Dominelli, Paolo B.

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 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.

New Findings What is the topic of this review?The limits to maximal aerobic capacity. What advances does it highlight?A synthesis of data and ideas about what limits maximal aerobic capacity demonstrates the central roles of cardiac output, stroke volume and red blood cell mass in the complex physiological responses to maximal exercise. In healthy humans these factors, along with skeletal muscle blood flow, dominate systemic delivery of oxygen to the contracting muscles and set the upper limit of aerobic energy production by skeletal muscles. In elite athletes and patients with pulmonary disease the lungs can also limit oxygen uptake and delivery. AbstractIn this paper we review the physiological determinants of and discuss the role this variable plays as a determinant of endurance exercise performance. Because the ability to sustain a given pace during a competitive athletic event requires competitors to ‘manage’ fatigue and go as fast as possible without fatiguing prematurely, is one of the variables that sets the physiological upper limit for sustained energy production by the contracting skeletal muscles.

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.

Key points Haemoglobin affinity is an integral concept in exercise physiology that impacts oxygen uptake, delivery and consumption. How chronic alterations in haemoglobin affinity impact physiology is unknown. Using human haemoglobin variants, we demonstrate that the affinity of haemoglobin for oxygen is highly correlated with haemoglobin concentration. Using the Fick equation, we model how altered haemoglobin affinity and the associated haemoglobin concentration influences oxygen consumption at rest and during exercise via alterations in cardiac output and mixed‐venous . The combination of low oxygen affinity haemoglobin and reduced haemoglobin concentration seen in vivo may be unable to support oxygen uptake during moderate or heavy exercise. AbstractThe physiological implications, with regard to exercise, of altered haemoglobin affinity for oxygen are not fully understood. Data from the Mayo Clinic Laboratories database of rare human haemoglobin variants reveal a strong inverse correlation (r = −0.82) between blood haemoglobin concentration and P50, an index of oxygen affinity [Hb = −0.3135(P50) + 23.636]. In the present study, observed P50 values for high, normal and low oxygen‐affinity haemoglobin variants (13, 26 and 39 mmHg) and corresponding haemoglobin concentrations (19.5, 15.5 and 11.4 g dL−1 respectively) are used to model oxygen consumption as a fraction of delivery at rest ( = 0.25 L min−1, cardiac output = 5.70 L min−1) and during exercise ( = 2.75 L min−1, cardiac output = 18.9 l min−1). With high‐affinity haemoglobin, the model shows that normal levels of oxygen consumption can be achieved at rest and during exercise at the assumed cardiac output levels, with reduced oxygen extraction both at rest (16.8% high affinity vs. 21.7% normal) and during exercise (55.8% high affinity vs. 72.2% normal). With low‐affinity haemoglobin, which predicts low haemoglobin concentration, oxygen consumption at rest can be sustained with the assumed cardiac output, with increased oxygen extraction (31.1% low affinity vs. 21.7% normal). However, exercise at 2.75 l min−1 cannot be achieved with the assumed cardiac output, even with 100% oxygen extraction. In conclusion, the model indicates chronic alterations in P50 associate directly with Hb concentration, highlighting that human Hb variants can serve as ‘experiments of nature’ to address fundamental hypotheses on oxygen transport and exercise.

Key points The perceived intensity of exertional breathlessness (i.e. dyspnoea) is higher in older women than in older men, possibly as a result of sex‐differences in respiratory system morphology. During exercise at a given absolute intensity or minute ventilation, older women have a greater degree of mechanical ventilatory constraint (i.e. work of breathing and expiratory flow limitation) than their male counterparts, which may lead to a greater perceived intensity of dyspnoea. Using a single‐blind randomized study design, we experimentally manipulated the magnitude of mechanical ventilatory constraint during moderate‐intensity exercise at ventilatory threshold in healthy older men and women. We found that changes in the magnitude of mechanical ventilatory constraint within the physiological range had no effect on dyspnoea in healthy older adults. When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea. AbstractWe aimed to determine the effect of manipulating mechanical ventilatory constraint during submaximal exercise on dyspnoea in older men and women. Eighteen healthy subjects (aged 60–80 years; nine men and nine women) completed two days of testing. On day 1, subjects were assessed for pulmonary function and performed a maximal incremental cycle exercise test. On day 2, subjects performed three 6‐min bouts of cycling at ventilatory threshold, in a single‐blind randomized manner, while breathing: (i) normoxic helium‐oxygen (HEL) to reduce the work of breathing (Wb) and alleviate expiratory flow limitation (EFL); (ii) through an inspiratory resistance (RES) of ∼5 cmH2O L−1 s−1 to increase Wb; and (iii) ambient air as a control (CON). Oesophageal pressure, diaphragm electromyography, and sensory responses (category‐ratio 10 Borg scale) were monitored throughout exercise. During the HEL condition, there was a significant decrease in Wb (men: –21 ± 6%, women: –17 ± 10%) relative to CON (both P < 0.01). Moreover, if EFL was present during CON (four men and five women), it was alleviated during HEL. Conversely, during the RES condition, Wb (men: 42 ± 19%, women: 50 ± 16%) significantly increased relative to CON (both P < 0.01). There was no main effect of sex on Wb (P = 0.59). Across conditions, women reported significantly higher dyspnoea intensity than men (2.9 ± 0.9 vs. 1.9 ± 0.8 Borg scale units, P < 0.05). Despite significant differences in the degree of mechanical ventilatory constraint between conditions, the intensity of dyspnoea was unaffected, independent of sex (P = 0.46). When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea.

Exercise-induced arterial hypoxemia (EIAH) is characterized by the decrease in arterial oxygen tension and oxyhemoglobin saturation during dynamic aerobic exercise. Since the time of the initial observations, our knowledge and understanding of EIAH has grown, but many unknowns remain. The purpose of this review is to provide an update on recent findings, highlight areas of disagreement, and identify where information is lacking. Specifically, this review will place emphasis on (i) the occurrence of EIAH during submaximal exercise, (ii) whether there are sex differences in the development and severity of EIAH, and (iii) unresolved questions and future directions.

AbstractReducing the work of breathing during exercise improves locomotor muscle blood flow and reduces diaphragm and locomotor muscle fatigue and is thought to be the result of a sympathetically mediated reflex.AimThe aim of this study was to assess muscle sympathetic nerve activity (MSNA) when the work of breathing is experimentally lowered during dynamic exercise.MethodsHealthy subjects (n = 12; age = 29 ± 9 years) performed semi‐recumbent cycling trials at 40%, 60%, and 80% of peak workload. Exercise trials consisted of spontaneous breathing, reduced work of breathing (proportional assist ventilator), followed by further spontaneous breathing (post‐ventilator). MSNA was recorded from the median nerve.ResultsThere was no difference in work of breathing between PAV and post‐PAV at 40% peak work. At 60% peak work, the ventilator significantly (P < 0.05) reduced work of breathing (103 ± 39 vs 144 ± 47 J min−1), sympathetic nerve activity (35 ± 5 vs 42 ± 8 burst min−1), and (2.4 ± 0.5 vs 2.6 ± 0.5 L min−1) without influencing ventilation (86 ± 9 vs 82 ± 10 L min−1; P > 0.05), for PAV and post‐PAV respectively. During 80% peak work (n = 8), the ventilator significantly (P < 0.05) reduced work of breathing (235 ± 110 vs. 361 ± 150 J min−1), MSNA (48 ± 7 vs 54 ± 11 burst min−1), and (2.9 ± 0.6 vs 3.2 ± 0.7 L min−1) but not ventilation (121 ± 20 vs 123 ± 20 L min−1; P > 0.05), for PAV and post‐PAV respectively. There was a significant relationship between MSNA and (P < 0.0001) with a significant interaction due to the ventilator (P < 0.05).ConclusionLowering the normally occurring work of breathing during exercise results in commensurate reductions in MSNA. Our findings provide evidence of a sympathetically mediated vasoconstrictor effect emanating from respiratory muscles during exercise.