Cross, Troy J.

Growing evidence suggests that the larger conducting airways are smaller in women than men; however, evidence of this sex‐difference in airway geometry is yet to be demonstrated in a large cohort of adult, healthy non‐smokers. Furthermore, it is not known whether these sex differences persist after airway size is adjusted for its allometric relationship with absolute lung size. Purpose We examined the effect of sex on airway size in a large cohort of non‐smoking healthy adults after adjusting for the possible confounding effect of absolute lung size. Methods A total of 133 (75 men; 58 women) non‐smoking adults (50 ± 18 yrs) with normal pulmonary function (>80% pred.) participated in this study. Full thoracic CT scans were obtained in each participant during a breath‐hold at full inflation. Commercial software was used to automatically segment airways and assign 32 anatomical labels ranging from the 0 th to the 5 th generation. Intraluminal hydraulic diameters ( D h ) were obtained for each airway. An allometric relationship was assumed between D h and absolute lung size, as given by: D h = TLV β · e k , where TLV is the total lung volume at full inflation, β is the allometric scaling exponent, and k allowed for proportional effects of confounding variables. This allometric equation was log‐log transformed such that it could be examined using linear regression: e.g., ln( D h ) = β ·ln(TLV) + k . Sex, age and their interaction were allowed to contribute to both β and k as covariates. The model also included a term for reconstructed voxel size. Model averaging was used to provide parameter estimates of the log‐log transformed allometric equation. Results The allometric exponent, β , assigned to TLV was significant for all 32 anatomically labelled airways ( P < 0.05); neither sex nor age affected β . On the other hand, sex and age were significant mediators of k for the extra‐parenchymal airways only (Trachea, RMB, LMB, BronInt, see Figure 1, P < 0.05). Conclusions Our findings indicate that sex differences in D h remain present despite accounting for the allometric relationship between airway and lung size (see Figure 1). Importantly, however, this sex‐difference in airway size is seemingly confined to the extra‐parenchymal airways. Support or Funding Information This work was supported by NIH Grant HL71478. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Duchenne muscular dystrophy (DMD) is an inheritable disease that presents itself in diminished respiratory function and is the main contributor to mortality in these patients. The main respiratory concerns in DMD are reduced diaphragmatic function, reduced mucocilliary clearance, increased muscle proteolysis, and increased inflammation. The Gly16 variant of the β 2 ‐adrenergic receptor (ADRB2) has been identified as providing a protective effect for respiratory weakness. The aim of this study was to identify the influence of ADRB2 genotype on the age of use for nocturnal ventilatory assistance in DMD. Data from CINRG‐DNHS including 175 DMD patients (ages 3–25 years) with up to 9.7 years follow‐up were analyzed focusing on ADRB2 functional variants. We performed Cox proportional hazard and Kaplan‐Meier time to event analyses for the age of nocturnal ventilation use. There were no differences between genotype groups in age, height, weight, corticosteroid use, number of ambulatory patients, or age of loss of ambulation. The genotype groups differed significantly in the age at which nocturnal ventilation use was prescribed with the Gly16 demonstrating a 2.77‐fold increased risk of using nocturnal ventilation at any given age. These data suggest that genetic variations in the ADRB2 gene may influence the age of nocturnal ventilation use in DMD. Specifically, the Gly16 polymorphism of the ADRB2 may have a deleterious effect on age of nocturnal ventilation use in DMD. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol . 22:249–262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO 2 ) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (F I O 2 : 0.125) and normoxia (F I O 2 : 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort ( n = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p < 0.05). Throughout incremental exercise in hypoxia, SaO 2 was systematically higher after drug (peak exercise SaO 2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p < 0.001), whereas oxygen extraction (Ca-vO 2 diff) and consumption (VO 2 ) were similar (peak exercise Ca-vO 2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p = 0.417; peak VO 2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p = 0.127). Throughout incremental exercise in normoxia, SaO 2 was systematically higher after drug, whereas peak VO 2 was reduced (peak exercise SaO 2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p = 0.008; peak VO 2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO 2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

Background Locomotor muscle group III/IV afferent feedback contributes to sympathoexcitation. Sub‐systolic lower limb occlusion may stimulate this reflex. Purpose To examine the cardiovascular response to lower limb venous occlusion in healthy humans during rest and exercise. Methods Nineteen adults (9 men, 25±5 yr; mean±SD) participated in two visits. V1: 3 min seated rest followed by randomized bilateral thigh tourniquet inflation to 20, 40, 60, 80, 100 mmHg for 2 min with 2 min deflation between occlusions. V2: Recumbent cycle ergometer exercise at 30% peak work with occlusion described in V1. We measured mean, systolic and diastolic pressure, cardiac output, heart rate, and stroke volume (MAP, SBP, DBP, CO, HR, and SV, respectively). Results At rest, MAP (85±18 mmHg) increased at 100 mmHg (Δ4±5, p<0.05) mediated by increased DBP (71±15 mmHg) at 100 mmHg (Δ5±4, p<0.05) with no change in SBP. During exercise, MAP (89±11 mmHg) increased at 60 (Δ7±7), 80 (Δ14±8), and 100 (Δ16±8) mmHg occlusions via increased SBP (133±22 mmHg) at 60 (Δ12±14), 80 (Δ20±13), and 100 (Δ26±13) mmHg and DBP (68±9 mmHg) at 60 (Δ5±5), 80 (Δ10±7), and 100 (Δ12±7) (p<0.05, all). Although, CO and SV did not change, HR (108±11 bpm) increased at 40 (Δ5±4), 60 (Δ8±5), 80 (Δ13±7), and 100 mmHg (Δ15±7) (p<0.05, all). Conclusion Stimulation of locomotor muscle group III/IV afferents via sub‐systolic occlusion contributes to cardiovascular control.

There are growing concerns that the COVID-19 pandemic has facilitated a sedentary shift in our physical activity habits. A reduction in physical activity during the pandemic may be secondary to restrictive policies implemented at the government-level, typically those policies which limit interpersonal contact; for example, physical/social distancing. It is without question that social distancing is a necessary measure to mitigate community transmission of the novel virus; however, these policies often limit the public’s opportunities to engage in physical activity. The strictest enforcement of social distancing occurs during an authority-mandated ‘lockdown’ (also known as a ‘shelter-in-place’ or ‘stay-at-home’ order). This Viewpoint focuses on the current evidence demonstrating that physical activity declines during a COVID-19 ‘lockdown’. We highlight the point that most of the available evidence stems from investigations using non-validated, self-reported measures of physical activity and discuss the caveats therewith. This Viewpoint explores whether current evidence reflects an ‘actual’ or rather a ‘perceived’ reduction in physical activity, and raises the question of whether this distinction matters in the end.

The modified Campbell diagram provides one of the most comprehensive assessments of the work of breathing (Wb) during exercise, wherein the resistive and elastic work of inspiration and expiration are quantified. Importantly, a necessary step in constructing the modified Campbell diagram is to obtain a value for chest wall compliance (CCW). To date, it remains unknown whether estimating or directly measuring CCW impacts the Wb, as determined by the modified Campbell diagram. Therefore, the purpose of this study was to evaluate whether the components of the Wb differ when the modified Campbell diagram is constructed using an estimated versus measured value of CCW. Forty-two participants ( n = 26 men, 16 women) performed graded exercise to volitional exhaustion on a cycle ergometer. CCW was measured directly at rest via quasistatic relaxation. Estimated values of CCW were taken from prior literature. The measured value of CCW was greater than that obtained via estimation (214 ± 52 mL/cmH2O vs. 189 ± 18 mL/cmH2O; P < 0.05). At modest-to-high minute ventilations (i.e., 50–200 L/min), the inspiratory elastic Wb was greater and expiratory resistive Wb was lower, when modified Campbell diagrams were constructed using estimated compared with measured values of CCW ( P = 0.001). These differences were however small and never exceeded ±5%. Thus, although our findings demonstrate that estimating CCW has a measurable impact on the determination of the Wb, its effect appears relatively small within a cohort of healthy adults during graded exercise.

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.

The work and power of breathing (Wb & Pb, respectively) have been extensively studied in humans during exercise. Through the measurement of the Wb & Pb during exercise, we yield insight into the energetic demands of the respiratory muscles across a wide range of minute ventilations. It must be noted, however, that the methodological approach to quantifying Wb & Pb is very inconsistent in the literature. The 3 most popular methods of calculating Wb & Pb are: (1) the integrated pressure‐volume (PV) loop; (2) the Otis diagram; and (3) the Campbell diagram. Each of these methods are based on different theoretical assumptions and, as such, do not necessarily provide a consistent measure of Wb & Pb. A comparison of the Wb & Pb measured via these 3 methods during exercise is presently lacking. PURPOSE To compare values of the Wb & Pb obtained during incremental exercise as determined by the integrated PV, Otis and Campbell methods. METHODS Twenty‐three young, healthy adults (10 women; 21 ± 1 yrs) visited the laboratory on two separate occasions. The first occasion was used to obtain informed consent and to screen participants for normal pulmonary function (>85% age‐predicted). On the second visit, participants were instrumented with an esophageal balloon catheter to estimate variations in pleural pressure. Quasi‐static relaxation curves were obtained to measure chest wall recoil pressure. Participants then completed an incremental cycling protocol until volitional exhaustion. The total Wb & Pb were computed according to the numerical procedures for the integrated PV, Otis and Campbell methods. The Wb & Pb of each method were compared at standardized minute ventilations obtained during incremental. RESULTS The total Wb & Pb as determined via the Campbell method was systematically higher than the other two methods (integrated PV & Otis) at any given minute ventilation during exercise (Figure ; P < 0.05). Interestingly, the integrated PV method produced values for total Wb & Pb that were lower than those of the Otis method for minute ventilations below 80 L·min −1 , yet were higher at minute ventilations greater than 110 L·min −1 (Figure ; P <0.05). When expressed as a percentage of the values obtained via the Campbell diagram, it was clear that the Otis method constituted a decreasing proportion of total Wb & Pb as minute ventilation increased (Figure ; P <0.05), whereas the integrated PV method yielded values that represented an increasing proportion during exercise ( P <0.05). CONCLUSION The Campbell method produced the highest values at any given minute ventilation. Importantly, however, the Otis method tended to progressively underestimate the total Wb & Pb relative to the Campbell, while the opposite was true of the integrated PV method, as minute ventilation increased during exercise. Investigators must be cognizant of these differences when choosing a method to quantify the Wb & Pb during exercise. Support or Funding Information This research was funded by preliminary data funds provided by Northern Arizona University (JWD). TJC was supported by the Irene Diamond Fund/American Federation for Aging Research Postdoctoral Transition Award during the time of this study. The power of breathing (Pb) determined by the integrated pressure‐volume (PV), Otis and Campbell methods. Values represent means ± 95% confidence intervals. The left panel ( A ) represents the total Pb values obtained via the 3 different methods. The right panel ( B ) illustrates the percentage of the Campbell method's total Pb that is constituted by the integrated PV and Otis methods, separately. Only portions where no significant differences (NS) were observed have been illustrated. Figure 1