Wiggins, Chad C.

AbstractOxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum human capacity for oxygen uptake and utilization (V̇O2max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin‐oxygen affinity. However, the effect of such alterations on V̇O2max at extreme altitudes remains largely unknown due to the rarity of mutations affecting hemoglobin‐oxygen affinity. This work uses a mathematical model that couples pulmonary oxygen uptake with systemic oxygen utilization under conditions of high metabolic demand to investigate the effect of hemoglobin‐oxygen affinity on V̇O2max as a function of altitude. The model includes the effects of both diffusive and convective limitations on oxygen transport. Pulmonary oxygen uptake is calculated using a spatially‐distributed model that accounts for the effects of hematocrit and hemoglobin‐oxygen affinity. Systemic oxygen utilization is calculated assuming Michaelis–Menten kinetics. The pulmonary and systemic model components are solved iteratively to compute predicted arterial and venous oxygen levels. Values of V̇O2max are predicted for several values of hemoglobin‐oxygen affinity and hemoglobin concentration based on data from humans with hemoglobin mutations. The model predicts that increased hemoglobin‐oxygen affinity leads to increased V̇O2max at altitudes above ~4500 m.

The central neural mechanisms affecting sympathetic neuronal discharge strategies supporting homeostatic adjustments in human muscle sympathetic nerve activity (MSNA) remain unclear. This study investigated the hypothesis that central alpha-2 adrenergic mechanisms affect sympathetic action potential (AP) discharge, recruitment, and latency patterns within human MSNA (peroneal nerve microneurography and continuous wavelet transform). An alpha-2 adrenergic agonist (dexmedetomidine) was infused in eight healthy male and female participants (5 females; 28 ± 7years). Data were recorded during a 5-minute resting control condition, a 10-minute intravenous dexmedetomidine loading dose (0.225 μg/kg), and a dexmedetomidine maintenance dose (~0.1 μg/kg/hr). Data are reported as mean (SD) for the 5-minute control condition and 2-minutes of the dexmedetomidine infusion when MSNA bursting activity was demonstrably reduced. Two-tailed paired t-tests were performed. Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg; P < 0.01) but did not affect heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.75). Dexmedetomidine reduced integrated MSNA burst frequency (14 ± 6 to 4 ± 3 bursts/min; P < 0.01), sympathetic AP frequency (75 ± 46 to 16 ± 14 AP/min; P < 0.01), APs per burst (5 ± 1 to 4 ± 1 AP/burst; P = 0.01), AP clusters per burst (3.5 ± 0.7 to 3.0 ± 0.7 clusters/burst; P = 0.03), and de-recruited the largest AP clusters (12 ± 3 to 7 ± 2 AP clusters; P < 0.01). Despite de-recruiting large AP clusters with short conduction times, dexmedetomidine elicited shorter sympathetic AP conduction times (1.18 ± 0.12 to 1.14 ± 0.13 s; P = 0.03). Six participants performed a Valsalva Maneuver (20 s, 40 mmHg mouth pressure) during the control condition and during the dexmedetomidine maintenance dose. Data are reported as mean (SD) change (Δ) from the 2-minute period preceding the Valsalva Maneuver to the Valsalva Maneuver for each condition. During the control condition, Valsalva Maneuver increased AP frequency (Δ 311 ± 317 AP/min; P = 0.048), recruited larger previously silent AP clusters (Δ 2 ± 1 AP clusters; P < 0.01), and elicited shorter AP conduction times (Δ ‑0.09 ± 0.07 s; P = 0.02). Compared to the control condition, Valsalva Maneuver performed during the dexmedetomidine maintenance dose condition elicited lesser increases in AP frequency (Δ 116 ± 189 AP/min; P vs. control = 0.02) and lesser recruitment of larger previously silent AP clusters (Δ 0 ± 1 AP clusters; P vs. control = 0.02). Dexmedetomidine did not affect the latency reduction elicited by Valsalva Maneuver (Δ ‑0.07 ± 0.14 s; P vs. control = 0.61). These data suggest that human central alpha-2 adrenergic mechanisms affect: i) sympathetic postganglionic neuronal discharge and recruitment patterns, and ii) synaptic delays within the sympathetic neurocircuitry influencing AP latency. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). 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.

Background: Patients with respiratory manifestations of acute COVID-19 infection have enlarged luminal areas of central conducting airways demonstrated on computed tomography imaging and abnormal pulmonary function. In some cases, COVID-19 symptoms may persist for more than 4 weeks, referred to as long COVID, and the effect on airway luminal area remains unknown. Herein, we report airway luminal cross-sections areas among a long COVID group, compared to individuals with an acute COVID-19. We aim to investigate if large conducting airways sizes are different between acute COVID-19 and long COVID patients. Methods: A cohort of 181 people with long COVID were screened, of which 20 people (9 men, 11 women; 55.9 ± 14.1 years) were included in analyses. Twenty age, height, and sex matched patients with an acute (< 4 weeks of persistent symptoms from diagnosis) COVID-19 infection (55.7 ± 15.2 years) served as a comparison group. We used a three-dimensional reconstruction of computed tomography imaging to measure luminal areas of the trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi at proximal, middle, and distal cross-sectional points in both groups. Airway luminal area was taken as the average of the three points. We compared average lumen area of long COVID patients with acute COVID-19 individuals, using an independent samples t-test. Results: We found no significant difference comparing measurements of the following airway luminal cross-sectional areas: trachea (277.7 ± 100.4 vs. 268.0 ± 70.5 mm2 p=0.73), right main bronchus (191.0 ± 66.1 vs. 190.1 ± 49.0 mm2, p=0.96), bronchus intermediate (112.3 ± 33.4 vs. 109.3 ± 27.9 mm2, p=0.76), right upper lobe bronchus (74.4 ± 21.0 vs. 73.7 ± 25.5 mm2, p=0.92), left main bronchus (129.1 ± 50.1 vs. 136.9 ± 38.0 mm2, p=0.58), left lower lobe bronchus (57.8 ± 18.2 vs. 59.0 ± 13.4 mm2, p=0.82), and left upper lobe bronchus (80.1 ± 19.5 vs. 77.9 ± 22.9 mm2, p=0.75) in the long COVID and acute COVID-19 groups respectively. Conclusion: In patients with long COVID, compared to those with an acute COVID-19 infection, we did not see differences in central airway luminal areas. Further analysis of a larger cohort is needed to determine whether enlarged airway luminal areas, associated with acute COVID-19, persist in long COVID. This research will expand knowledge on functional consequences for patients with long COVID. Funding: F32HL154320 to JWS; 5R35HL139854 to MJJ. 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.

Background: Interstitial lung disease (ILD) encompasses several pulmonary disorders associated with scarring and fibrosis of pulmonary tissue. People with idiopathic pulmonary fibrosis, a subset of ILD, have greater central airway luminal area compared to age- and sex-matched healthy controls when evaluated using microcomputed tomography, a process examining the luminal area of ex-vivo lung tissue. In this study we aimed to confirm these findings using a different method of airway assessment, three-dimensional (3D) reconstruction of computed tomography (CT) scans. Moreover, in health, males have larger central airways than height-matched females, but it remains unknown if there are sex differences in airway area among people with ILD. We hypothesized that sex differences observed in healthy people would persist among people with ILD. Methods: A cohort of 399 patients with lung CT scans were screened, of which 19 people (7 females) with ILD were included in analyses after exclusions. People with ILD were matched based on sex, age, and height to 19 healthy controls. We assessed cross-sectional luminal area at the midpoint of seven conducting airways (trachea, left and right main bronchus, intermediate bronchus, left and right upper lobe, and left lower lobe). Results from pulmonary function tests were also abstracted, as available. To examine sex differences, we compared airway luminal area, normalized to participant height, between males and females with ILD. Sex differences were analyzed using a univariate ANOVA test. Results: People with ILD had a preserved ratio of forced expiratory volume in the first second to forced vital capacity (101 ±12%predicted) and decreased diffusing capacity for carbon monoxide (55 ±23%predicted). People with ILD had airways that were between 19.6%-45.0% larger than controls (p<0.05). Composite physiologic index, a marker of ILD severity, was not different between sexes (p=0.07). Males with ILD had significantly larger, luminal areas than females in two central airways - right main bronchus (1.46±0.41 vs. 1.07±0.22 mm2/cm, p=0.04) and left upper lobe (0.54±0.10 vs. 0.43±0.08 mm2/cm, p=0.02). However, luminal area of other central airways, including: trachea (2.15±0.57 vs. 1.65±0.32 mm2/cm, p=0.051), bronchus intermediate (0.77±0.23 vs. 0.61±0.13 mm2/cm, p=0.12), right upper lobe (0.47±0.15 vs. 0.40±0.06 mm2/cm, p=0.26), left main bronchus (0.93±0.33 vs. 0.69±0.16 mm2/cm, p=0.09), and left lower lobe (0.41±0.13 vs. 0.40±0.08 mm2 /cm, p=0.79) were not different between sexes in people with ILD. Conclusion: Sex differences observed in healthy people are potentially preserved in ILD, but a more robust sample is required to fully elucidate these findings. Illuminating any sex differences in ILD pathophysiology may provide knowledge to treat and improve clinical outcomes in ILD. Funding: National Heart, Lung, and Blood Institute (F32HL154320 to JWS; 5R35HL139854 to MJJ). 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.

Purpose: The present work was performed to provide an updated and comprehensive systematic review and meta-analysis on the potential ergogenic effects associated with ischemic preconditioning (IPC). In this context, this systematic review and meta-analysis aimed to determine the magnitude of the potential ergogenic effect of IPC and the influence of descriptive factors that contribute to the variability of its potential ergogenic effect. We hypothesized that IPC would be associated with improved exercise performance, and putative factors would modulate this association. Methods: On October 17, 2022, a systematic search of three databases (PubMed, Scopus, and Web of Science) was performed. The electronic search yielded 2,876 unique records, of which 79 were included in analyses after abstract and full-text screening. Eligible study designs included within subjects cross-over, sham controlled study, with a randomized or counter balanced study design. Prespecified analyses aimed to determine whether the ergogenic effect of IPC is influenced by: 1) exercise parameters (type of exercise, fraction of inspired oxygen, and muscle group(s) involved in exercise) and 2) IPC parameters (dosage, duration, and timing before onset of exercise). Results: The meta-analysis model demonstrated that exercise performance was improved with IPC compared to the sham control (pooled standard paired difference (SPD), 0.156; 95% confidence interval (CI), 0.084 to 0.227; Z = 4.258; P < 0.001; n = 105). Both remote IPC (pooled SPD, 0.219; 95% CI, 0.071 to 0.368; Z = 2.894; P = 0.004) and local IPC (pooled SPD, 0.159; 95% CI, 0.088 to 0.231; Z = 4.386; P < 0.001) demonstrated ergogenic effects on performance. Subgroup analyses based on the fraction of inspired oxygen level revealed improved exercise performance in normoxic (pooled SPD, 0.169; 95% CI, 0.100 to 0.237; Z = 4.805; P < 0.001) but not hypoxic (pooled SPD, 0.160; 95% CI, -0.029 to 0.349; Z = 1.659; P = 0.097) conditions. The most notable improvement in exercise performance following IPC was demonstrated during cycling (pooled SPD, 0.116; 95% CI, 0.023 to 0.209; Z = 2.454; P = 0.014), running (pooled SPD, 0.180; 95% CI, 0.056 to 0.303; Z = 2.847; P = 0.004), and leg press (pooled SPD, 0.421; 95% CI, 0.034 to 0.808; Z = 2.131; P = 0.033) performance tests. Conclusion: Overall, IPC demonstrated a clear ergogenic effect on exercise performance across various exercise modalities under normoxic environmental conditions. The enhanced exercise performance following IPC was most pronounced in aerobic tests of performance which predominantly recruited large muscle groups in the lower extremities: cycling, running, and leg press. 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.

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 P50 - defined as the oxygen tension at which 50% of hemoglobin is saturated. Humans with rare hemoglobin mutations causing a low P50 (high hemoglobin-oxygen affinity) have demonstrated remarkable preservation of exercise tolerance at high altitude conditions (~3,000m). However, the influence of a low P50 on V̇O2max at extreme altitudes (>5,500m) remains largely unexamined. To examine the dependence of V̇O2max on P50 and altitude, we developed a computational model of oxygen uptake and utilization. We hypothesized that a low P50 would result in a better maintained V̇O2max at extreme altitudes compared to conditions of normal P50 and high P50 (low hemoglobin-oxygen affinity). Methods: We created a model that couples pulmonary oxygen uptake with systemic oxygen utilization to estimate V̇O2max as a function of P50, hemoglobin concentration, and altitude. Fixed values for cardiac output and tissue oxygen demand for V̇O2max 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 V̇O2max were determined as a function of P50, hemoglobin concentration, and altitude. Results: We present the results for several cases of P50 (low, normal, and high) and hemoglobin concentrations as a function of altitude. For a low P50, 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 P50. Additionally, a low P50 led to better maintenance of V̇O2max at ~8,850m (~38% decrease from sea-level V̇O2max) compared to values determined for normal P50 and high P50 (~53% and ~67% decrease from sea-level V̇O2max, respectively, P<0.05). Conclusion: This model demonstrates the importance of P50 in the determination of V̇O2max at various altitudes. At low altitudes, a low P50 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 P50 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.

Background Individuals with spinal cord injury (SCI) have lower levels of physical activity compared to the nondisabled population. Exercise guidelines recommend moderate or vigorous exercise to improve cardiovascular health and reduce cardiometabolic risk factors in persons with SCI. High-intensity interval training (HIIT) is a popular exercise choice and encompasses brief periods of vigorous exercise paired with intermittent periods of recovery. Objectives This review describes the available literature on HIIT for individuals with SCI, including differences in protocol design and suggested areas of further investigation. Methods Our institution’s library system performed the comprehensive search. The primary keywords and phrases used to search included spinal cord injury, high-intensity interval training, tetraplegia, paraplegia, and several other related terms. Results Initially 62 records were screened, and 36 were deemed outside the scope of this review. Twenty-six studies published between 2001 and 2021 fulfilled the eligibility criteria and were divided among two researchers for review and analysis. All records required persons with SCI and a standardized HIIT intervention. Study design varied widely with respect to mode of exercise, prescribed intensity, duration of performance intervals, and session duration. This variability necessitates further investigation into the specifics of a HIIT prescription and the associated outcomes for persons with SCI. Conclusion Standardization of HIIT protocols may lead to more robust conclusions regarding its effects on cardiorespiratory fitness as well as mitigation of cardiometabolic risk factors. Meta-analyses will eventually be needed on proper dosing and session parameters to improve cardiorespiratory fitness and cardiometabolic risk factors.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15–20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.