The dependence of maximum oxygen uptake on hemoglobin-oxygen affinity and altitude: a computational modeling approach

Background: Hemoglobin, the primary oxygen-carrying protein in humans, provides the intermediate link between pulmonary oxygen uptake and tissue oxygen consumption. Oxygen transport is greatly influenced by the hemoglobin-oxygen affinity, which is commonly characterized by the metric P 50 - defined as the oxygen tension at which 50% of hemoglobin is saturated. Humans with rare hemoglobin mutations causing a low P 50 (high hemoglobin-oxygen affinity) have demonstrated remarkable preservation of exercise tolerance at high altitude conditions (~3,000m). However, the influence of a low P 50 on V̇O 2 max at extreme altitudes (>5,500m) remains largely unexamined. To examine the dependence of V̇O 2 max on P 50 and altitude, we developed a computational model of oxygen uptake and utilization. We hypothesized that a low P 50 would result in a better maintained V̇O 2 max at extreme altitudes compared to conditions of normal P 50 and high P 50 (low hemoglobin-oxygen affinity). Methods: We created a model that couples pulmonary oxygen uptake with systemic oxygen utilization to estimate V̇O 2 max as a function of P 50 , hemoglobin concentration, and altitude. Fixed values for cardiac output and tissue oxygen demand for V̇O 2 max at sea level were assigned in accordance with experimental data. The pulmonary oxygen uptake model assumes a single blood compartment exposed to alveolar gas, from which the arterial oxygen tension may be estimated from venous input. Using the alveolar gas equation, we interpolated respiratory parameters from data obtained during human sojourn to the summit of Everest. The systemic oxygen utilization model uses arterial input parameters along with Michaelis-Menten kinetics to compute oxygen consumption. The Fick principle was used to determine the venous oxygen tension, which was assumed to approximate tissue oxygen tension. From these values, systemic oxygen extraction and V̇O 2 max were determined as a function of P 50 , hemoglobin concentration, and altitude. Results: We present the results for several cases of P 50 (low, normal, and high) and hemoglobin concentrations as a function of altitude. For a low P 50 , the model demonstrated a greater arterial oxygen saturation, greater oxygen content, and lower systemic extraction at extreme altitudes compared to values determined for cases of normal and high P 50 . Additionally, a low P 50 led to better maintenance of V̇O 2 max at ~8,850m (~38% decrease from sea-level V̇O 2 max) compared to values determined for normal P 50 and high P 50 (~53% and ~67% decrease from sea-level V̇O 2 max, respectively, P<0.05). Conclusion: This model demonstrates the importance of P 50 in the determination of V̇O 2 max at various altitudes. At low altitudes, a low P 50 does not confer an advantage in terms of oxygen utilization, likely due to diffusive oxygen limitations. However, at high and extreme altitudes, a greater convective oxygen transport associated with a low P 50 likely outweighs impairments in oxygen diffusivity. This project was supported by the National Institutes of Health R-35-HL139854. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.