Box Extension 24.5

Blood and Circulation in Mammals at High Altitude

The study of blood O₂ transport in humans and other mammals at high altitude is, in its own particular way, one of the most intriguing chapters in the annals of evolutionary physiology. This is true because in the past 30 years, the blood responses of lowland people at high altitude have morphed from being touted as exceptional examples of adaptation to being cited as defining examples of maladaptation. A key reason for the change of perspective has been a gradual recognition of the important point discussed in Box 23.2 that responses of predominantly lowland species—such as humans—at high altitude may sometimes represent misplaced expressions of responses that evolved in lowland populations to meet lowland challenges. For example, when the low atmospheric O₂ partial pressure at altitude induces tissue hypoxia, the hypoxia might trigger responses—not necessarily advantageous at high altitude—that evolved to help with lowland anemia. As we discuss blood and circulation at high altitude, keep in mind a critical point emphasized in Box 23.2: Lowland people and lowland species spending time at high altitude need to be distinguished from native highland groups. *

If you think back to the oxygen cascade for people in the high Andes in Box 23.2, you will recall that when people—whether native lowlanders or highlanders—are exposed to the reduced atmospheric partial pressure of O₂ at high altitude, they do not experience an equal reduction in their venous O₂ partial pressure. The venous partial pressure, in fact, is reduced far less than the atmospheric partial pressure. A key reason for this conservation of venous O₂ partial pressure is blood O₂ transport. The drop in O₂ partial pressure between arterial and venous blood is much smaller at high altitude than at sea level (see Box 23.2). This smaller drop in O₂ partial pressure is important because it helps keep the O₂ partial pressure in the systemic tissues from falling too low.

The principal explanation for the reduced arteriovenous (a-v) drop in O₂ partial pressure at high altitude does not entail any special adaptations. Instead, the reduced a-v drop is simply a consequence of the shape of the mammalian oxygen equilibrium curve. Living at high altitude lowers the arterial O₂ partial pressure. Figure 24.6 illustrates the consequence: When the arterial O₂ partial pressure is moved off the plateau of the equilibrium curve, there is a sharp reduction in the a-v drop in partial pressure required for the blood to yield any particular quantity of O₂.

In the search for special high-altitude adaptations, three aspects of blood and circulation have been studied: (1) the oxygen-carrying capacity of the blood, (2) the hemoglobin O₂ affinity, and (3) the rate of blood circulation.

Regarding the oxygen-carrying capacity, when lowland people and some other species of lowland mammals go to high altitude, their oxygen-carrying capacities typically rise to well above sea-level values. Secretion of erythropoietin (see Box 24.2) is increased, causing an increase in the number of red blood cells (RBCs) per unit of blood volume: a state known as polycythemia (“many cells in the blood”). This change can be dramatic. For example, if lowland people go from sea level to 4000–5000 m, their oxygen-carrying capacity may increase from 20 to 28 mL O₂ per 100 mL of blood. This sort of response was long touted as a vivid illustration of adaptative phenotypic plasticity. By now, however, sufficient comparative data have accumulated that we can make the following statement with good confidence: Species of mammals (and birds) that are native to high altitudes do not have unusually high RBC concentrations or oxygen-carrying capacities. Moreover, among people, some native highland peoples—notably the Tibetan highlanders—do not exhibit the strong erythropoietin response shown by lowlanders and have oxygen-carrying capacities near those of lowlanders at sea level. Why is an elevated RBC concentration in general not favored at high altitude? Researchers now have evidence that an elevated RBC concentration can make the blood too viscous, placing a greater workload on the heart and sometimes interfering with regional blood flow. In an effort to carry out a direct test, researchers have medically removed RBCs from lowland people displaying high RBC concentrations at high altitude; some (but not all) studies of this sort have found that the subjects experienced either no change or an improvement in their ability to function. Overall, careful comparative studies have shown that evolution favors little or no increase in RBC concentration at high altitude. The response of lowland people probably evolved as a mechanism for lowlanders near sea level to compensate for anemia (caused by disease or blood loss) and is a misplaced response—triggered erroneously—at high altitude.

With regard to O₂ affinity, lowland humans and some other lowland species undergo an increase in the concentration of 2,3-DPG in their RBCs at high altitude. When this change was first discovered, it was claimed to help prevent tissue hypoxia by lowering the O₂ affinity of hemoglobin and thus promoting O₂ unloading into the systemic tissues. By now we realize that this claim might not be even theoretically correct because it is myopically focused on just one part of the oxygen equilibrium curve and fails to consider effects on loading as well as unloading. More to the point, the collection of comparative data on many additional species now permits confidence in the following conclusion: Species of mammals (and birds) native to high altitudes typically have either ordinary O₂ affinities or particularly high—sometimes dramatically high—O₂ affinities (which help hemoglobin take up O₂ in the lungs). Thus, if lowland humans at high altitude have a reduced affinity, we must be wary of interpreting it as being beneficial. This topic is discussed further in Box Extension 24.5.

Regarding the rate of circulation, although an increase might at first seem logically to be expected at high altitude, cardiac output is not systematically elevated in humans or other mammals, either at rest or at any given level of exercise. An increase in circulatory rate is not a general attribute of high-altitude animals, and theoretical analyses discussed in Box Extension 24.5 clarify why. This said, researchers recently found that in the special case of Tibetan highlanders, circulatory rate is unusually high and a key to limiting tissue hypoxia.

In all, the study of blood and circulation at high altitude has a complex history, which we can see in retrospect got off on the wrong foot because researchers sometimes assumed uncritically that the responses of lowland humans must be beneficial. Taking a broad view, hemoglobin O₂ affinity is often particularly high in native highland mammals and birds, and this is the most convincing generality now known in the study of blood and circulation.

Exploring hemoglobin O₂ affinity in more depth, an interesting conclusion from recent research is that we must question the reality of the decrease in O₂ affinity originally reported for humans at high altitude. Much of the early evidence for this response came from studies of red cell 2,3-DPG in lowland people sojourning at high altitude. Researchers now recognize that the effects of any one hemoglobin modulator cannot be interpreted in isolation: If the concentration of 2,3-DPG within RBCs increases (as initially reported), that change in itself does not necessarily mean that the affinity of hemoglobin for O₂ goes down. Blood pH is typically shifted in an alkaline direction in lowlanders at high altitude because the hyperventilation we discussed in Box 23.2 tends to lower the CO₂ concentration of the blood. With the blood pH elevated and the blood CO₂ concentration lowered, the operation of the Bohr effect could cancel the 2,3-DPG effect. A recent careful reassessment of people native to the Andes revealed that their hemoglobin O₂ affinities are indistinguishable from those of people at sea level. Moreover, during the American Medical Expedition to Mount Everest in 1981, a famous research expedition, the P50 values of the climbers—all native lowlanders—remained unaltered up to about 6000 m (then fell), and in a recent simulation study (“Everest II”) during which lowland people lived in a hypobaric chamber for 40 days, the Bohr effect and 2,3-DPG effect offset each other so that the P50 stayed unchanged. Humans, therefore, in fact seem often to resemble many native-highland mammals in having unaltered O₂ affinities at high altitude.

As mentioned earlier, cardiac output is not systematically elevated in humans or other mammals at high altitude, although Tibetan highlanders exhibit an unusually high circulatory rate. Recent theoretical analyses help explain why an increase in circulatory rate is not the norm. To see the point of these analyses, consider a person at rest. At high altitude, the O₂ partial pressure in the lungs is lowered by comparison with sea level. Consequently, as noted earlier in this box, the O₂ partial pressure of arterial blood is on the steep part of the oxygen equilibrium curve, not on the high-partial-pressure plateau. With the arterial partial pressure on the steep part of the curve, any change in the arterial O₂ partial pressure will alter the O₂ content (mL O₂/100 mL) of the arterial blood significantly. If the heart pumps blood faster to try to assist with the problems of high altitude, the arterial O₂ partial pressure tends to go down a bit, in part because the speeding blood has a reduced opportunity to reach full equilibrium with alveolar air. On the steep part of the oxygen equilibrium curve, the reduction in arterial O₂ content because of decreased equilibration may be great enough that it offsets the advantages of pumping more blood per unit of time. Theory indicates, therefore, that in general the heart is not in a good position to help raise tissue partial pressures of O₂ at high altitude.

* Altitude physiology is discussed also in Boxes 8.3 and 23.2 (which includes information on high-flying birds).