Wheatley, Courtney M.

In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.

AbstractThis study aimed to evaluate the influence of physical activity on incidence of acute mountain sickness (AMS) by continuous activity monitoring in a free-living sample of South Pole workers over the initial 72 h at altitude exposure of 2,840 m (9,318 ft). Body Media activity monitors were worn by 47 healthy participants. AMS was defined by the Lake Louise symptom questionnaire. Venous blood samples were taken at sea level and approximately 48 h after high altitude exposure. AMS incidence was 34% (n=16/47) over the first 48 h and 40% (n=19/47) over 72 h. On day 2 at high altitude, individuals with AMS demonstrated a significantly greater increase in the percent change in physical activity metrics from baseline: total energy expenditure 19±13 vs. 5±7%, total steps 65±51 vs. 10±18%, metabolic equivalent of tasks 21±13 vs. 7±13%, and time spent performing moderate to vigorous physical activity 114±79 vs. 26±27% for individuals with AMS vs. no AMS, respectively, p<0.05. In addition, erythropoietin and vascular endothelial growth factor were 1.69 and 1.75 times higher, respectively, in those with AMS. In conclusion, workers who engaged in increased physical activity and activity intensity during initial exposure to the South Pole were more susceptible to developing AMS.

Background: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aβ-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a β-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged β-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. Methods: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C 2 H 2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). Results: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m 2 vs healthy = 1.84 ± 0.04 m 2 , P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m 2 vs healthy = 39.9 ± 2.5 mL/beat/m 2 , P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm −5 vs healthy = 1616 ± 74 dynes*s/cm −5 , P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV ( P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F (2,14) = 7.982, P < .01) and SV index (F (2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). Conclusions: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

Cardiac hemodynamic assessment during cardiopulmonary exercise testing (CPET) is proposed to play an important role in the clinical evaluation of individuals with cystic fibrosis (CF). Cardiac catheterization is not practical for routine clinical CPET. Use of oxygen pulse (O 2 pulse) as a noninvasive estimate of stroke volume (SV) has not been validated in CF. This study tested the hypothesis that peak exercise O 2 pulse is a valid estimate of SV in CF. Measurements of SV via the acetylene rebreathe technique were acquired at baseline and peak exercise in 17 mild-to-moderate severity adult CF and 25 age-matched healthy adults. We calculated [Formula: see text]. Baseline relationships between SV and O 2 pulse were significant in CF ( r = .80) and controls ( r = .40), persisting to peak exercise in CF ( r = .63) and controls ( r = .73). The standard error of estimate for O 2 pulse-predicted SV with respect to measured SV was similar at baseline (14.1 vs 20.1 mL) and peak exercise (18.2 vs 13.9 mL) for CF and controls, respectively. These data suggest that peak exercise O 2 pulse is a valid estimate of SV in CF. The ability to noninvasively estimate SV via O 2 pulse during routine clinical CPET can be used to improve test interpretation and advance our understanding of the impact cardiac dysfunction has on exercise intolerance in CF.