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ABSTRACT Introduction An adequate increase in minute ventilation to defend arterial oxyhemoglobin saturation (SpO 2 ) during hypoxic exercise is commonly viewed as an important factor contributing to large inter-individual variations in the degree of exercise performance impairment in hypoxia. Although the hypoxic ventilatory response (HVR) could provide insight into the underpinnings of such impairments, it is typically measured at rest under isocapnic conditions. Thus, we aimed to determine whether 1) HVR at rest and during exercise are similar and 2) exercise HVR is related to the degree of impairment in cycling time trial (TT) performance from normoxia to acute hypoxia (∆TT). Methods Sixteen endurance-trained men (V˙O 2peak , 62.5 ± 5.8 mL·kg −1 ·min −1 ) performed two poikilocapnic HVR tests: one during seated rest (HVR REST ) and another during submaximal cycling (HVR EX ). On two separate visits, subjects ( n = 12) performed a 10-km cycling TT while breathing either room air (F i O 2 = 0.21) or hypoxic gas mixture (F i O 2 = 0.16) in a randomized order. Results HVR EX was significantly ( P < 0.001) greater than HVR REST (1.52 ± 0.47 and 0.22 ± 0.13 L·min −1 ·%SpO 2 −1 , respectively), and these measures were not correlated ( r = −0.16, P = 0.57). ∆TT was not correlated with HVR REST ( P = 0.70) or HVR EX ( P = 0.54), but differences in ventilation and end-tidal CO 2 between hypoxic and normoxic TT and the ventilatory equivalent for CO 2 during normoxic TT explained ~85% of the variance in performance impairment in acute hypoxia ( P < 0.01). Conclusion We conclude that 1) HVR is not an appropriate measure to predict the exercise ventilatory response or performance impairments in acute hypoxia and 2) an adequate and metabolically matched increase in exercise ventilation, but not the gain in the ventilatory response to hypoxia, is essential for mitigating hypoxia-induced impairments in endurance cycling performance.

ABSTRACT Although over 100 studies and reviews have examined the ergogenic effects of dietary nitrate (NO 3 − ) supplementation in young, healthy men and women, it is unclear if participant and environmental factors modulate the well-described ergogenic effects—particularly relevant factors include biological sex, aerobic fitness, and fraction of inspired oxygen (F i O 2 ) during exercise. To address this limitation, the literature was systematically reviewed for randomized, crossover, placebo-controlled studies reporting exercise performance outcome metrics with NO 3 − supplementation in young, healthy adults. Of the 2033 articles identified, 80 were eligible for inclusion in the meta-analysis. Random-effects meta-analysis demonstrated that exercise performance improved with NO 3 − supplementation compared with placebo ( d = 0.174; 95% confidence interval (CI), 0.120–0.229; P < 0.001). Subgroup analyses conducted on biological sex, aerobic fitness, and F i O 2 demonstrated that the ergogenic effect of NO 3 − supplementation was as follows: 1) not observed in studies with only women ( n = 6; d = 0.116; 95% CI, −0.126 to 0.358; P = 0.347), 2) not observed in well-trained endurance athletes (≥65 mL·kg −1 ·min −1 ; n = 26; d = 0.021; 95% CI, −0.103 to 0.144; P = 0.745), and 3) not modulated by F i O 2 (hypoxia vs normoxia). Together, the meta-analyses demonstrated a clear ergogenic effect of NO 3 − supplementation in recreationally active, young, healthy men across different exercise paradigms and NO 3 − supplementation parameters; however, the effect size of NO 3 − supplementation was objectively small ( d = 0.174). NO 3 − supplementation has more limited utility as an ergogenic aid in participants with excellent aerobic fitness that have optimized other training parameters. Mechanistic research and studies incorporating a wide variety of subjects (e.g., women) are needed to advance the study of NO 3 − supplementation; however, additional descriptive studies of young, healthy men may have limited utility.

Background In humans, maximal exercise capacity is reduced during hypoxic environmental conditions. In response to hypoxia, the hemoglobin binding affinity is decreased, promoting oxygen off‐loading at the tissue level and causing a right‐shift of the oxyhemoglobin dissociation curve (ODC). However, comparative biology demonstrates many species (e.g. Bar‐headed geese), who are adapted to hypoxia instead have high‐affinity hemoglobin (left‐shifted ODC). Therefore we studied unique human participants with hemoglobinopathies that result in high affinity hemoglobin (HAH) to investigate the role of oxygen affinity in exercise performance and tissue oxygenation during hypoxic conditions. Methods HAH participants (n=5, 1M/4F, Age= 34±11 yr, P 50 =16±1 mmHg) and matched control participants (n=12, 5M/7F, age=39±12 yr, and P 50 =26±1 mmHg) completed two incremental exercise tests to exhaustion on a cycle ergometer under two conditions: 1) room air (F i O 2 = 0.21, NORM), and 2) normobaric hypoxia gas mixture (F i O 2 = 0.15, HYP), separated by a 45 minute break. The vastus lateralis (VL) muscle was studied using frequency‐domain near infrared spectroscopy (NIRS) to measure concentrations of oxygenated ([OxyHb+Mb]), deoxygenated ([DeoxyHb+Mb]) hemoglobin and myoglobin, and tissue saturation (S t O 2 ). Data were analyzed using a three‐way (Inspirate [HYP, NORM], Hb type [Normal, HAH], exercise intensity [Rest, 40, 60, 80, 100% normoxic PPO]) univariate analysis of variance. Results HAH had an attenuated decline in exercise tolerance (peak power output at maximal exertion) in HYP compared to controls (HAH: 2.9±6.4% decline vs CTL: 11.7±5.4% decline, P<0.05). There was a significant effect of Hb type on [DeoxyHb+Mb] (P=0.048) suggesting less O 2 offloading in HAH compared to controls in the VL at rest and throughout graded exercise in both NORM and HYP. There were no significant effects of inspirate or exercise intensity on [DeoxyHb+Mb], and no significant differences in [OxyHb+Mb] between HAH and controls. There was a significant effect of Hb type on S t O 2 in NORM controls (P<0.01) However, during hypoxic exercise S t O 2 was the same in both HAH and controls except at end exercise (HAH 64.1±6.4% vs CTL: 62.1±4.2%, P<0.05). Conclusion HAH individuals have less oxygen off‐loading at rest and during exercise but higher tissue saturation during exercise in NORM compared to controls. Our results suggest that the similar levels of exercise capacity in hypoxia for HAH are due, at least in part, to maintenance of microvascular extraction similar to that during normoxic exercise. Future studies utilizing direct measurements of skeletal muscle blood flow during exercise are needed to understand integrative exercise in HAH patients. Support or Funding Information This work was funded by NIH R‐35‐HL139854 and the Mayo Foundation. Muscle oxygenation during graded exercise tests in normoxia and hypoxia. Data are presented as means ± standard error. Abbreviations: [OxyHb+Mb], concentration of oxygenated hemoglobin+myoglobin; [DeoxyHb+MB], concentration of deoxygenated hemoglobin+ myoglobin; PPO, peak power output. † denotes significant main effect of Hb types across all workloads. * denotes significant difference from CTL at same %PPO. Figure 1

Although over 100 studies and reviews have examined the ergogenic effects of dietary nitrate (NO 3 − ) supplementation ( e.g. beetroot juice) in young, healthy men and women, it is unclear if participant and environmental factors modulate the well‐described ergogenic effects—particularly relevant factors include biological sex, aerobic fitness and fraction of inspired oxygen (F i O 2 ) during exercise. To address this limitation, the literature was systematically reviewed for randomized, cross‐over, placebo‐controlled studies reporting exercise performance outcome metrics with NO 3 − supplementation in young, healthy adults. There were 2,033 articles identified, and 80 articles met inclusion criteria for the meta‐analysis. Random‐effects meta‐analysis demonstrated that exercise performance was improved with NO 3 − supplementation compared to placebo ( d =0.174, 95% CI [0.120–0.229], P <0.001). Subgroup analyses conducted on biological sex, aerobic fitness and F i O 2 demonstrated that the ergogenic effect of NO 3 − supplementation was: 1) not observed in studies with only women ( n =6, d=0.116, 95% CI [−0.126–0.358], P =0.347), 2) not observed in participants with moderate aerobic fitness (less than 45 mL·kg −1 ·min −1 ; n =4, d =0.168, 95% CI [−0.134–0.469], P =0.276) or elite aerobic fitness (65 mL·kg −1 ·min −1 or greater; n =26, d =0.021, 95% CI [−0.103–0.144], P =0.745) and 3) was not modulated by F i O 2 (hypoxia: n =17, d =0.214, 95% CI [0.054–0.375], P =0.009 vs. normoxia n =97, d =0.175, 95% CI [0.114–0.237], P <0.001). Together, the meta‐analyses demonstrated a clear ergogenic effect of NO 3 − supplementation in recreationally‐active, young, healthy men across many different exercise paradigms and NO 3 − supplementation parameters; however, the effect size of NO 3 − supplementation was objectively small . Although NO 3 − supplementation may be effective in moderately fit, healthy men, NO 3 − supplementation has limited utility as an ergogenic aid in participants that have optimized other training parameters. Mechanistic research and studies incorporating a wide variety of subjects ( e.g. women) are needed to advance the study of NO 3 − supplementation; however, additional descriptive studies of young healthy men may have limited utility. Figure 1 Figure 2

Background Lower body negative pressure (LBNP) simulates hemorrhage, evoking compensatory cardiovascular mechanisms of increased heart rate (HR) while stroke volume (SV) and cardiac output (CO) progressively decline, ultimately leading to presyncope. Previous work has shown that circulating levels of plasma epinephrine are elevated during LBNP; however, the role of early administration of epinephrine in compensatory cardiovascular mechanisms to simulated hemorrhage is not well understood. Purpose We hypothesized that during simulated hemorrhage, a low‐dose exogenous infusion of epinephrine in humans would: 1) augment HR response, 2) attenuate the decline of SV and CO, and 3) prolong time to tolerance. Methods Nine healthy subjects (5M/4F, 35±9yrs, BMI 25±1 kg·m −2 ) participated in LBNP on two separate study days. Protocols on each day consisted of a 10‐minute pre‐infusion baseline, 15‐minute infusion period (randomized to saline or epinephrine, dose = 0.1 μg·kg −1 ·min −1 , delivered through a peripherally inserted central catheter), 10‐minute post‐infusion baseline, and 5 minute stages of progressive LBNP with stepwise increases of 10–15 mmHg negative pressure until tolerance (systolic blood pressure less than 80 mmHg, bradycardia, or voluntary termination due to presyncopal symptoms). Heart rate (HR; electrocardiogram) and blood pressure (BP; radial arterial catheter) were recorded continuously. Cardiovascular function (HR, SV, CO, and systemic vascular resistance (SVR)) was determined using arterial waveform analysis. Data were analyzed via percent tolerance using repeated measures ANOVA with student method for pairwise comparisons. Results Infusion of exogenous epinephrine lowered MAP (p<0.01) and diastolic blood pressure (DBP; p<0.001), but raised systolic blood pressure (SBP; p=0.019) throughout all stages of LBNP. Epinephrine compared to saline augmented mean HR, SV and CO to the penultimate stage of LBNP (p≤0.01 for all cardiac measures) and concurrently reduced SVR (p=0.002). However, time to tolerance was not significantly different between epinephrine and saline conditions (1415 ± 79 vs. 1475 ± 150s, respectively; p=0.69). Discussion Our findings suggest that during simulated hemorrhage exogenous epinephrine can augment cardiac function without increasing tolerance to progressive central hypovolemia. During the epinephrine infusion, benefits to cardiac function may have been limited by reduced vascular resistance. Support or Funding Information The United States Department of Defense W81XWH‐13‐2‐0038

Objective Bronchopulmonary dysplasia (BPD) is a condition of neonatal chronic lung disease due to disruption or dysregulation of pulmonary development. It is associated with decreased septation, alveolar hypoplasia, and abnormal disruption of pulmonary alveolar capillaries resulting in increased pulmonary resistance. However, the pathophysiology of BPD in the large conducting airways is not fully understood. The objective of our study was to determine if the luminal area of the central airways, measured by imaging, are altered in patients with a history of BPD. We hypothesized that compared to age‐ and sex‐matched controls, BPD patients would have a decreased luminal area of the central conducting airways and lung volume. Methods Fourteen BPD patients (8M/6F; Age=5.7±5.5 yrs) who had undergone a chest computed tomography (CT) scan were retrospectively identified. Age and sex matched controls (8M/6F, Age=5.6±5.3 yrs) who had undergone a CT scan for trauma were used for comparison. Measurement and analysis were performed by a single investigator using commercially available software (Aquarius, TeraRecon Inc.) that reconstructs the airways into 3D. Measurements of luminal airway area were conducted at three points based on anatomic bifurcations (corresponding to the beginning, middle and end of the airway) for each of the following structures: trachea, left main bronchus, left upper lobe, left lower lobe, right main bronchus, intermediate bronchus, and right upper lobe. Each airway’s luminal area was calculated based on the averages of the three measures obtained for each anatomic airway structure. Independent Student’s t‐test was used for statistical analysis. Results Airway luminal area was not different between BPD patients and matched controls (trachea: 89.8±57.1 vs 87.4±58.6 mm 2 ; right main bronchus: 58.8±40.8 vs 64.0±44.5 mm 2 ; intermediate bronchus: 33.6±21.2 vs 41.0±28.9 mm 2 ; left main bronchus: 39.3±27.1 vs 46.6±36.5 mm 2 ; left lower lobe: 22.7±14.6 vs 29.9±18.9 mm 2 ; p>0.05 for all comparisons; BPD and controls, respectively). Total lung volume detected in the CT scans was not different between BPD patients and matched controls (3069±1073 vs 3215±984 cm 3 , p>0.05). Conclusions Our results suggest the luminal areas of the large conducting airways in patients with BPD are not different from matched controls. Given the degree of respiratory complications and sequelae associated with BPD, our findings suggest future research should focus on alveolar and vascular impaired physiological and anatomic developments versus the large conducting airways. Support or Funding Information National Institutes of Health Grants R35‐HL139854 (MJJ), F32 HL‐131151 (SEB), T32 DK‐007352‐39 (CCW) and Mayo Clinic Internal Funding and Natural Science and Engineering Council of Canada RGPIN‐2019‐04615 (PBD)