Influence of high affinity haemoglobin on the response to normoxic and hypoxic exercise

Abstract

Key points: Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange.

Abstract: The longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P₅₀ = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P₅₀ = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end-exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects' oxyhaemoglobin saturation ( $S_{a,O_2}$ ) was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake ( ${\dot{V}}_{O_2\max }$ ) (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in ${\dot{V}}_{O_2\max }$ between trials was related to the change in $S_{a{O}_2}$ (r = -0.75, p < 0.0001). Compared to normoxia, the controls' alveolar-to-arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia.

Keywords: maximal oxygen uptake; oxygen delivery; pulmonary gas exchange; submaximal exercise.

Figure 1.

Variables relating to acid base status at the end of exercise. Thin dashed lines are individual points. The 21% and 15% represent the inspired oxygen concentrations for the normoxia and hypoxia trial respectively. PaCO₂, arterial carbon dioxide tension. **, significantly effect of haemoglobin; †, significantly effect of inspirate. p<0.05.

Figure 2.

Relative change in maximal oxygen uptake (Panels A and B) and peak power output (Panels C and D) during hypoxic exercise for those with normal haemoglobin (Panels A and C) and high affinity haemoglobin (Panels B and D). Individual values are presented for each trial along with the group means±SD (Average). The 21% and 15% represent the inspired oxygen concentrations for the normoxic and hypoxic trial, respectively. Hb, haemoglobin, ⩒O_2max, maximal oxygen uptake. *, significantly different from the normal haemoglobin.

Figure 3.

The relationship between the change in maximal oxygen uptake between the exercise trials and the change in oxyhaemoglobin saturation between trials at maximal exercise. ⩒O_2max, maximal oxygen uptake; SaO₂, arterial oxygen saturation.

Figure 4.

Pulmonary gas exchange throughout both exercise trials. Panel A depicts individual values for each subject whereas Panel B is the average regression for the groups. AaDO₂, alveolar to arterial oxygen difference; ⩒O₂, oxygen uptake. *, significantly different from all other groups. P<0.05.

Figure 5.

Arterial blood gases, alveolar to arterial oxygen gradients and oxyhaemoglobin saturation for both exercise trials in controls and high affinity haemoglobin variants. There was a significant three-way interaction for Panels C and D. For Panel C, the asterix (*) represents the controls on room air were significantly lower than all other groups. For Panel D, the Asterix (*) represents that the high affinity subjects had significantly greater oxyhaemoglobin saturation for each inspirate. PaO₂, arterial oxygen tension; PaCO₂, arterial carbon dioxide tension; AaDO₂, alveolar to arterial oxygen difference; FO₂Hb, fraction of haemoglobin saturated with oxygen. ⩒O₂, oxygen uptake. **, significant main effect of inspirate; ‡, significant main effect of intensity type. P<0.05.

Figure 6.

Arterial oxygen content, haematocrit, and mean arterial pressure along with heart rate for the two exercise trials. CaO₂, arterial oxygen content; MAP, mean arterial pressure. ⩒O₂, oxygen uptake. There was a significant main effect for exercise intensity for all panels. **, significant main effect of inspirate; †, significant main effect of haemoglobin type, ‡ significant main effect of intensity P<0.05.

Figure 7.

Arterial metabolite variables and economy during both exercise trials. ⩒O₂, oxygen uptake. **, significant main effect of inspirate, †, significant main effect of haemoglobin type ‡ significant main effect of intensity. P<0.05.

Figure 8.

Ventilatory variables during both exercise trials in controls and high affinity haemoglobin variants. ⩒_E, minute ventilation; RER, respiratory exchange ratio; ⩒O₂, oxygen uptake; ⩒CO₂, carbon dioxide production. **, significant main effect of inspirate, ‡ significant main effect of intensity. P<0.05.