Baker, Sarah E.

The timing and magnitude of sex differences in athletic performance during early human development, prior to adulthood, is unknown. Objective To compare swimming velocity of boys and girls for all Olympic‐length freestyle swimming events to determine the age of divergence in swimming performance. Methods We collected the all‐time top 100 U.S. freestyle swimming performance times of boys and girls age 5 to 18 years for the 50m to 1500m events. Results Swimming performance improved with increasing age for boys and girls ( p <0.001) until reaching a plateau, which initiated at a younger age for girls (15 years) than boys (17 years; sex×age; p <0.001). Prior to age 10, the top 5 swimming records for girls were 3% faster than the top boys ( p <0.001). For the 10 th –50 th places, however, there were no sex‐related differences in swimming performance prior to age 10 ( p =0.227). For both the top 5 and 10 th –50 th places, the sex difference in performance increased from age 10 (top 5, 2.5%; 10 th –50 th places, 1.0%) until age 17 (top 5, 7.6%; 10 th –50 th places, 8.0%). For all places, the sex difference in performance at age 18 was larger for sprint events (9.6%; 50–200m) than endurance events (7.1%; 400–1500m; p <0.001). Additionally, the sex‐related difference in performance increased across age and US ranking from 2.4% for 1 st place to 4.3% for 100 th place ( p <0.001), indicating less depth of performance in girls than boys. However, annual participation was ~20% higher in girls than boys for all ages ( p <0.001). Conclusion The top 5 girls demonstrated faster swimming velocities and the 10 th –50 th place girls demonstrated similar swimming velocities than boys (until ~10 years). After age 10, however, boys demonstrated increasingly faster swimming velocities than girls until 17 years. Collectively, these data suggest girls are faster, or at least not slower, than boys prior to the performance‐enhancing effects of puberty. Support or Funding Information This study was supported by the National Institutes of Health R‐35‐HL139854‐02 (MJJ), HL139854‐02S1 (AJC), 5T32DK007352‐40 (JWS), and the Mayo Foundation. Elite swimming performance. Mean swimming velocity from 5 to 18 years of the top 100 fastest US boys (blue circles) and girls (red triangles) for the 50, 100, 200, 400, 800 and 1500m freestyle swimming distances. Figure 1 Sex differences in performance of the top 5 places. The primary plot (heat map) displays the sex differences in swimming velocity (% boy’s swimming velocity) of the top 5 US rankings in each freestyle event distance and age, negative values (red) indicate faster performance of girls. The top displays the mean sex difference across age, and the right plot displays the mean sex difference across swimming event distance. 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

Background Maintaining baroreflex sensitivity is integral to ensuring blood pressure maintenance and end‐organ perfusion during hemorrhage. This is especially true under conditions of hypoxemia, where decreased tolerance to central hypovolemia is commonly observed. Hypoxia activates peripheral chemoreceptors and reduces baroreceptor‐vascular resistance reflex sensitivity. However, a direct role for the peripheral chemoreceptors in the hemodynamic response to hemorrhage in hypoxia remains unclear. Objective We tested the hypothesis that attenuation of peripheral chemoreceptor activity (low‐dose dopamine; 1–2 μg/kg/min) during acute hypoxia would promote maintenance of mean arterial pressure, pulse pressure, and other hemodynamic markers [heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR)] during simulated hemorrhage. Methods Ten healthy men (35±3 years, BMI 25±1 kg/m 2 ) participated in a randomized, double‐blind, placebo controlled study. Participants completed two experimental visits (saline and low‐dose dopamine) at which lower body negative pressure (LBNP) was conducted during hypoxia (SpO 2 ~85%; PaO2 ~52 mmHg) delivered via a non‐rebreather mask. Ventilation [V̇ (turbine transducer)], arterial blood pressure (brachial artery catheter), HR (ECG), and central venous pressure (peripherally inserted central catheter) were measured continuously and SV, CO, and TPR were calculated. Following a 5‐min rest, participants underwent LBNP for 5‐min at 3 intervals (−15, −30, and −45 mmHg). Outcome values were analyzed and compared using a mixed linear model (SAS PROC MIXED) with a direct product AR(1) covariance structure using indicator variables for saline vs. dopamine. Data from the mixed linear model are reported as an estimated change per 15 mmHg of LBNP. Results Dopamine had no effect on hypoxia P a O 2 , P a CO 2 , V̇ or respiratory rate (all P >0.05) and this relationship persisted throughout all LBNP stages. The mixed linear model showed no effect of dopamine vs. saline on changes in: central venous pressure (−1.1±0.4 vs −1.3±0.3 mmHg, P =0.15), mean arterial pressure (−4.7±2.3 vs −5.3±1.4 mmHg, P =0.25), pulse pressure (−6.7±1.5 vs −8.3±1.4 mmHg, P =0.50), HR (7.8±1.5 vs 6.1±1.5 bpm, P =0.41), SV (−10.9±1.9 vs −11.6±3.3 mL, P =0.41), CO (−0.3±0.2 vs −0.4±0.4 L · min −1 , P =0.31) or TPR (0.2±0.4 vs 0.7±0.6 mmHg · L · min −1 P =0.27). Discussion Intravenous infusion of low‐dose dopamine designed to attenuate peripheral chemoreflex activity during acute hypoxia did not alter the integrated hemodynamic response to simulated hemorrhage. Our data suggests that peripheral chemoreceptors have a limited role during hypoxic central hypovolemia. More research is needed to understand the sensitivity and cross‐talk between chemoreceptors and baroreceptors during hemorrhage. Support or Funding Information Funding: W81XWH‐13‐2‐0038 (DOD), DK90541 (NIH), UL1 TR000135 (NIH).

Background Sympathetic nerve activity and its effect on blood pressure are altered by female sex hormones; however, this effect differs between exogenous and endogenous hormones. With oral contraceptive (OC) use, cross‐sectional data has demonstrated higher blood pressure (BP) with no corresponding change in muscle sympathetic nerve activity (MSNA). This results in a higher BP/MSNA ratio with OC use although contributing mechanisms are unclear. The higher BP/MSNA ratio in women on OC suggests OC use may limit the ability of sympathetic baroreflex (sBRS) to suppress MSNA. Alternatively, a “burst” of MSNA could result in a greater change in BP (augmented neurovascular transduction). Objective The goal of this study was to determine if OCs alter blood pressure control through autonomic mechanisms in young women. Hypotheses We hypothesized (1) sympathetic baroreflex sensitivity would be decreased and (2) neurovascular transduction would be augmented in women on OCs compared to naturally cycling women. Methods We conducted a retrospective analysis of data from healthy young women taking OCs (n=30, 25±4yrs) and with natural menstrual cycles (n=23, 27±4yrs). Women were studied during the placebo phase of OC use or early follicular phase of the menstrual cycle. Heart rate (HR, 3‐lead ECG), BP (arterial line or photoplethysmography for both groups), and MSNA (peroneal nerve microneurography) were measured over 5 min of quiet rest and data were analyzed for measures of sBRS and neurovascular transduction (Ensemble, Elucimed Inc., Dunedin, New Zealand). Results Groups did not differ in mean BP (Control: 94±9, OC:92±8mmHg, p=0.60), or HR (Control: 61±8, OC: 62±9 bpm, p=0.57), but women on OCs had lower MSNA than controls (Control: 16±6, OC: 12±5 bursts/min, p=0.006). There were no significant differences in TPR (Control: 0.022±0.005, OC: 0.020±0.005 mmHg min/L, p=0.12), however there was a trend toward increased cardiac output in women on OCs (Control: 4.45±0.86, OC: 4.94±1.02 L/min, p=.068). There were no significant group differences in sBRS (Control: −4.3±2.1, OC: −4.0±2.6 bursts ·100 heartbeats −1 ·mmHg −1 , p=0.79), or neurovascular transduction (Control: 0.093±0.042, OC: 0.091±0.058 ΔmmHg/% burst area, p=0.87). Furthermore, there were no significant correlations between BP and BRS, MSNA, or transduction in either group. Conclusions Our data strengthen previous findings which have shown women taking OCs have higher BP for a given MSNA. The analysis we performed build on these results and demonstrate that the increase in BP for a given MSNA in women taking OCs is not due to attenuated sBRS or augmented neurovascular transduction. This work has advanced our understanding of the alteration of blood pressure with OC use in young women. Support or Funding Information NIH HL083947

Background Repetitive hypoxic apneas, similar to what is observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP) in humans. This resetting of the baroreflex is associated with increased BP in preclinical models of sleep apnea (chronic intermittent hypoxia, CIH); however, the majority of our understanding comes from men. There are data to suggest female rats exposed to CIH do not develop high BP. With this, we sought to examine potential sex‐related differences in the effect of intermittent hypoxia (IH) on the sympathetic baroreflex. We hypothesized young men would exhibit resetting of the baroreflex to higher BP following IH, with no change in young women. Methods BP and muscle sympathetic nerve activity (MSNA) were assessed in 17 men (30±1 yrs) and 10 women (28±1 yrs) during quiet normoxic rest prior to and following 30‐min of experimental IH [30‐s hypoxic exposures (0.05 F i O 2 ) alternating with 90‐s room air breathing] resulting in 15 hypoxic events (91.7±0.5 % SpO2). Sympathetic baroreflex sensitivity was evaluated using the modified Oxford technique before and after 30‐min of IH. Results Diastolic BP increased in men following IH (71±2 to 74±2 mmHg; p<0.01) with no change in women (75±3 to 75±3 mmHg; p=0.97). Sympathetic baroreflex sensitivity did not change following IH in either group (Men: −1.8±0.2 to −1.9±0.3; Women: −1.6±0.3 to −2.1± 0.5 bursts/100 heart beats/mmHg; Main effect of IH, p=0.14; Interaction of group and IH, p=0.28). Conclusion Acute IH resets the sympathetic baroreflex to higher BP in young men, with no change in young women. Baroreflex sensitivity slopes were unchanged in either group following IH. Our results support sex differences in the effect of IH on sympathetic control of BP and show that young women are protected from the BP‐raising effects of IH. These data enhance our understanding of sex‐specific mechanisms that may contribute to the development of hypertension in sleep apnea. Support or Funding Information NIH HL130339, Mayo Clinic Center for Biomedical Discovery

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)

Background Psychological stress and insufficient sleep are both associated with an increased risk of developing hypertension. While the underlying mechanisms are not well defined, it has been postulated that this may be facilitated by modulation of baroreflex control of sympathetic activity. Short periods (<5 min) of mental stress attenuate sympathetic baroreflex sensitivity (sBRS), but it is currently unclear whether this holds true for longer bouts of stress. As such, we sought to examine the effect of 10 min of mental stress on sBRS. Additionally, we evaluated the impact of experimental sleep restriction on baroreflex control of blood pressure during mental stress. We hypothesized that mental stress would attenuate sBRS, and that prolonged exposure to restricted sleep would result in a greater reduction in sBRS during mental stress. Methods Fourteen healthy adults (10M/4F, 25±1 yrs) underwent 10 min of mental stress consisting of a 5‐min mental arithmetic task, followed immediately by a 5‐min Stroop color‐word conflict test. Heart rate (electrocardiography), blood pressure (finger photoplethysmography), and muscle sympathetic nerve activity (microneurography of the common peroneal nerve) were continuously measured to determine sBRS at baseline and during mental stress. A subset of participants (n=9) completed the mental stress protocol under both experimental sleep restriction (4 hr/night) and control sleep conditions (8–9 hr/night) while inpatient at a hospital‐based clinical research unit. Subjects underwent a 3‐night acclimation period, followed by 9 or 14 nights of either sleep restriction or control sleep. Data from Day 2/1 or Day 13/15 (during control sleep only) were used to assess the effect of mental stress alone, and data from Day 13/15 (under both conditions) were used to assess the effect of sleep restriction. Results Acute mental stress resulted in a marked blunting of sBRS from baseline (−2.7±0.5 to −1.5±0.4 bursts·100hb −1 ·mmHg −1 , p=0.04). Examining the mental stress interventions individually revealed a significant decrease in sBRS during the initial 5 min of stress (mental arithmetic, p=0.03), but not during the subsequent 5 min of testing (Stroop test, p=0.75). Mental stress also reduced baroreflex function following sleep restriction (main effect of condition, p<0.01); however, the reduction in sBRS was not significantly different in restricted sleep compared to control (main effect of visit, p=0.78). There was no significant interaction effect between sleep restriction and mental stress (p=0.81). Conclusions These data provide further support that, in young healthy individuals, sBRS is attenuated early in mental stress but quickly returns to baseline values. In contrast, prolonged sleep restriction does not appear to alter sympathetic control of blood pressure. Support or Funding Information NIH HL114024 (VKS), NIH HL114676 (VKS), NIH HL083947 (MJJ), FAER Medical Student Anesthesia Research Fellowship (NMP)

Objective Exercise is a cornerstone of therapeutic intervention for individuals with cystic fibrosis (CF). However, daily breathing treatments (e.g. chest physiotherapy and inhalation of nebulized albuterol) typically last ~90 minutes, providing a time‐barrier to completing daily exercise. Thus, the purpose of our study was to determine the effects of a combination therapy (exercise and nebulized albuterol) on airway function and bronchodilator delivery. We tested the hypotheses that combination therapy (exercise + nebulized albuterol) would 1) augment the bronchodilator effect compared to either intervention alone, and 2) increase the plasma concentration of albuterol compared to nebulized albuterol alone. Methods Participants with CF (n=9, 5 female, 25±2yrs, forced expiratory volume in 1 second (FEV 1 ) =82±5%predicted) first completed a screening visit (V̇O 2max test, cycle ergometer) and then three study visits in a randomized order. During each study visit, participants completed measures of airway function [FEV 1 and forced expiratory flow from 25–75% of forced vital capacity (FEF 25–75 )], and a blood draw (n=8) to determine plasma albuterol concentration. Participants then completed one of three interventions [albuterol only, (A): 2.5mg nebulized albuterol over 15min; exercise only (E): 30min cycling exercise at 50% of peak watts; albuterol and exercise (A+E): 30min cycling exercise at 50% of peak watts with 2.5mg nebulized albuterol nebulized over the last 15min of cycling). Airway function and plasma albuterol were measured at 0, 15, 30, 45, 60, 90, 120, 180, and 240min after the intervention. Additional plasma albuterol measures were taken 5, and 6hrs post intervention. Data are mean±SD. Results Delivery of nebulized albuterol during exercise did not augment or prolong the bronchodilator effect compared to exercise or albuterol alone. The transient improvement in airway function during the interventions—increase in FEV 1 (time=0.050, intervention p=0.166, interaction p=0.135) or increase in FEF 25–75 (time p=0.001, intervention p=0.207, interaction p=0.990) — was not different between the three interventions. Delivery of nebulized albuterol during exercise did not increase the plasma concentration of albuterol compared to nebulized albuterol alone. The maximum plasma concentration of albuterol (C max ) and the area under the curve (AUC) of albuterol concentration over time were not different between interventions (C max = 2.57±1.60 vs. 2.56±1.13ng·mL −1 , p=0.982; AUC 0–6hrs = 6.1±3.6 vs. 6.9±3.3hr·ng·mL −1 , p=0.188; A vs. A+E interventions, respectively). Conclusions Delivery of nebulized albuterol during moderate intensity exercise did not significantly alter bronchodilator effects or plasma levels of albuterol compared to albuterol or exercise alone. These data suggest that delivery of nebulized albuterol during exercise is safe and effective, but does not augment bronchodilator effects or drug delivery. This combination intervention (A+E) may be a time efficient method for individuals with cystic fibrosis to gain therapeutic effects of exercise and breathing treatments. Support or Funding Information F32 HL131151, Cystic Fibrosis Research Inc.

Objectives We aimed to determine if epinephrine played a beneficial role on middle cerebral artery velocity (MCAv) during physiologically stressful stimuli prior to cardiovascular collapse. MCAv was assessed during lower body negative pressure (LBNP) under conditions of a saline or epinephrine infusion. We hypothesized that (1) epinephrine would augment the change in MCAv from baseline to LBNP tolerance, (2), epinephrine would increase MCAv for a given LBNP stimulus, (3) at a given percent of LBNP tolerance epinephrine and saline will be similar and (4) that epinephrine would improve LBNP tolerance. Methods Nine participants (35±9yrs, n=5 male, 4 female) underwent a LBNP protocol to physiological tolerance during two study visits, performed at least two weeks apart, and randomized to saline or epinephrine (dose=0.1μg/kg/min) infusions (peripherally‐ inserted central catheter). Blood pressure (radial artery catheter) and middle cerebral artery velocity (transcranial Doppler) were assessed. MCAv and cerebrovascular conductance index (CvCi) were analyzed during baseline (three minutes), physiological tolerance (one minute), during LBNP at a given stimulus (three minutes; −15, −30, −45 mmHg of LBNP), and during relative percentages of LBNP tolerance [three minutes; 20, 40, 60, and 80% of LBNP tolerance time (s)]. Baseline was defined as measures taken after 15 minutes of saline or epinephrine infusion. Results In both saline and epinephrine conditions, MCAv and CvCi decreased from baseline to tolerance (Saline MCAv: 69.7±7.5 vs 44.9±4.9 cm/s, p<0.05; Epinephrine MCAv: 80.9±5.9 vs 56.5±6.7 cm/s, p<0.05; Saline CvCi: 0.69±0.06 vs 0.58±0.067 cm/s/mmHg, p>0.05; Epinephrine CvCi: 0.80±0.06 vs 0.70±0.078 cm/s/mmHg, p<0.05). Epinephrine augmented MCAv at a given LBNP stimulus from baseline to −15, −30, and −45 mmHg (MCAv: Treatment effect: p<0.05; CvCi: Treatment effect: p=0.05). At a relative percent of LBNP tolerance, epinephrine increased MCAv, but when blood pressure was controlled for with CvCi there was no treatment effect between epinephrine and saline (MCAv: Treatment effect: p<0.05; CvCi: Treatment effect: p>0.05). Time to tolerance was not significantly different between saline and epinephrine conditions (1469±168 vs. 1445±82s, p=0.88). Conclusions Epinephrine increased MCAv during LBNP. These data suggest that epinephrine plays a beneficial role during stressful physiological stimuli such as hemorrhage in humans by augmenting cerebral blood flow prior to cardiovascular collapse. However, epinephrine did not improve LBNP tolerance. Support or Funding Information The United States Department of Defense W81XWH‐13‐2‐0038

Background In humans, exercise tolerance is determined by the balance of diffusive and convective elements of oxygen transport. Mathematical models have suggested that alterations in hemoglobin‐oxygen (Hb‐O 2 ) binding affinity (P 50 ) have minimal effects of on oxygen delivery. However, there is limited experimental data in humans to evaluate these models during exercise in humans. Purpose We sought to investigate skeletal muscle blood flow and vascular conductance (hyperemic response to exercise and hypoxia) during exercise in otherwise healthy participants with chronically high Hb‐O 2 affinity (HAH). We hypothesized that patients with HAH would have a blunted hyperemic response to both handgrip and hypoxia due to the marked polycythemia that is typical in participants with HAH compared to controls. Methods Participants with HAH (n=6, 3 men, age= 37±12 yr, P 50 =15±2 mmHg) and control participants matched for age, sex, and BMI (CTL, n=5, 3 men, age=41±8 yr, and P 50 =26±1 mmHg) completed two intensities (10% and 20% maximal voluntary contraction (MVC)) of rhythmic handgrip exercise with a duty cycle of 1s contraction and 2s relaxation (20 contractions·min −1 ). Each exercise intensity was performed breathing three different gas mixtures: 21%, 15%, and 10% oxygen. Brachial artery mean blood velocity was measured using Doppler ultrasound. Beat‐by‐beat blood pressure was measured via arterial catheterization. Forearm blood flow (FBF) was calculated as the product of mean blood velocity (cm·s −1 ) and brachial artery cross‐sectional area (cm 2 ) and expressed as milliliters per minute (mL·min −1 ), and forearm vascular conductance (FVC) was calculated as (FBF) × (mean arterial pressure) −1 × 100 and expressed as mL·min −1 ·mmHg −1 . Data were analyzed using a three‐way ANOVA (Inspirate [21%, 15%, 10% O 2 ], group [CTL, HAH], handgrip intensity [Rest, 10% and 20% MVC]). Results During normoxia (21% O 2 ), groups were not different in FBF (P>0.05), FVC (P>0.05) or arterial saturation (S a O 2 , P=0.54). Similarly, the moderate hypoxia condition (15% O 2 ), groups were not different in FBF (P>0.05), or FVC (P>0.05) despite a preservation in arterial saturation in HAH (S a O 2 , CTL: 89.0±0.7% vs. HAH: 95.1±1.7%, P<0.001). However, with more severe hypoxic exposure (10% O 2 ), FBF and FVC were higher in HAH than controls during the 20% MVC exercise (P<0.05). HAH also had higher FBF (P<0.05) and trended towards higher FVC in the 10% MVC exercise (P=0.08). Interestingly, arterial saturation was drastically higher for HAH at the end of handgrip exercise (20% MVC) in 10% O 2 (CTL: 69.2±4.5% vs. HAH: 89.1±1.4%, P<0.001). Conclusion As predicted in mathematical models, Hb‐O 2 binding affinity had little effect on skeletal muscle blood flow and forearm vascular conductance during light exercise under normoxic and moderate hypoxic conditions (21% and 15% O 2 ). However, with a greater physiological stress to skeletal muscle O 2 uptake in a more severe hypoxic condition (10% O 2 ), participants with HAH, contrary to our initial hypothesis, had preserved arterial O 2 saturation and a greater hyperemic response than controls. Support or Funding Information This work was supported by the NIH (5T32DK007352‐39 to CCW, R35HL139854 to MJJ) Rest 10% MVC 20% MVC FBF, mL·min − 1 21% O 2 CTL 87 ± 8 327 ± 25 589 ± 26 HAH 142 ± 19 420 ± 29 716 ± 68 15% O 2 CTL 173 ± 61 357 ± 63 707 ± 62 HAH 156 ± 66 539 ± 111 930 ± 143 10% O 2 CTL 154 ± 72 386 ± 81 668 ± 57 HAH 244 ± 133 703 ± 199 * 932 ± 118 * FVC, mL·min − 1 ·mmHg − 1 21% O 2 CTL 94 ± 9 356 ± 27 621 ± 24 HAH 130 ± 19 363 ± 25 617 ± 63 15% O 2 CTL 187 ± 63 384 ± 54 758 ± 53 HAH 137 ± 44 453 ± 79 764 ± 226 10% O 2 CTL 171 ± 71 431 ± 73 708 ± 67 HAH 221 ± 109 718 ± 136 917 ± 172 Abbreviations: FBF, forearm blood flow; FVC, forearm vascular conductance; MVC, maximal voluntary contraction; CTL, control group; HAH, high‐affinity Hb group. Values are presented as mean±SE. * indicates significant difference (P<0.05) from CTL group at same %MVC.