View Abstract

A2367 - Effect of GBT440, an R-State Stabilizer of Hemoglobin, on Hypoxic Maximal Exercise
Author Block: G. Stewart1, S. Chase1, T. Cross1, B. Ziegler1, M. Joyner2, T. Curry2, J. Lehrer3, N. Vlahakis3, B. Johnson1; 1Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States, 2Department of Anesthesia and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States, 3Global Blood Therapeutics, South San Francisco, CA, United States.
Introduction: Arterial hypoxemia may result from pathophysiologic states such as idiopathic pulmonary fibrosis or from environmental effects such as rapid ascent to high altitude. In both of these states, reduced loading of oxygen onto hemoglobin reduces exercise capacity, affects quality of life, and may be related to the development of other symptoms. Left shifting of the oxygen dissociation curve could improve oxygen uptake and arterial oxygen saturation; however, it is unknown how this would affect exercise capacity under hypoxic conditions. We investigated the effect of GBT440, an allosteric modulator of hemoglobin, on hypoxic exercise in healthy subjects and hypothesized that GBT440 would improve oxygen saturation without reducing maximal exercise capacity. Methods: 8 subjects (5M/3F, Age:36±7y, BMI:24±2kg·m-2, VO2, peak:49±2ml·kg-1·min-1) were recruited. Subjects performed an incremental exercise test to exhaustion under hypoxic (12.5% O[[Unsupported Character - Codename ­]]2) conditions. During each 3 minute stage, gas exchange was continuously collected, an arterial blood sample was taken, and cardiac output was measured using the open circuit acetylene technique. Subjects took 900mg of GBT440 per day for 14 days before repeating the maximal exercise test. Results: Subjects reached a similar VO2peak and peak power with small decrements in time to exhaustion (pre vs post: Power; 208±10W vs 208±10W; VO2peak: 35±2ml·min-1·kg-1 vs 33±2ml·min-1·kg-1 Time to exhaustion; 13.6±0.5s vs 13.0±0.6). VCO2 and ventilation were similar between days at all stages of the exercise test, but the VE/VCO2 ratio was elevated on drug. The rating of perceived exertion and dyspnea were similar between days. Cardiac output, heart rate, stroke volume, and mean arterial pressure were similar between days. Arterial oxygen saturation (SaO2), partial pressure of oxygen (PaO2), and oxygen content (CaO2) were increased throughout exercise on drug (pre vs post: SaO2, rest: 83±3% vs 91±2%, peak: 71±3% vs 78±2%; PaO2, rest: 49±4mmHg vs 60±5mmHg, peak: 41±2mmHg vs 45±2mmHg; CaO2, rest: 17±1mLO2·dL blood vs 19±1mLO2·dL blood, peak: 16±1mLO2·dL blood vs 17±1mLO2·dL blood). The arterial-venous oxygen difference was similar between days. Conclusion: GBT440 improves oxygen saturation causing an increase in the arterial partial pressure of oxygen and oxygen content during hypoxic exercise, while maintaining the extraction of oxygen at the tissue. VO2 was not reduced, and subjects did not perceive a difference in exercise intensity or dyspnea. These results suggest that GBT440 could be an effective measure to improve oxygen saturation in several physiological conditions; however, further studies should investigate the effect of improved oxygen saturation on patient outcomes.