Hemoglobin is a tetramer consisting of two α-subunits and two β-subunits (Coates, 1975). Each subunit contains a heme group that is capable of reversibly binding O₂ (Perutz, 1963). When hemoglobin is fully saturated four O₂ molecules are bound independently to each of the four subunits of the hemoglobin molecule. Hemoglobin undergoes a conformational shift with each O₂ molecule that binds, existing in a T (tense) state when deoxygenated and a R (relaxed) state when oxygenated, commonly described by a two-state model (Monod et al., 1965). As each individual subunit becomes oxygenated, a conformational shift further increases binding affinity for O₂ (Mihailescu and Russu, 2001). This cooperativity in O₂ binding to hemoglobin gives rise to the sigmoidal shape of the O₂ dissociation curve (Figure 1).

Hemoglobin is subject to allosteric regulation by multiple ligands. Most notably, higher concentrations of H⁺ and CO₂ reduce Hb-O₂ affinity (Riggs, 1960; Ho and Russu, 1987). This pH dependent change of Hb-O₂ affinity is termed the Bohr effect (Bohr et al., 1904). Hb-O₂ affinity is also reduced at higher temperatures (Weber and Campbell, 2011). For example, an increase of temperature from 37 to 40°C raises P₅₀ from normal values of ∼27 to 30 mmHg (Hlastala et al., 1977). Additionally, the magnitude of the Bohr effect is greater at higher temperatures, further promoting O₂ off-loading from hemoglobin (Hlastala et al., 1977). The cooperative effect of a more acidic environment along with higher temperatures, as occurs during rigorous exercise, significantly reduces Hb-O₂ affinity such that P₅₀ may increase up to ∼40 mmHg within the vasculature (Thomson et al., 1974). In the case of severe respiratory alkalosis, a fivefold increase in minute ventilation may reduce arterial P_CO2 from normal values of ∼40 mmHg to as low as 7 mmHg and blood pH may exceed 7.7 (Houston et al., 1987; West, 2006). At extreme altitudes, in vivo P₅₀ may be reduced to less than 20 mmHg due to changes in blood P_CO2 and pH (West, 1984; Winslow et al., 1984).

The erythrocytic concentrations of 2,3-DPG and Cl^– are associated with more long-term modulation of Hb-O₂ affinity. In effect, 2,3-DPG and Cl^– bind to deoxygenated hemoglobin and stabilize the T state, reducing Hb-O₂ affinity (Benesch et al., 1967; Brewer, 1974). 2,3-DPG reduces Hb-O₂ affinity and increases the cooperativity of hemoglobin, which “right-shifts” the O₂ dissociation curve and steepens the slope (Tyuma et al., 1971). In addition, an influx of Cl^– into the red blood cell, coupled to the outward transport of bicarbonate, reduces Hb-O₂ affinity (Wieth et al., 1982; Perutz et al., 1994; Prange et al., 2001). These ligands elicit independent effects on Hb-O₂ affinity, and complex in vivo interactions between ligands give rise to the physiological P₅₀ of hemoglobin. For example, 2,3-DPG and Cl^– compete for binding to hemoglobin and the effect 2,3-DPG on Hb-O₂ affinity disappears at high concentrations of Cl^– (Imai, 1982). In addition, the Bohr effect is more pronounced at greater concentrations of 2,3-DPG (Bauer, 1969). The interested reader may consult other sources for more detailed discussions on modulation of Hb-O₂ affinity (Antonini and Brunori, 1970; Mairbaurl and Weber, 2012).

The severity and duration of hypoxia is an important factor when considering in vivo modulation of Hb-O₂ affinity in humans. During sojourns to altitudes of ∼4500 m or less, humans demonstrate a reduced Hb-O₂ affinity due to elevated production of 2,3-DPG (Lenfant et al., 1968). At these elevations, hyperventilation reduces blood P_CO2 and potentially results in respiratory alkalosis (Dempsey and Forster, 1982). However, renal compensation leads to the excretion of excess bicarbonate and conservation of H⁺, normalizing blood pH to sea-level values after a few days at high altitude (Goldfarb-Rumyantzev and Alper, 2014; Bird et al., 2021). At higher elevations (4500–5400 m), hyperventilation becomes so pronounced that renal compensation is insufficient and blood pH increases (West, 2006). The rise in blood pH increases Hb-O₂ affinity, counteracting the effects of an elevated 2,3-DPG production such that P₅₀ approximates values observed at sea-level (Mairbaurl and Weber, 2012). As humans travel above ∼5400 m, Hb-O₂ affinity increases as the respiratory alkalosis becomes more severe (West, 1984).

Contemporary studies suggest a potential role of hemoglobin found in cells other than erythrocytes such as alveolar epithelial cells, lung cells, and mesangial cells (Du et al., 2012; Saha et al., 2014). Within these non-erythrocytic cells, the production of hemoglobin appears to be upregulated in response to hypoxia (Cheung et al., 1997; Tezel et al., 2009; Grek et al., 2011), potentially serving as a “reservoir” for O₂ (Saha et al., 2014). Therefore, a key area for future investigation is the relationship between non-erythroid hemoglobin production and hypoxia tolerance. However, there is currently minimal evidence to suggest that non-erythroid hemoglobin provides a functional impact on cardiovascular adjustments during hypoxia.

Several pharmacological methods which transfuse 2,3-DPG depleted red blood cells into both animals and humans have allowed investigation into the role of high Hb-O₂ affinity in O₂ transport (Riggs et al., 1973; Woodson et al., 1973; Wranne et al., 1974; Bakker et al., 1976; Malmberg et al., 1979; Woodson and Auerbach, 1982; Birchard and Tenney, 1991). However, methods used to achieve 2,3-DPG depletion often alter acid-base balance and total blood volume, potentially confounding the observed cardiorespiratory adjustments (Birchard and Tenney, 1991). More recent developments of pharmaceuticals that induce high Hb-O₂ affinity allow examination of altered Hb-O₂ affinity with fewer complications (Dufu et al., 2017; Kalfa et al., 2019; Stewart et al., 2020, 2021). For example, voxelotor binds allosterically to some, but not all hemoglobin and increases Hb-O₂ affinity. Hemoglobin modified with voxelotor exhibits a reduced Bohr effect compared to unmodified hemoglobin (Pochron et al., 2019), which may limit O₂ off-loading during instances where blood pH decreases such as rigorous exercise.

In general, allosteric modifiers allow for the manipulation of Hb-O₂ affinity with less perturbations in acid-base balance associated with 2,3-DPG depletion techniques. However, in healthy humans voxelotor induces only a modest decrease in P₅₀ of ∼2 mmHg (Stewart et al., 2020, 2021) compared to the greater range from 3 to 10 mmHg obtained via 2,3-DPG depletion (Gillette et al., 1974; Wranne et al., 1974). The ability to pharmacologically alter Hb-O₂ affinity in humans both acutely and chronically may provide additional insights on the context-dependent circumstances at which high Hb-O₂ affinity is advantageous (i.e., magnitude and duration of hypoxia).

Currently, over 200 distinct mutations resulting in high Hb-O₂ affinity have been identified (Charache et al., 1966; Mangin, 2017). By definition, high Hb-O₂ affinity is characterized by a P₅₀ less than 24 mmHg (Figure 1; Rumi et al., 2009; Mangin, 2017). However, a majority of high Hb-O₂ affinity hemoglobinopathies examined are associated with P₅₀ values ranging from 12 to 17 mmHg (Table 1). Both the amino acid substitution and location at which the substitution occurs within the hemoglobin molecule may affect Hb-O₂ affinity, cooperativity, and response to modulatory ligands. Within the hemoglobin mutations represented in this review (Table 1), all exhibit reduced cooperativity and only Hb Andrew-Minneapolis demonstrates a reduced Bohr effect (Adamson et al., 1969; Boyer et al., 1972; Nute et al., 1974; Zak et al., 1974; Wranne et al., 1983; Berlin et al., 2009). Lower cooperativity gives rise to the unique shape of the standard O₂ dissociation curve in humans with high Hb-O₂ affinity (Figure 1). However, the complex interactions between modulatory factors and subsequent effects on in vivo Hb-O₂ affinity have not been clearly elucidated in mutated hemoglobin molecules.

Due to a lower P₅₀, O₂ off-loading is likely compromised in those with high Hb-O₂ affinity. Evidence for compromised O₂ off-loading may be seen through compensatory increases in hematocrit resulting in a higher O₂ carrying capacity per unit of blood (Charache et al., 1966; Mangin, 2017; Shepherd et al., 2019). It is thought that the kidneys sense a reduction of O₂ off-loading and promote red blood cell production in response, functioning as a “critmeter” (Donnelly, 2001). In addition to an elevated hematocrit humans with high Hb-O₂ affinity likely develop skeletal muscle adaptations to compromised O₂ off-loading such as a greater percentage of non-oxidative (type II) muscle fibers than their counterparts with normal Hb-O₂ affinity (Wranne et al., 1983). Additionally, a greater accumulation of metabolic byproducts (e.g., lactate and H⁺) during high-intensity exercise have been reported in humans with high Hb-O₂ affinity compared to those with normal Hb-O₂ affinity (Länsimies et al., 1985; Dominelli et al., 2020). Those with high Hb-O₂ affinity demonstrate a similar lactate accumulation at the end of exhaustive exercise during both normoxia and hypoxia, whereas controls demonstrate a reduced lactate accumulation during hypoxia compared to normoxia (Dominelli et al., 2020). A possible explanation for these observations may be that humans with high Hb-O₂ affinity obtain similar power outputs in normoxia and hypoxia and therefore demonstrate a similar metabolite accumulation between the two conditions; whereas those with normal Hb-O₂ affinity have a reduced power output and lower lactate concentrations during hypoxia compared to normoxia.

The observed differences in skeletal muscle fiber composition and utilization of metabolic pathways supporting exercise between humans with high Hb-O₂ affinity and humans with normal Hb-O₂ affinity may be due to differences in O₂ off-loading kinetics and tissue P_O2 (Wranne et al., 1983). In general, many physiological compensatory responses coinciding with high Hb-O₂ affinity remain uncharacterized. Key areas for future investigation include adaptations to high Hb-O₂ affinity possibly affecting capillary density, blood flow distribution, and skeletal muscle aerobic capacity (Dempsey, 2020).

Brief periods of hypoxia require both cardiovascular and respiratory adjustments to maintain adequate O₂ delivery (Rowell and Blackmon, 1987; Bärtsch and Saltin, 2008; Naeije, 2010). One crucial immediate adjustment in response to hypoxia is increased ventilation which raises alveolar ventilation, increases arterial P_O2 and protects against arterial O₂ desaturation (Otis et al., 1956; Dempsey and Forster, 1982). At a given alveolar P_O2, humans with high Hb-O₂ affinity have similar minute ventilation compared to humans with normal Hb-O₂ affinity (Hebbel et al., 1977; Rossoff et al., 1980; Dominelli et al., 2019). Yet, due to the left-shifted nature of their oxygen dissociation curve, those with high Hb-O₂ affinity have a higher arterial O₂ saturation at a given alveolar P_O2 (Figure 2A; Hebbel et al., 1977; Rossoff et al., 1980; Dominelli et al., 2019).

In addition to increased ventilation, hypoxia is associated with increased cardiac output, primarily through an elevated heart rate (Brown and Grocott, 2013; Siebenmann and Lundby, 2015). As arterial O₂ saturation decreases during hypoxia, cardiac output increases and peripheral arterioles dilate to match O₂ delivery and demand (Ekblom et al., 1975; Phillips et al., 1988). These observations suggest that the change in heart rate during acute hypoxia is closely linked to systemic O₂ delivery (Casey and Joyner, 2011; Joyner and Casey, 2014; Siebenmann and Lundby, 2015). During acute hypoxia, humans with high Hb-O₂ affinity display a lesser increase in heart rate, and presumably cardiac output, likely due to better maintained arterial O₂ content (Figure 2B; Hebbel et al., 1977; Dominelli et al., 2019). Since arterial O₂ saturation remains fairly constant in humans with high Hb-O₂ affinity during modest reductions of P_O2, as occurs at moderately high altitude, arterial O₂ content is better maintained and heart rate increases to a lesser extent compared to those with normal Hb-O₂ affinity.

Peripheral chemosensors located at both the carotid and aortic bodies respond to acute changes in arterial P_O2 and P_CO2, such as during normobaric and hypobaric hypoxia (Lahiri and Forster, 2003). Stimulation of peripheral chemosensors during hypoxic exposure causes an increase in minute ventilation and sympathetic activity in an attempt to maintain O₂ homeostasis (Powell et al., 1998; Bernardi et al., 2001; Fletcher, 2001). Examination of humans with high Hb-O₂ affinity provides support for low P_O2 being a strong stimulus in the hypoxic ventilatory response, rather than arterial O₂ saturation or content (Hebbel et al., 1977; Rossoff et al., 1980; Dominelli et al., 2019). Some evidence suggests that aortic chemosensors sense changes in arterial O₂ content and heart rate is adjusted accordingly (Lugliani et al., 1971; Wasserman, 1978; Lahiri et al., 1980, 1981). Therefore, the lower heart rate during hypoxia among humans with high Hb-O₂ affinity compared to controls may be caused by decreased sensory stimulus of the aortic chemosensors (Dominelli et al., 2019). However, the mechanistic stimulation of the peripheral chemosensors requires that O₂ be dissociated from hemoglobin to be sensed (Lopez-Barneo et al., 2001). Therefore, the relationship between O₂ content and P_O2 sensed at the carotid chemosensors remains unclear and contention exists regarding mechanisms of O₂ sensing and regulation of systemic blood flow (Ward, 2008). Detailed discussions into the mechanism of O₂ sensing are provided elsewhere (Lopez-Barneo et al., 2001; Kumar and Prabhakar, 2012).

The observed relationship between ventilation and arterial O₂ saturation may present a disadvantage to humans with high Hb-O₂ affinity during acute hypoxic exposure. Since the stimulus for ventilation is closely linked to arterial P_O2 and not arterial O₂ saturation during brief periods of hypoxia (Biscoe, 1971; Guz, 1975; Weil and Zwillich, 1976), humans with high Hb-O₂ affinity have an excessive ventilatory response despite only a modest drop in arterial O₂ saturation and delivery (Figure 2A). Excessive ventilation increases O₂ consumption by respiratory muscles (Cherniack, 1959; Robertson et al., 1977). Although accounting for a small percentage of total O₂ consumption during rest, respiratory muscle O₂ demand increases during hyperventilation or exercise (Aaron et al., 1992; Coast et al., 1993; Dominelli et al., 2015). Thus, during exercise, there are increased and competitive demands for O₂ in metabolically active tissue including both exercising muscle and respiratory muscle (Harms et al., 2000; Sheel et al., 2001; Romer and Polkey, 2008; Dominelli et al., 2017). This competition for blood flow between respiratory and exercising muscle limits exercise tolerance at higher and extreme altitudes and is often referred to as “respiratory steal” (Pugh et al., 1964; Schoene, 2001; Helfer et al., 2016). The physiological consequences of “respiratory steal” are likely exacerbated at more extreme altitudes as hyperventilation, and thus metabolic demand of respiratory muscle, becomes more pronounced. Therefore, the excessive hyperventilation during acute hypoxic exposure may be disadvantageous for humans with high Hb-O₂ affinity due to increased O₂ consumption by respiratory muscles with minimal improvement in arterial O₂ saturation.

In addition to acute hypoxic exposure, the benefits of high Hb-O₂ affinity have been observed through examination of cardiorespiratory adjustments during 10-days of residing at high altitude (Leadville, Colorado, ∼3100 m elevation) (Hebbel et al., 1978). Two humans with high Hb-O₂ affinity and two of their siblings with normal Hb-O₂ affinity were examined during the acclimatization period. Changes in arterial 2,3-DPG concentration and pH were similar during the stay at high altitude in both sets of siblings. However, peak and average heart rate during acclimatization were lower in the siblings with high Hb-O₂ affinity. During hypoxia, impaired O₂ delivery to the kidneys prompts erythropoietin production (Donnelly, 2001; Nangaku and Eckardt, 2007; Haase, 2013). Erythropoietin stimulates red blood cell production and leads to a subsequent increase in O₂ carrying capacity to compensate for impaired O₂ delivery (Erslev, 1991; Jelkmann, 2011). Humans with high Hb-O₂ affinity showed smaller increases in erythropoietin production when residing at high altitude (Hebbel et al., 1978). A lesser erythropoietin production during high-altitude acclimatization suggests that O₂ delivery is better preserved among humans with high Hb-O₂ affinity. Similarly, Hall et al. (1936) showed that mammals native to high altitude display a reduced erythropoietic response during travel from low altitude to high altitude. Combined, these findings suggest that lessened cardiovascular adjustments are needed to maintain adequate O₂ delivery during high-altitude acclimatization in humans with high Hb-O₂ affinity compared to those with normal Hb-O₂ affinity.

Marked physiological compensations are required to maintain homeostasis during sojourn to extreme altitudes (West, 2006). Hb-O₂ affinity increases at altitudes greater than ∼5400 m due to severe respiratory alkalosis with insufficient renal compensations (see section “Hemoglobin-Oxygen Affinity”). During ascent to the summit of Mt. Everest, ∼8100 m, climbers had a reduction in P₅₀ from ∼26 mmHg to less than ∼20 mmHg (West, 1984). A more recent study examining blood oxygenation of four climbers reported arterial saturations ranging from 34 to 70% at the summit of Everest (Grocott et al., 2009). Without an increase of Hb-O₂ affinity due to respiratory alkalosis it is likely that humans would not be able to reach the summit without supplemental O₂.

As extreme altitude challenges the ability to transport O₂ from atmospheric air to tissue, the modulation of Hb-O₂ affinity is crucial to maintain adequate O₂ consumption. Enhanced O₂ loading in the lungs due to high Hb-O₂ affinity is even more advantageous at extreme altitude than at high altitude, where ambient P_O2 can fall to as low as 40 mmHg, outweighing potential limitations in O₂ off-loading (Eaton et al., 1974). The ventilatory response during hypoxia is similar between humans with genetic mutations leading to high Hb-O₂ affinity and those with normal Hb-O₂ affinity (Hebbel et al., 1977; Rossoff et al., 1980; Dominelli et al., 2019). Under the circumstances of extreme altitude, humans with high Hb-O₂ affinity may develop respiratory alkalosis to a similar degree as observed in humans with normal Hb-O₂ affinity (West, 1984; Grocott et al., 2009). In addition, some genetic hemoglobin mutations demonstrate a preserved Bohr effect, such that Hb-O₂ affinity would decrease during respiratory alkalosis by a similar magnitude compared to non-mutated hemoglobin (Adamson et al., 1969; Boyer et al., 1972; Nute et al., 1974; Wranne et al., 1983; Berlin et al., 2009). A physiological consequence of respiratory alkalosis would be further left-shifted O₂ dissociation curve adding additional protection against arterial desaturation. Therefore, humans with genetic modifications resulting in high Hb-O₂ affinity and a preserved Bohr effect may ascend to extreme altitudes with fewer physiological complications (i.e., Acute mountain sickness, high-altitude cerebral edema, and impaired cognitive function) compared to sojourners with normal Hb-O₂ affinity. However, to our knowledge no humans with genetic high Hb-O₂ affinity have been examined at altitudes greater than ∼3100 m and the proposed physiologic responses to higher and extreme altitudes are theoretical.

Groups of indigenous humans who have resided at high altitude for many generations display genotypic and phenotypic adaptations to the hypoxic environment (Beall, 2007, 2014; Moore, 2017; Tymko et al., 2019; Storz, 2021). Recent evidence has suggested an adaptive increase of Hb-O₂ affinity among high altitude natives of the Qinghai-Tibetan Plateau (>3500 m) compared to sea-level residents (Simonson et al., 2014; Li et al., 2018). However, others have reported that some high-altitude populations [Nepalese (>3800 m), Peruvian (>4500 m), and Qinghai-Tibetan (>3500 m) natives] do not show this adaptive increase in Hb-O₂ affinity (Samaja et al., 1979; Winslow et al., 1981; Tashi et al., 2014). Additional studies may improve understanding of changes in Hb-O₂ affinity observed among high-altitude natives and molecular mechanisms underlying such adaptation.

The Qinghai-Tibetan natives had a P₅₀ ∼2 mmHg lower than the sea-level residents (24.5 vs. 26.2 mmHg, respectively) (Simonson et al., 2014). However, the high-altitude natives did not display improvements in pulmonary gas exchange or peak exercise capacity during hypoxia compared to the sea-level residents, suggesting no clear benefit of high Hb-O₂ affinity in the population examined. These findings, contradictory to those observed in humans with genetic mutations resulting in high Hb-O₂ affinity, could be explained by differences in the magnitude of P₅₀. The high-altitude natives studied had a P₅₀ of ∼25 mmHg, in contrast to values ranging from 12 to 17 mmHg observed in humans with genetic mutations resulting in high Hb-O₂ affinity (Table 1). Therefore, the P₅₀ observed in the high-altitude native population is probably not low enough to warrant significant alterations in pulmonary gas exchange, O₂ extraction, and exercise capacity during hypoxia. In addition, adaptations of high-altitude populations, which affect multiple steps within the O₂ transport cascade (Beall, 2007), may confound our ability to clearly dissociate the role of increased Hb-O₂ affinity in humans native to high altitude.

Studies examining the effects of pharmacologically induced high Hb-O₂ affinity on O₂ consumption during normoxia have provided discordant results in both humans and animals (Riggs et al., 1973; Woodson et al., 1973; Wranne et al., 1974; Valeri et al., 1975; Yhap et al., 1975; Bakker et al., 1976; Malmberg et al., 1979; Ross and Hlastala, 1981; Woodson and Auerbach, 1982; Stewart et al., 2020, 2021). Recently, Stewart et al. (2021) showed that pharmaceutical induction of high Hb-O₂ affinity (only ∼2 mmHg decrease in P₅₀) using voxelotor reduced normoxic maximal O₂ consumption (V˙O_2max) in humans. The decrement in normoxic V˙O_2max observed by Stewart et al. (2021) could be due to both an increase in Hb-O₂ affinity and a reduced Bohr effect: the transient reduction of Hb-O₂ affinity with decreasing pH (Pochron et al., 2019). A reduced Bohr effect in exercising muscle would further compromise O₂ off-loading, particularly during periods of high metabolic demand (Mairbäurl, 2013). Conversely, some mathematical models suggest that normoxic V˙O_2max is relatively insensitive to modest increases in Hb-O₂ affinity despite limitations in O₂ off-loading (Wagner, 1997; Shepherd et al., 2019).

In corroboration with results found through mathematical modeling, humans with high Hb-O₂ affinity show no difference in normoxic V˙O_2max values compared to similar age, sex-matched controls with normal Hb-O₂ affinity (Länsimies et al., 1985; Dominelli et al., 2020). However, there is evidence for altered metabolic processes among humans with high Hb-O₂ affinity compared to controls during exercise testing. During cycling exercise in normoxia, humans with high Hb-O₂ affinity may have greater reliance on anaerobic metabolism during heavy to maximal exercise, as evidenced by lower blood pH and pronounced lactate production compared to controls (Wranne et al., 1983; Länsimies et al., 1985; Dominelli et al., 2020). In addition, humans with high Hb-O₂ affinity seem to display a worsened exercise efficiency during cycling, i.e., higher O₂ consumption for a given power output (Dominelli et al., 2020). Theoretically, compromised O₂ off-loading due to high Hb-O₂ affinity may give rise to the greater reliance on anaerobic metabolism, which contributes to the worsened exercise efficiency observed (Dominelli et al., 2020). In brief, current evidence indicates that humans with high Hb-O₂ affinity have similar normoxic V˙O_2max values despite altered metabolic processes during high-intensity exercise.

Little is known about the relationship between high Hb-O₂ affinity and compensatory mechanisms that facilitate adequate O₂ extraction. Wranne et al. (1983) demonstrated that the arterial-venous O₂ extraction was abnormally low during exercise in humans with high Hb-O₂ affinity, suggesting that O₂ off-loading may be compromised within muscle during whole-body exercise. However, humans with high Hb-O₂ affinity had a ∼25% greater O₂ carrying capacity than those with normal Hb-O₂ affinity, likely compensating for the diminished arterial-venous O₂ extraction both at rest and during exercise. The potential benefits of high Hb-O₂ affinity are likely contingent on the capacity to extract O₂ from blood (Wearing et al., 2021). The capacity of O₂ off-loading and diffusion to the mitochondria are crucial to maximize O₂ utilization in cases of high Hb-O₂ affinity, especially during peak whole-body exercise. Therefore, future research should focus on the relationship between high Hb-O₂ affinity and compensatory mechanisms which facilitate adequate O₂ extraction within peripheral tissue such as alterations in the microvascular architecture, flow of the red blood cells through the microvasculature, and the diffusion gradients driving O₂ to the mitochondria.

Maximal O₂ consumption in humans decreases with increasing severity of hypoxia (Faulkner et al., 1968; Grover, 1970; Lawler et al., 1988; Ferretti et al., 1997; Wehrlin and Hallén, 2006; Wagner, 2010; West, 2010). However, humans with high Hb-O₂ affinity are better able to maintain V˙O_2max during hypoxia compared to those with normal Hb-O₂ affinity (Figure 3). As previously described, Hebbel and colleagues examined four siblings, two with high Hb-O₂ affinity and two with normal Hb-O₂ affinity, during 10 days of high-altitude acclimatization (Leadville, Colorado, ∼3100 m elevation). At high altitude V˙O_2max decreased by ∼28 and 19% compared to sea-level values in the two siblings with normal Hb-O₂ affinity (Hebbel et al., 1978). On the other hand, the two siblings with high Hb-O₂ affinity did not demonstrate a reduction in V˙O_2max at high altitude compared to low altitude (Hebbel et al., 1978).

Similarly, experiments using acute normobaric hypoxia showed that humans with high Hb-O₂ affinity had better maintained V˙O_2max during hypoxia compared to humans with normal Hb-O₂ affinity (Dominelli et al., 2020). In addition, peak power output during cycling exercise was better preserved in those with high Hb-O₂ affinity (Dominelli et al., 2020). At both high altitude and normobaric hypoxia, there was no difference in maximal heart rate during exercise in humans with high Hb-O₂ affinity compared to those with normal Hb-O₂ affinity (Hebbel et al., 1978; Dominelli et al., 2020). Previous studies indicate that an increase in blood viscosity associated with an elevated hematocrit, common in humans with chronic high Hb-O₂ affinity, may limit blood flow and maximal cardiac output in humans (Richardson and Guyton, 1959; Schumacker et al., 1985; Çınar et al., 1999). On the contrary, some studies suggest that systemic blood flow at rest and during exercise within animals is not reduced at a hematocrit of ∼50–60% (Gaehtgens et al., 1979; Schumacker et al., 1985; Lindenfeld et al., 2005). However, hematocrits greater than 60% likely result in a substantially elevated blood viscosity such that systemic blood flow is restricted (Weisse et al., 1964; Gaehtgens et al., 1979; Schumacker et al., 1985). Therefore, it is unclear whether cardiac output and systemic blood flow is limited among humans with high Hb-O₂ affinity where hematocrit often ranges from ∼55 to 65%.

The reduction of V˙O_2max during hypoxia is directly related to the degree of arterial desaturation (Hughes et al., 1968; Calbet et al., 2003a). As such, a higher arterial O₂ saturation in humans with high Hb-O₂ affinity for a given level of hypoxia likely contributes to the preservation of hypoxic V˙O_2max (Figure 3). In humans with normal Hb-O₂ affinity at high altitude, hypoxic V˙O_2max is less than values measured at sea-level and hypoxic V˙O_2max either remains the same or progressively increases during acclimatization (Saltin et al., 1968; Calbet et al., 2003b). Despite acclimatization, hypoxic V˙O_2max does not reach values previously measured at sea-level (Calbet et al., 2003b). In contrast, humans with high Hb-O₂ affinity have a better maintained hypoxic V˙O_2max upon transition to high altitude, but it is unknown how humans with high Hb-O₂ affinity may acclimatize to high altitude and subsequent effects on hypoxic V˙O_2max.