Citations

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 Despite improvements in military aircraft safety, many aviation incidents are attributed to hypoxia. The correlation between moderate hypoxia and cognitive function are well studied but results remain controversial. Comparatively, the effects of severe hypoxia are still not well understood. In the present study, we examined the executive cognitive function and physiological indices under both moderate and severe hypoxia conditions. Purpose To examine the relationship between executive function and physiological indices during acute hypoxia exposure. Methods Ten young healthy participants (4M/6F, 29±4 years) completed two different levels of hypoxia: 1) 10 minute moderate hypoxia (MH; F i O 2 = 0.118) and 2) 3 minute severe hypoxia (SH; F i O 2 = 0.077) following 3 minute baseline (BL; F i O 2 =0.209). Reaction time and errors of commission (defined as a response to a non‐target stimulus) were evaluated continuously using a custom Go/No‐go test at baseline and throughout hypoxia exposure. In this Go/No‐go test, participants were required to push a key when upper case “A” or “@” appeared but not when lower case “a” appeared on a computer monitor as quick and as accurately as possible. The stimuli were presented one at a time at any one of nine differing locations across the screen. Cerebral oxygenation (rSO 2 ) was continuously monitored with near‐infrared spectroscopy (NIRS) positioned above the left supraorbital ridge. Finger oxygen saturation (S p O 2 ) was continuously assessed using a pulse oximetry. Data were analyzed in every 30 seconds and are presented as mean±SE. Two‐way ANOVA and Bonferroni test for multiple comparisons was used to evaluate significant differences. Results Both S p O 2 and rSO 2 were reduced with SH (S p O 2 %, BL: 99.3±0.1% vs. SH: 70.7±1.5%, P<0.01; rSO 2 %, BL: 70±4% vs. SH: 58±4%, P<0.01). In SH, correlations of S p O 2 and rSO 2 were significant to the number of errors during the cognitive performance task (S p O 2 ; R= −0.65, rSO 2 ; R= −0.58, Both P<0.01). SH significantly increased errors of commission of the last 30 seconds in 3 minute hypoxic exposure. (BL: 0.6±0.2 errors vs. SH: 1.7±0.5 errors, P<0.01). SH significantly decreased reaction time over hypoxic exposure (BL: 0.43±0.01 sec vs. SH: 0.41±0.01 sec, P<0.01). Comparatively, MH did not elicit an increase in the number of errors of commission nor a decrease in reaction time (Both, P>0.05). Conclusion Executive function deteriorated during severe hypoxia. Oxygenation of the prefrontal lobe which controls inhibition may be related to the increase in commission errors. Devices that monitor physiological indices such as S p O 2 or rSO 2 might be beneficial for a model to predict executive deterioration. Support or Funding Information This project was funded by the Office of Naval Research (ONR), grant number N00014‐18‐D‐7001‐TO1.

Background Cognitive deficits resulting from mild hypoxia are difficult to quantify and reproduce consistently. The changes in executive function during acute hypoxia are still controversial. The purpose of present study was to assess changes in executive function during acute moderate hypoxia using a continuous performance test (Connors’ Continuous Performance test, CCPT‐II). Methods Nine young, healthy adults (7 women; 28 ± 1 years; BMI: 24.5 ± 3.0 kg·m −2 ) performed two sets of CCPT‐II during two different conditions: 1) 7 minutes of baseline (fraction of inspired oxygen (F i O 2 ) = 0.21) and 2) 10 minutes of hypoxia (F i O 2 =0.118). The CCPT‐II is a test of executive cognitive function which requires subjects to strike a key when any letter except the letter X appeared on a computer monitor as quickly and accurately as possible. Reaction time, commission errors (response to X), and omission errors (failure to respond to a letter other than X) were recorded for each 140s of the CCPT‐II block. Arterial oxygen concentration (P a O 2 ) was measured during the last 30sec of baseline and hypoxia from brachial artery catheter samples. Results P a O 2 was reduced in hypoxia ( baseline : 103.1 ± 1.5 mmHg vs. hypoxia : 43.2 ± 1.0 mmHg, P <0.01). During the trials of the CCPT‐II performed during hypoxia, reaction time was lower (i.e. faster) than during baseline ( baseline : 451 ± 18 ms. vs. hypoxia : 437 ± 13 ms., P<0.01). Additionally, the number of commission errors was greater in hypoxia ( baseline : 1.3 ± 0.6 errors·block −1 vs. hypoxia : 2.1 ± 0.8 errors·block −1 , P<0.01). However, the number of omission errors was not different between the two conditions ( baseline : 0.4 ± 0.2 errors·block −1 vs. hypoxia : 0.2 ± 0.1 errors·block −1 , P=0.92). Conclusions The number of commission errors increased and the reaction time decreased during the CCPT‐II test performed in moderate hypoxia compared to baseline, demonstrating a decline in cognitive function during hypoxia. The faster and less accurate responses during hypoxia suggest a suppression of inhibitory pathways in the prefrontal or motor cortex that may contribute to the observed acute reduction in executive cognitive function. Support or Funding Information This project was funded by the Office of Naval Research (ONR), grant number N00014‐18‐D‐7001‐TO1.

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.

We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing patterns and the role of the carotid chemoreceptors. We hypothesized exposure to acute IH would increase muscle sympathetic nerve activity (MSNA) via an increase in action potential (AP) discharge rates and within-burst firing. We further hypothesized any change in discharge patterns would be attenuated during acute chemoreceptor deactivation (hyperoxia). MSNA (microneurography) was assessed in 17 healthy adults (11 male/6 female; 31 ± 1 yr) during normoxic rest before and after 30 min of experimental IH. Prior to and following IH, participants were exposed to 2 min of 100% oxygen (hyperoxia). AP patterns were studied from the filtered raw MSNA signal using wavelet-based methodology. Compared with baseline, multiunit MSNA burst incidence ( P < 0.01), AP incidence ( P = 0.01), and AP content per burst ( P = 0.01) were increased following IH. There was an increase in the probability of a particular AP cluster firing once ( P < 0.01) and more than once ( P = 0.03) per burst following IH. There was no effect of hyperoxia on multiunit MSNA at baseline or following IH ( P > 0.05); however, hyperoxia following IH attenuated the probability of particular AP clusters firing more than once per burst ( P < 0.01). Acute IH increases MSNA by increasing AP discharge rates and within-burst firing. A portion of the increase in within-burst firing following IH can be attributed to the carotid chemoreceptors. These data advance the mechanistic understanding of sympathetic activation following acute IH in humans.

New Findings What is the central question of this study? What is the role of β2‐adrenergic receptor (β2AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β2AR‐mediated vasodilatation in both groups of women? What is the main finding and its importance? β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women. Abstractβ2‐Adrenergic receptor (β2AR)‐mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β2AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β2AR agonist terbutaline is blunted in older postmenopausal women (59 ± 4 years) compared to young premenopausal women (27 ± 3 years) and to assess NO contribution to β2AR‐mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra‐arterial infusions of terbutaline at 0.1–2.0 µg (100 ml tissue)−1 min−1 with and without the NO synthase inhibitor l‐NG‐monomethylarginine (l‐NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P = 0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P > 0.05) and rose significantly within each group during terbutaline infusion (P < 0.05). There were significant group × dose interactions for FBF (P = 0.01) and FVC (P = 0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l‐NMMA co‐infusion vs. without l‐NMMA (P = 0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l‐NMMA co‐infusion (P > 0.05 for all). These data suggest that β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women.

New Findings What is the central question of this study? Are sex difference in the central airways present in healthy paediatric patients? What is the main finding and its importance? In patients ≤12 years we found no sex differences in central airway luminal area. After 14 years, the males had significantly larger central airway luminal areas than the females. The sex differences were minimized, but preserved when correcting for height. Luminal area is the main determinant of airway resistance and our finding could help explain sex differences in pulmonary system limitations to exercise in paediatric patients. Abstract Cross‐sectional airway area is the main determinant of resistance to airflow in the respiratory system. In paediatric patients (<18 years), previous evidence for sex differences in cross‐sectional airway area was limited to patients with history of pulmonary disease or cadaveric studies with small numbers of subjects. These studies either only report tracheal data and do not include a range of ages or correct for height. Therefore, we sought to assess sex differences in airway luminal area utilizing paediatric patients of varying ages and no history of respiratory disease. Using three‐dimensional reconstructions from high‐resolution computed tomography scans, we retrospectively assessed the cross‐sectional airway area in healthy paediatric females ( n = 97) and males ( n = 128) over a range of ages (1–17 years). The areas of the trachea, left main bronchus, left upper lobe, left lower lobe, right main bronchus, intermediate bronchus and right upper lobe were measured at three discrete points by a blinded investigator. No differences between the sexes were noted in the cross‐sectional areas of the youngest (ages 1–12 years) patients ( P > 0.05). However, in patients ≥14 years the cross‐sectional areas were larger in the males compared to females in most airway sites. For instance, the cross‐sectional size of the trachea was 25% (218 ± 44 vs . 163 ± 24 mm 2 , P < 0.01) larger in males vs . females among ages 13–17 years. When accounting for height, these sex differences in airway areas were attenuated, but persisted. Our results indicate that sex differences in paediatric airway cross‐sectional area manifest after age ≥14 years and are independent of height.

Key points Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange. AbstractThe longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P50 = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P50 = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end‐exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects’ oxyhaemoglobin saturation () was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake () (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in between trials was related to the change in (r = −0.75, p < 0.0001). Compared to normoxia, the controls’ alveolar‐to‐arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia.

Arterial oxygen tension and oxyhemoglobin saturation ([Formula: see text]) decrease in parallel during hypoxia. Distinguishing between changes in oxygen tension and oxygen content as the relevant physiological stimulus for cardiorespiratory alterations remains challenging. To overcome this, we recruited nine individuals with hemoglobinopathy manifesting as high-affinity hemoglobin [HAH; partial pressure at 50% [Formula: see text] (P50) = 16 ± 0.4 mmHg] causing greater [Formula: see text] at a given oxygen partial pressure compared with control subjects ( n = 12, P50 = 26 ± 0.4 mmHg). We assessed ventilatory and cardiovascular responses to acute isocapnic hypoxia, iso-oxic hypercapnia, and 20 min of isocapnic hypoxia (arterial Po2 = 50 mmHg). Blood gas alterations were achieved with dynamic end-tidal forcing. When expressed as a function of the logarithm of oxygen partial pressure, ventilatory sensitivity to hypoxia was not different between groups. However, there was a significant difference when expressed as a function of [Formula: see text]. Conversely, the rise in heart rate was blunted in HAH subjects when expressed as a function of partial pressure but similar when expressed as a function of [Formula: see text]. Ventilatory sensitivity to hypercapnia was not different between groups. During sustained isocapnic hypoxia, the rise in minute ventilation was similar between groups; however, heart rate was significantly greater in the controls during 3 to 9 min of exposure. Our results support the notion that oxygen tension, not content, alters cellular Po2in the chemosensors and drives the hypoxic ventilatory response. Our study suggests that in addition to oxygen partial pressure, oxygen content may also influence the heart rate response to hypoxia.NEW & NOTEWORTHY We dissociated the effects of oxygen content and pressure of cardiorespiratory regulation studying individuals with high-affinity hemoglobin (HAH). During hypoxia, the ventilatory response, expressed as a function of oxygen tension, was similar between HAH variants and controls; however, the rise in heart rate was blunted in the variants. Our work supports the notion that the hypoxic ventilatory response is regulated by oxygen tension, whereas cardiovascular regulation may be influenced by arterial oxygen content and tension.