With haemoglobin as with politics – should we shift right or left?

The relative importance of a rightvs. left-shifted oxyhaemoglobin dissociation curve (ODC) in adaptation to environmental hypoxia has been debated since the 1940s. Over the past several decades, textbook accounts have largely supported the importance of a reduced HbO2 affinity secondary to increased red cell metabolism of 2,3-diphosphoglycerate (DPG). In theory, this right-shifted ODC would protect tissue capillary PO2 and improve O2 off-loading via enhanced diffusion at the peripheral tissue. However, we need to consider that this proposed advantage due to slightly higher ‘standard P50’ (pH 7.40, PCO2 40, 37°) may not always translate to in vivo conditions under some durations and/or severities of hypoxic exposure, where an accompanying hypocapnic alkalosis will counteract the 2,3-DPG-induced rightward shift to varying degrees via the Bohr effect (Barcroft et al. 1923; Winslow, 2007). In addition, comparative physiologists remind us that an increased, not decreased, HbO2 affinity exists in many hypoxia-tolerant species, including birds, fish, and even in some hypoxia-dwelling mammals including the human fetus (Storz, 2016). The proposed advantage of a decreased P50 in hypoxia resides in improved systemic O2 transport as SaO2 is increased at any given arterial PO2 and a more non-linear slope of the left-shifted ODC would better preserve the alveolar gas to capillary PO2 gradient responsible for pulmonary diffusion. So, given these opposing influences would you prefer a liberal or conservative shift in HbO2 affinity? or are you indifferent? or ‘undecided’? The proposed enhancements in oxygen delivery conferred by rightand left-shifted ODC are likely to be especially important during exercise in hypoxic environments. However, most theoretical models predict that even substantial increases or decreases in P50 would confer little effect on VO2 max over a wide range of altitudes. Apparently, these predictions reflect balanced effects of a changing P50 on pulmonary vs. muscle O2 exchange. Dominelli and colleagues at the Mayo Clinic have now provided in the latest issue of the Journal experimental support to the ‘lefties’ camp in this controversy. They studied otherwise healthy patients with beta chain mutated Hb variants and high O2 affinity Hb (HAH) who possess a standard P50 which averaged only 55–60% of that in controls (Dominelli et al. 2020). Their study confirms prior case studies of HAH patients and importantly has added statistical power, included some siblings of the HAH patients in the control group, and added measures of arterial blood oxygenation and acid-base status during incremental exercise to volitional maximum in normoxia and acute moderate hypoxia simulating 3100 m altitude. As predicted, during hypoxic exercise in the HAH group: a) SaO2 was considerably higher than controls at comparable PaO2; and b) the alveolar to arterial PO2 difference was unchanged from normoxia whereas it was widened in controls. Peak work rates were reduced to variable extents in both groups at 3100 m simulated altitude, as control subjects averaged −12 ± 5% below normoxia, with most showing a >10% decline; whereas HAH subjects averaged −4 ± 5% with the majority showing <5% decline. Most importantly, the individual variability in these hypoxic effects on max exercise appeared to be determined by the arterial HbO2 saturation, as evidenced by the strong correlation between hypoxia-induced reductions in VO2 peak and the corresponding reductions in SaO2. The importance of exercise-induced arterial HbO2 desaturation as a key determinant of systemic O2 transport and exercise performance parallels that demonstrated in many highly trained athletes who experience marked decrements in performance at even mild elevations in altitude. This thorough documentation of a resistance to the negative effects of hypoxia on peak exercise performance in humans with high HbO2 affinity and therefore enhanced systemic O2 transport raises some fascinating questions: