100% O2, which was administered once they reached their previous submaximal level. Subjects exercised again to exhaustion to determine whether maximal power output would increase after elimination of ambient hypoxia, as it does in acclimatized lowlanders (Calbet et al. 2002). While Inline graphic could not be measured while breathing 100% O2, the maximal power output and heart rate were recorded and compared to maximal watts and heart rate achieved without supplemental oxygen.

Variables measured and data collection

Inline graphic, Inline graphic, expiratory ventilation (Inline graphic), cardiac output (QT) and heart rate (HR) were measured continuously from rest until exhaustion, using 10 s averaging, under ambient conditions (barometric pressure (PB) = 454–459 mmHg, Davis Perception II). At rest, and during the final 2 min of both submaximal and maximal exercise, arterial blood samples (2 ml) were taken anaerobically into sterile heparinized syringes that were kept in an ice slurry before and after sample collection. Blood gas variables were measured immediately or within a few minutes of collection. All of the data collected, equipment, and methods used in this study are summarized in Table1. [Hb] and haematocrit values were measured from arterial blood samples and analysed using a Mindray Hematology Analyser (BC-2300, Shenzhen, People’s Republic of China). Inline graphic, Inline graphic and pH were measured using an iSTAT hand-held electrode system at 37ºC. Core temperature could not be measured, and was estimated at 37.0ºC for all subjects as the short duration and limited power output during peak exercise (<2 min) would not be expected to affect core temperature beyond an average of 0.6ºC (data from Wagner et al. 1986, 1987). Peak power averaged only 151 W, due to hypoxia, which further acted to limit core temperature changes. Since no lactate analyser was available, base excess was calculated from pH and Inline graphic using the Siggaard-Andersen nomogram to quantify metabolic acidosis generated during exercise. Mixed venous [O2] and Inline graphic (and [CO2] and Inline graphic) were calculated by mass conservation using the Fick principle and measured values of Inline graphic, QT, and arterial O2 concentration. The partial pressure of O2 in the blood at which Hb is 50% saturated (P50) was computed from the Inline graphic–saturation relationship (Simonson et al. 2014). Previously established Fortran programs were used to determine diffusing capacity in lung (DL) and muscle (DM) using a forward integration algorithm (Wagner & West, 1972) that is based on the Kelman subroutines describing the O2 and CO2 dissociation curves (Kelman, 1966, 1967). These algorithms find the values of diffusing capacity in each tissue that match measured arterial Inline graphic in the case of lung and measured venous Inline graphic in the case of muscle, assuming a homogeneous organ in each case.

Table 1.

Measurements collected and data analysed at rest and during graded exercise to determine values for analyses of each step of the oxygen transport chain

Inline graphic, Inline graphic, Inline graphic Expired gas analysis (Oxycon, Carefusion); measured
Arterial Inline graphic, Inline graphic, pH, base excess (BE) Arterial sample (i-STAT, Abbott); measured
Cardiac output (QT) [Hb], haematocrit Impedance cardiography (Physioflow); measured Arterial blood sample; measured
Oxygen saturation, [O2] Forehead oximetry (Nelcor); measured
Standard P50 Computed from Inline graphic/saturation relationship; calculated
Venous [O2], Inline graphic Calculated by mass conservation; calculated
Lung diffusing capacity (DL) Bohr Integration using above data; calculated
Muscle diffusing capacity (DM)
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Analysis

Individual O2 transport variables at maximal exercise were first plotted as a function of [Hb] using linear regression in MatLab 2013v. Variables examined included Inline graphic kg–1, minute ventilation (Inline graphic kg–1), Inline graphic, Inline graphic, base deficit, alveolar–arterial Inline graphic (A-aInline graphic) difference, diffusion capacity in lung (normalized to vital capacity, VC), i.e. DL/VC, cardiac output (QT kg–1), and diffusion capacity in muscle (DM kg–1), some of which are published in Simonson et al. 2014. Next, Inline graphic kg–1 was plotted as a function of individual O2 transport variables, including Inline graphic kg–1, Inline graphic, Inline graphic, A-aInline graphic difference, base deficit, DL/VC, QT kg–1, and DM kg–1. Multiple linear regression (MatLab 2013v) was used to assess the significance of standardized predictors, including [Hb], Inline graphic, Inline graphic, Inline graphic, A-aInline graphic difference, base deficit, DL/VC, QT kg–1, DM kg–1 and age. Interaction effects were further assessed for significant predictors. P values < 0.05 were used to establish statistical significance.

Results

Pertinent O2 transport data in the 21 Tibetan and nine Han Chinese subjects at maximal exercise breathing air at 4200–4300 m are provided in Table2 (and Simonson et al. 2014). The wide range of [Hb] in Tibetans provided variation to test the hypothesis that exercise capacity would relate negatively to [Hb]. All subjects included in this study fulfilled at least two of the following criteria for peak Inline graphic: (1) maximal heart rate at exhaustion as previous reported in individuals of Tibetan ethnicity (176 beats min–1 3 days after descending from an altitude of 4400 m, within 100 m of that of our studies, to 3685 m; Curran et al. 1998); (2) respiratory exchange ratio > 1.10; (3) no further increase (or a decrease) in Inline graphic with increasing workload; (4) no further increase in heart rate despite an increase in workload; (5) rest to peak exercise increase in base deficit of 6 mmol l−1 or more. Overall, at exhaustion, average heart rate was 172 beats min–1; RER was 1.19; and base deficit was 13 mmol l−1 (rising from 4 mmol l−1 at rest), similarly in Tibetans and Han Chinese. There was no [Hb] dependence of these Inline graphic criteria.

Oxygen transport and exercise capacity

Tibetans with lower [Hb] reached a higher Inline graphic kg–1 compared to Tibetans with higher [Hb] (r = −0.45; P < 0.05; Fig.1). In addition, data were collected from Han Chinese subjects at altitude, although this population is genetically distinct and, as a historically lowland population, has not been exposed to hundreds of generations of selective pressure (Simonson et al. 2012; Wuren et al. 2014). The Han Chinese subjects, whose [Hb] falls in a higher range than more than half of the Tibetan subjects examined (from 18.1 to 21.1 g/dl −1 (11.2 – 13.1 mmol−1) in nine Han Chinese males), exhibit a similar relationship to exercise capacity (r = −0.83; y = −3.2x + 99).

Figure 1.

Figure 1

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Haemoglobin concentration ([Hb]) versus peak Inline graphic

Relationships between haemoglobin concentration ([Hb]) and peak Inline graphic (Inline graphic kg–1) in 21 male Tibetan subjects at 4200 m.

Figure 2 shows the relationships between [Hb] and significant variables in Tibetans and, in separate panels, Han Chinese. Relationships between [Hb] and QT kg–1 (r = –0.54; P < 0.01; Fig.2A) and between [Hb] and DM kg–1 (r = –0.44; P < 0.05; Fig.2B) indicate that both cardiac output and muscle diffusing capacity were higher at lower [Hb]. In contrast, Inline graphic, Inline graphic (ventilation), and diffusion in the lung (as reflected by both the A-aInline graphic difference and DL/VC) were not associated with [Hb] and are therefore not shown. The nine Han Chinese who exhibit elevated [Hb] also exhibit significant relationships between [Hb] and and QT kg–1 (r = −0.70; y = −0.03x + 0.7) and Inline graphic (r = 0.79; y = 1.1x + 4.9) (Fig.2C and D), and there is no statistical difference between Tibetan and Han Chinese in each of the relationships examined.

Figure 2.

Figure 2

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Haemoglobin concentration ([Hb]) compared to components of oxygen transport at 4200 m

Components of the oxygen transport cascade compared to haemoglobin concentration ([Hb]) in Tibetan and Han Chinese males. Cardiac output (QT kg–1; A) and diffusing capacity in muscle (DM kg–1; B) are significantly related to [Hb]; arterial Inline graphic (Inline graphic, ventilation) and lung-related (alveolar–arterial difference) components are not associated with [Hb] in Tibetans. Relationships between [Hb] and QT kg–1 (P < 0.04; C) and Inline graphic (P < 0.02; D) are also shown for 9 Han Chinese.

The above O2 transport-related variables were next individually examined with respect to Inline graphic kg–1, again using only the Tibetan data for the regression line construction. In addition to its significant relationship with [Hb] (Fig.1), Inline graphic kg–1 was found to be positively and strongly associated with QT kg–1 (r = 0.71; P < 0.001; Fig.3B), diffusion capacity in muscle (r = 0.84; P < 0.001; Fig.3C), and negatively associated with Inline graphic (r = –0.54; P < 0.02; Fig.3A). In nine Han Chinese subjects, peak Inline graphic kg–1 tracked with Inline graphic (r = –0.75; y = −2.1x + 92; Fig.3D) and DM kg–1 (r = 0.72; y = 12x + 22; Fig.3E), and no statistical difference was observed between Tibetan and Han Chinese data sets. In a multifactorial system such as O2 transport, such pairwise linear regressions are limited in their information content, which led us to conduct multiple linear regression analysis for the 21 Tibetan subjects. Each of the significant univariate predictors was tested and included in the model (QT kg–1 and DM kg–1 at P < 0.001; Inline graphic at P < 0.05), and explains the majority of variation in Inline graphic kg–1 (R2 = 0.88; y = −0.19Inline graphic + 0.38QT kg–1 + 0.63DM kg–1; Fig.4).

Figure 3.

Figure 3

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Components of oxygen transport associated with exercise capacity

Relationships observed between ventilation (Inline graphic, P <0.01; A), QT kg–1 (P < 0.001l; B), and DM kg–1 (P < 0.001; C), with Inline graphic kg–1 in Tibetans; Inline graphic and A-aInline graphic difference did not exhibit a relationship with Inline graphicpeak kg–1. Relationships between Inline graphic kg–1 and Inline graphic (P < 0.02; D), and DM kg–1 (P < 0.03; E) are also shown for 9 Han Chinese.

Figure 4.

Figure 4

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Measured versus predicted peak VO2 in 21 Tibetan males at 4200 m. Highly significant relationship (r = 0.95; p < 0.001) between measured VO2peak/kg (y axis) compared to that predicted by linear regression; standardized predictors include PaCO2 (b = −0.18), cardiac output (QT)/kg (b = 0.38), diffusion capacity in muscle (DM)/kg (b = 0.63).

Subjects breathing 100% O2 exhibited an average increase in peak power of 16 W (from 152 to 168 W) (P < 0.0001), which was consistent among Tibetan (n = 21) and Han Chinese (n = 8; no data available for one Han Chinese subject) groups. Therefore, the increase in available O2 resulted in only a 10% increase in maximal power output, which is relatively minor compared to the corresponding ∼30% increase observed in individuals of European ancestry acclimatized to altitudes of 4200–4300 m (Reeves et al. 1992; Pronk et al. 2003).

Discussion

Summary of main findings

The principal finding was that Tibetans with sea-level range [Hb] had enhanced exercise capacity compared to those with elevated [Hb]. The second major finding was that this [Hb] dependency of Inline graphic within Tibetans was facilitated by higher cardiac output and greater muscle O2 diffusing capacity, but not by respiratory factors including ventilation and gas exchange. As a group, however, Tibetans exhibit greater DL/VC compared to the nine Han Chinese counterparts. The third major finding was that eliminating hypoxaemia by breathing 100% O2 led to an average increase in peak work rate of only 16 W, or 10% compared to acclimatized lowlanders at this altitude, who would have been able to increase work rate by ∼30% (i.e. back to prior sea level values) upon breathing O2 (Pronk et al. 2003). The fourth major finding was that Han Chinese and Tibetans with the same high [Hb] performed similarly in all respects examined.

[Hb] in this group of subjects and their health status

[Hb] among the high-altitude (>4200 m) inhabitants examined (Tibetan = 17.7 ± 2.1 g dl−1 (11.0 ± 1.3 mmol l−1); Han Chinese = 19.0 ± 0.8 g dl−1 (11.8 ± 0.5 mmol l−1); P < 0.02) is consistent with previous reports at comparable altitude (Beall, 2000; Wu et al. 2005; Beall et al. 2010; Simonson et al. 2010). It is therefore reasonable to believe that subjects were representative of a high-altitude Tibetan resident population. While iron stores or binding capacity were not measured, medical history including dietary information gave no reason to suspect a pathological cause of the sea-level [Hb] in those Tibetans with non-elevated [Hb], nor a lifestyle or health-related reason for less exercise capacity in the higher [Hb] group (all subjects reported as non-athletic, many self-described as herders). Andean highlanders exhibiting anaemia (defined as [Hb] < 15.8 g dl−1) at altitude exhibit both a reduced aerobic capacity (Tufts et al. 1985) and a left-shifted Hb-dissociation curve that maintains arterial saturation similar to pre-exercise levels, suggesting different mechanisms for anaemia compensation at high versus low altitude in this population (Beard et al. 1988). The Tibetans studied here, exhibiting [Hb] 15.2–22.9 g dl−1 (9.4–14.2 mmol l−1), also exhibit an increased blood O2 binding affinity, although this is not associated with [Hb], alveolar–arterial Inline graphic difference, or peak O2 uptake per kilogram (Simonson et al. 2014).

There were no symptoms or signs of chronic mountain sickness (CMS) in the subjects with elevated [Hb] at altitude. If the low [Hb] was due to undiscovered pathology, it is all the more remarkable that these Tibetan subjects had greater exercise capacity. It is, however, recognized that it is not possible to exclude confounding factors in the [Hb]–exercise capacity relationship completely.

Physiological basis for greater exercise capacity in subjects with low [Hb] at altitude relative to those with higher [Hb]

Considering that increased [Hb] leads to more O2 binding sites and thus more O2 carried in blood at a given Inline graphic, it seems counterintuitive that Tibetans have adapted with a low [Hb] at altitude. This is because a lower [Hb], if the only factor different between low and high [Hb] Tibetans, would only reduce capacity to transport O2 to the muscles. Moreover, since polycythaemia is a universal response to ascent to altitude in healthy lowlanders, having more red cells should be beneficial to exercise at altitude. Similarly, the horse has a huge splenic red cell reservoir that is pumped into the circulation within seconds of galloping which has been shown (by splenectomy) to greatly enhance their exercise capacity (Persson & Bergsten, 1975). Blood volume, a separate benefit of splenic contraction, may be more important than [Hb] as most of the loss in exercise after splenectomy is reversed by infusion of blood with resting [Hb] in horses (Hopper et al. 1991). The literature contains many reports suggesting that a high [Hb] (even short of chronic mountain sickness) does not promote exercise capacity as demonstrated by acute isovolumic dilution in Danish subjects acclimatized to 5260 m (Calbet et al. 2002) nor upon acute [Hb] reduction in a single Peruvian high-altitude native (Winslow et al. 1985). Additional studies suggest optimal [Hb] is rather near sea-level values (Villafuerte et al. 2004; Schuler et al. 2010). The likely explanation for lack of benefit to exercise capacity from an elevated [Hb] at altitude is that the gains in circulatory transport afforded by a higher [Hb] with more O2 binding sites are mostly offset by reductions in the ability to move O2 by diffusion between alveolar gas and capillary blood in the lungs and between muscle microcirculatory vessels and the mitochondria (Wagner, 1996). When [Hb] is elevated, time to diffusive equilibration in these vascular beds is prolonged. Piiper & Scheid (1981) expressed this best when they showed that the compound constant D/(ßQ) determined the degree of diffusion equilibration to be expected in the lungs (where D is lung diffusing capacity) or muscle (where D is muscle diffusing capacity). Here Q is muscle blood flow or cardiac output, and ß is the (average) slope of the O2–Hb dissociation curve. Since ß must increase when total [Hb] increases, D/(ßQ) must fall, other factors being equal, and diffusion equilibration takes longer. As a result, Inline graphic is lower, and muscle venous Inline graphic higher (i.e. extraction is less) when [Hb] is higher (again, all other factors being constant), and overall O2 transport is impaired, counterbalancing the positive effect of more circulatory transport capacity.

This line of reasoning requires that positive changes in other parts of the O2 transport system must explain greater exercise capacity when [Hb] is low, and a major purpose of this study was to identify any such changes should a low [Hb] be found to be associated with greater exercise capacity. The changes associated with [Hb] are cardiac output and in muscle O2 diffusional conductance. Moreover, if we consider that the Tibetans with higher [Hb] reflect the pre-adaptive ‘norm’ – that is, the [Hb] without genetic changes that lead to reduced [Hb] – it is notable that the outcome is not just maintained exercise capacity as [Hb] falls, but greatly increased exercise capacity in Tibetans with lower compared to higher [Hb] (Fig.1).

The positive relationships observed between [Hb] and cardiac output and exercise capacity suggest that changes in cardiac preload, contractility, or afterload (singly or in combination) are involved in increased cardiac output when [Hb] is reduced. Similarly, greater muscle O2 diffusive transport, modelled as described in the Methods section, is observed in Tibetan males with lower [Hb] in addition to a higher Inline graphic kg–1, suggesting more efficient O2 transfer from red cells to mitochondria of metabolizing cells. Such changes could be attributed to muscle capillarity (i.e. increased number of capillaries per muscle fibre), decreased fibre diameter, or alterations in fibre type. Assessment of these variables (in addition to others such as red cell mass and plasma volume), as well as gene expression and protein levels in respective tissues, will help to determine the structural and functional basis of these correlations, but such data were not obtained in the current study.

Although arterial Inline graphic (representing ventilation in relation to metabolic load) is not associated with [Hb] (P > 0.08), lower Inline graphic is associated with greater Inline graphic kg–1 in Tibetan males (Fig.3A). Previous reports indicate higher offspring survival in Tibetan women with elevated O2 saturation (Beall et al. 2004), and our previous work indicates an inverse relationship between [Hb] and O2 saturation in females but not males (Simonson et al. 2010). Whether this may be attributed to alterations in female ventilatory responses compared to males, and furthermore attributed to specific genetic changes, has yet to be determined. It will therefore be necessary to determine whether differences in exercise capacity and response vary between sexes.

High [Hb] Tibetans exhibit similar exercise capacity to Han Chinese

It is important to note the similarity of exercise capacity and response among Tibetans with elevated [Hb] and Han Chinese subjects who exhibit equivalent [Hb]. This indicates that Tibetans with erythrocytosis at altitude exhibit comparable physiological outcomes to native lowland Han Chinese at altitude, at least with respect to exercise capacity and the O2 transport components measured here. No statistical difference was detected between Tibetan and Han Chinese in each of the relationships examined. The variation in the Tibetan sample, however, extends across a much larger range (11 Tibetans have [Hb] lower than the lowest level in the Han), reflecting innate, gene-by-environment, differences in these populations.

It is unclear whether components observed in high [Hb] Tibetans and Han Chinese are a result of the same, non-adaptive genetic backgrounds or if such similarities reflect different physiological mechanisms that converge towards elevated [Hb] and the exercise capacity and responses examined. The nine Han Chinese examined in this study, however, had successfully resided at altitudes above 4000 m for more than 2 years without illness and may not be an accurate representation of the population (as Han exhibit greater incidence of altitude illness compared to Tibetans (MacInnis et al. 2010) and such subjects would not have been included in our study). Additionally, ancestral ‘standing’ beneficial genetic variants may be present in both groups. All this considered, it will be necessary to determine whether the ‘least’ adapted high [Hb] Tibetans and well-acclimatized lowland Han Chinese share genetic variants which relate to elevated [Hb] and exercise capacity and response.

Elimination of hypoxaemia and peak work rate

The difference between exercise capacity in ambient conditions and upon administration of 100% O2 is significant (P < 0.0001) but relatively small (16 W) compared to the corresponding ∼30% increase observed in individuals of European ancestry acclimatized to altitudes of 4200–4300 m (Reeves et al. 1992; Pronk et al. 2003). This raises the possibility that Tibetans have developed fine-tuned mechanisms (possibly a reduction in mitochondrial mass to minimize metabolic machinery/biogenesis costs (Kayser et al. 1996)) to efficiently utilize limited O2 available at high altitude. Similar results have been reported in Andeans (Hochachka, 1998), suggesting such conservation may be utilized in both highland groups.

Primary and secondary targets of adaptive change within Tibetans

A question these findings raise is whether low [Hb] at altitude, comparable to sea-level values, is the primary target of adaptive change, i.e. did low [Hb] come first and QT kg–1 and/or DM kg–1 follow or vice versa. Altitude-induced polycythaemia and the associated increase in blood viscosity is not beneficial, and may underlie the pathogenesis of chronic mountain sickness (CMS) (Vargas & Spielvogel, 2006a). The incidence of CMS is lower among Tibetans (less than a few per cent; Wu et al. 1992) compared to Andeans (15.6%; Monge et al. 1992), who exhibit [Hb] few to several grams per decilitre higher than Tibetan natives. Yet the late onset of CMS (post-reproductive age; Moore et al. 2007) suggests protection from CMS alone would not explain the adaptive genetic signals that have been associated with lower [Hb] compared to other ethnic groups at altitude (Simonson et al. 2012), although maternal [Hb] during pregnancy could be a primary target. In either case, if [Hb] was the primary driver of evolutionary change, alterations at one or more steps of the O2 transport cascade would be necessary to compensate for reduction in O2 transport capacity. While examination within a Tibetan population exhibiting a range of [Hb] is shown here, further consideration of population differences, as observed in Tibetan–Han DL/VC (Table2), may indicate fixed or nearly fixed differences compared to native lowland groups.

An alternative hypothesis based on the data presented within Tibetan subjects examined here is that changes related to cardiac and/or skeletal muscle were the primary targets of adaptation and, consequently, the shift in [Hb] towards sea-level values was secondary to improved cellular O2 availability resulting from enhanced cardiovascular function and/or muscle diffusion capacity. We suggest that this view has merit because most compensatory changes tend to restore function towards baseline rather than resulting in greater function than before. Thus, were the Hb change primary, compensation might have been expected to restore exercise capacity, but to a much lesser degree than shown by Tibetans with lower [Hb]. However, the observation was that exercise capacity was greater in those Tibetans with [Hb] in the sea-level range. In this case, it is plausible that the genetic associations with [Hb] are in fact secondary signals (side-effects), or possibly occurred separately following changes in circulatory and/or O2 muscle diffusion components of the O2 transport cascade.

Considering that male Tibetans examined here with lower [Hb] have increased exercise capacity, cardiac output and O2 diffusion capacity in muscle, it will be important to determine whether associations between each of these O2 transport components and the [Hb]-associated adaptive loci are significant or whether cardiac and muscle changes are related via increased blood flow, which serves to increase O2 conductance. Increased flow may result in gene expression changes in muscle (Drummond et al. 2008) or, alternatively, genetic changes in muscle and heart attributed to the same or independent outcomes. Such gains in efficiency would diminish the stimulus to elevate [Hb], which may be reduced as the result of a separate adaptive event.

Genomic targets of selection at EGLN1, PPARA, and EPAS1 loci are associated with low [Hb] in Tibetans at altitude (Beall et al. 2010; Simonson et al. 2010; Yi et al. 2010). While not examined here, it is plausible that adaptive copies at these loci underlie variation in other components of O2 transport. These genes, in addition to others that have not been associated with [Hb] but reported as selection candidates in multiple genomic studies (Simonson et al. 2012), may also be related to physiological variables highlighted in this study (i.e. heart/skeletal muscle structure and function, ventilation). Aside from EGLN1 (Lorenzo et al. 2014; Song et al. 2014), however, precise functional variants remain unknown. Ultimately, adaptive functional genetic variants, and combinations thereof, should be examined in a physiological context.

Limitations

As our study was conducted in a remote village at 4200 m, various logistical challenges were anticipated and addressed as follows. One concern was altitude and inhospitable conditions would affect equipment performance of the Inline graphic/Inline graphic system, the device used to measure cardiac output, and the blood gas analyser. We therefore collected Inline graphic/Inline graphic data during an incremental exercise protocol from a single subject at 2200 m and again at simulated 4200 m and from another subject at 2200 m and under ambient conditions at 4200 m in the Tibetan village. Repeated daily measurements in both subjects at different altitudes indicate consistency in the Inline graphic/Inline graphic system, and a slope of the relationship between Inline graphic and watts that lay within the normal range of 9–11 ml min−1 W−1 (supplemental material available).

While we were unable to engage subjects in additional tests for repeated measurement of blood gas variables (requiring an additional arterial catheterization), we performed a quality-control check by comparing our data with those of reports in acclimatized subjects at comparable altitude. The average resting alveolar Inline graphic and Inline graphic in our cohort corresponds well to measurements collected in acclimatized subjects at altitude (Table2, Rahn & Otis, 1949).

We utilized the non-invasive impedence cardiography (PhysioFlow Enduro) in order to make the key measurement of QT in each subject during rest, submaximal, and maximal exercise. While various reports have validated use of this equipment (Charloux et al. 2000; Richard et al. 2001; Tordi et al. 2004), this is not always the case (Siebenmann et al. 2014). In our study, the relationship between PhysioFlow QT and Carefusion-measured Inline graphic was linear, as expected, and was also in agreement with values predicted by the established relationship between QT and Inline graphic (QT ≈ 5 + 5Inline graphic; as illustrated in Barker et al. 1999) upon incremental increase during exercise at 4200 m. Therefore, the cardiac output data presented are supported not only by other reports regarding its accuracy but also by satisfying a known relationship using independent measures from the Carefusion Inline graphic system and PhysioFlow QT output. Again, supplemental material reporting these relationships is available.

A further limitation was to determine DMO2 (muscle O2 diffusion conductance) from values for venous Inline graphic computed from the Fick principle, knowing Inline graphic, cardiac output and arterial O2 concentration. This computation estimates mixed venous O2 levels, not those coming from the exercising muscle, which would be lower. This would then cause DMO2 to have been underestimated. However, leg blood flow must be lower than cardiac output. Since cardiac output was used in the calculation, this would per se have given an overestimate of DMO2. If we use reasonable estimates of non-exercising tissue metabolic rate and blood flow and subtract them from Inline graphic and QT, respectively, estimated muscle venous Inline graphic and O2 content would have been similar, but with leg blood flow less than cardiac output, DMO2 would have been proportionally lower than reported here. We felt that it was simpler and more transparent to use measured data and whole-body estimation of DMO2 than to guess at non-exercising Inline graphic and blood flow and attempt correction of the data, but then to point out that absolute values reflect the whole-body transport process, not just the exercising muscles. However, the same computation was performed and simplifications used for all 30 subjects. Thus, the relative comparisons should be robust even if the absolute values of DMO2 are systematically in error.

We knew, based on previous reports (Simonson et al. 2010), that [Hb] in this specific population spans a wide range, but no prior data regarding relationships with this trait and exercise capacity and/or O2 transport had been collected. Therefore, we did not know what if any relationships would be identified between [Hb], exercise capacity, and components of oxygen transport, and thus decided it would be premature to design studies to add on to basic exercise measurements – such as measures of blood volume, iron stores, cardiac function by ECHO, etc. Given the important insights presented here, next steps should include such assessments in an effort to understand the structure and functional basis of enhanced cardiac function and O2 extraction in addition to ventilatory control differences that were found.

Conclusion

At altitude >4000 m, Tibetan males with sea-level [Hb], compared to those with elevated [Hb], exhibit greater exercise capacity, higher cardiac output, and greater O2 diffusional conductance in muscle but not lung. These components as well as PaCO2 are further associated with exercise capacity. The physiological and genetic relationships among [Hb], cardiac function and muscle O2 diffusional conductance remain to be elucidated. Supplemental (100%) O2 given during exercise increases peak work rate in Tibetans by only a third of that reported in Caucasian lowlanders acclimatized to altitude (with no difference between high and low [Hb] groups). Acclimatized Han Chinese males performed similarly in terms of exercise capacity and components of O2 transport to the high [Hb] Tibetan group, suggesting a lack of adaptive changes in these groups. As indicated in many reports, the fact that healthy Andeans are polycythaemic at altitude, while many Amhara Ethiopians and Tibetans are not, suggests distinct evolutionary paths between these native highland groups.

Acknowledgments

We thank all high-altitude inhabitants who participated in this study and anonymous reviewers for helpful comments.

Glossary

CMS

chronic mountain sickness

DL

DM, diffusion capacity in lung, muscle

Hb

haemoglobin

HIF

hypoxia inducible factor

O2

oxygen; peakInline graphic, volume of O2 utilized at peak exercise

P50

partial pressure of O2 in the blood at which Hb is 50% saturated

Inline graphic

partial pressure of inspired O2

Inline graphic

Inline graphic, partial pressure of O2, CO2

QT

cardiac output; Inline graphic, O2 saturation

Additional information

Competing interests

None declared.

Author contributions

Experiments were performed in the village of Maduo and The Center for High Altitude Research in Xining, Qinghai Province, China. P.D.W., T.S.S. and R.L.G. designed experiments. T.S.S., G.W., H.E.W., T.W., A.B., J.M.F., G.Q., F.G.B., M.Y., P.D.W. and R.L.G. performed data collection. T.S.S., G.W., and P.D.W. performed analysis and interpretation of data. All authors approved the final version of the manuscript.

Funding

National Institutes of Health (NIH) National Heart, Blood, and Lung Institute (NHBLI) P01 HL0981830-01A1; National Basic Research Program of China 2012CB518200; Program of International S&T Cooperation of China 0S2012GR0195; National Natural Science Foundation of China 30393133; NIH T32 HL098062-01A1; NIH K99 HL118215; Parker B. Francis Fellowship.

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