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Coronavirus disease-19 (COVID-19) has resulted in much acute morbidity and mortality worldwide. There is now a growing recognition of the post-acute sequela of COVID-19, termed long COVID. However, the risk factors contributing to this condition remain unclear. Here, we address the growing controversy in the literature of whether hospitalization is a risk factor for long COVID. We found that hospitalization is associated with worse pulmonary restriction and reduction in diffusion capacity at 3 months post-infection. However, the impact on mental health, functional and quality of life is equally severe in those who have and have not been hospitalized during the acute infection. These findings suggest that hospitalization is a risk factor for pulmonary complications of long COVID but not the overall severity of long COVID.

Obstructive sleep apnea (OSA) is a common disorder (~ 4%) that augments sympathetic nerve activity (SNA) and elevates blood pressure. The relationship between sympathetic vasomotor outflow and vascular responsiveness, termed sympathetic neurovascular transduction (sNVT), has been sparsely characterized in patients with OSA. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in diastolic pressure. Twelve participants with variable severities of OSA were recruited. We collected muscle sympathetic nerve activity (MSNA) (microneurography) and beat-by-beat diastolic pressure (finger photoplethysmography) during normoxia (FiO2 = 0.21) and hyperoxia (FiO2 = 1.0) to decrease MSNA burst frequency. MSNA burst sequences (i.e. singlets, doublets, triplets and quadruplets) were identified and coupled to changes in diastolic pressure over 15 cardiac cycles as an index of sNVT. sNVT slope for each individual was calculated from the slope of the relationship between peak responses in outcome plotted against normalized burst amplitude. sNVT slope was unchanged during hyperoxia compared to normoxia (normoxia 0.0024 ± 0.0011 Δ mmHg total activity [a.u.]−1 vs. hyperoxia 0.0029 ± 0.00098 Δ mmHg total activity [a.u.]−1; p = 0.14). sNVT slope was inversely associated with burst frequency during hyperoxia (r = −0.58; p = 0.04), but not normoxia (r = −0.11; p = 0.71). sNVT slope was inversely associated with the apnea–hypopnea index (AHI) (r = −0.62; p = 0.030), but not after age was considered. We have demonstrated that the prevailing MSNA frequency is unmatched to the level of sNVT, and this can be altered by acute hyperoxia.

Key points Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO2 production ( V E / V C O 2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD. The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on V E / V C O 2 , dyspnoea and exercise capacity in patients with mild COPD. Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced V E / V C O 2 and dyspnoea. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD. Abstract Patients with mild chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to dyspnoea and exercise intolerance. Previous research in mild COPD has demonstrated an elevated ventilatory equivalent to CO2 production ( V E / V C O 2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. The present study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower V E / V C O 2 and dyspnoea, and improve exercise capacity in patients with mild COPD. In this multigroup randomized-control cross-over study, 15 patients with mild COPD (FEV1 = 89 ± 11% predicted) and 15 healthy controls completed symptom-limited cardiopulmonary exercise tests while breathing normoxic gas or 40 ppm iNO. Compared with placebo, iNO significantly increased peak oxygen uptake (1.80 ± 0.14 vs. 1.53 ± 0.10 L·min-1 , P V E / V C O 2 by 3.8 ± 4.2 units (P = 0.002) and dyspnoea by 1.1 ± 1.2 Borg units (P V E / V C O 2 and dyspnoea. These data suggest that mild COPD patients demonstrate pulmonary microvascular dysfunction that contributes to increased V E / V C O 2 , dyspnoea and exercise intolerance. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD.

Previous work suggests that endurance-trained athletes have superior pulmonary vasculature function as compared to untrained individuals, which may contribute to their greater maximal oxygen uptake ([Formula: see text]OSixteen endurance-trained and sixteen untrained individuals with normal lung function completed this randomized double-blind cross-over study over four sessions. Experimental cardiopulmonary exercise tests were completed while breathing either normoxia (placebo) or 40 ppm of iNO, on separate days (order randomized). On an additional day, echocardiography was used to determine pulmonary artery systolic pressure at rest and during sub-maximal exercise (60 Watts) while participants breathed normoxia or iNO.Right ventricular systolic pressure was significantly reduced by iNO during exercise (Placebo: 34 ± 7 vs. iNO: 32 ± 7; p = 0.04). [Formula: see text]ODespite a reduction in right ventricular systolic pressure, the lack of change in [Formula: see text]O

The COVID-19 pandemic has resulted in significant acute morbidity and mortality worldwide. There is now a growing recognition of the longer-term sequelae of this infection, termed “long COVID”. However, little is known about this condition. Here, we describe a distinct phenotype seen in a subset of patients with long COVID who have reduced exercise tolerance as measured by the 6 min walk test. They are associated with significant exertional dyspnea, reduced health-related quality of life and poor functional status. However, surprisingly, they do not appear to have any major pulmonary function abnormalities or increased burden of neurologic, musculoskeletal or fatigue symptoms.

Obstructive sleep apnea (OSA) is a common disorder (~ 4%) that augments sympathetic nerve activity (SNA) and elevates blood pressure. The relationship between sympathetic vasomotor outflow and vascular responsiveness, termed sympathetic neurovascular transduction (sNVT), has been sparsely characterized in patients with OSA. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in diastolic pressure.Twelve participants with variable severities of OSA were recruited. We collected muscle sympathetic nerve activity (MSNA) (microneurography) and beat-by-beat diastolic pressure (finger photoplethysmography) during normoxia (FiOsNVT slope was unchanged during hyperoxia compared to normoxia (normoxia 0.0024 ± 0.0011 Δ mmHg total activity [a.u.]We have demonstrated that the prevailing MSNA frequency is unmatched to the level of sNVT, and this can be altered by acute hyperoxia.

COPD patients have increased central arterial stiffness and muscle sympathetic nervous activity (MSNA), both of which contribute to cardiovascular (CV) dysfunction and increased CV risk. Previous work suggests that COPD patients have elevated carotid chemoreceptor (CC) activity/sensitivity, which may contribute to the elevated MSNA and arterial stiffness. Accordingly, the effect of CC inhibition on central arterial stiffness, MSNA and CV function at rest in COPD patients was examined in a randomized placebo-controlled study. Thirteen mild-moderate COPD patients (FEV1 predicted ± SD: 83 ± 19%) and 13 age- and risk-matched controls completed resting CV function measurements with either intravenous saline or I.V. dopamine (2 μg kg min−1) while breathing normoxia or hyperoxia (100% O2). On a separate day, a subset of COPD patients and controls completed MSNA measurements while breathing normoxia or hyperoxia. Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). CC inhibition with dopamine decreased central and peripheral PWV, and MAP (P

Heightened arterial stiffness is a marker of cardiovascular risk and is elevated in chronic obstructive pulmonary disease (COPD). Physical activity has been shown to reduce arterial stiffness, and our previous work has shown that arterial stiffness is related to physical activity and exercise tolerance in COPD. The purpose of this study was to evaluate whether baseline physical activity and exercise tolerance influence the cardiovascular benefits associated with standard COPD outpatient pulmonary rehabilitation (PR).A total of 66 patients with COPD were recruited from the G.F. MacDonald Centre for Lung Health, Edmonton, Alberta, prior to entering PR. Another 23 COPD patients not attending the PR program were recruited as time controls (TC). Arterial stiffness (carotid-radial pulse wave velocity, PWV), physical activity (steps taken over three days), and 6-min walk distance (6MWD) were assessed before and after PR, or before and after six weeks of standard care.Thirty-nine PR and 11 TC completed all parts of the study. Following PR, there was no overall change in PWV. However, changes in arterial stiffness with PR were dependent on baseline exercise tolerance, with those patients with a 6MWD350 m showing a significant reduction in PWV following PR (6MWD350 m: 8.2 ± 1.6 to 8.5 ± 1.7 versus 6MWD350 m: 9.2 ± 0.6 to 7.3 ± 2.0 m/s, p 0.05). The PWV response to PR was not influenced by baseline physical activity levels.COPD patients with low exercise tolerance appear to derive the greatest cardiovascular benefits from PR.

Patients with mild chronic obstructive pulmonary disease (COPD) demonstrate resting pulmonary vascular dysfunction as well as a blunted pulmonary diffusing capacity (DLCO) and pulmonary capillary blood volume (VC) response to exercise. The transition from the upright to supine position increases central blood volume and perfusion pressure, which may overcome microvascular dysfunction in an otherwise intact alveolar-capillary interface. The present study examined whether the supine position normalized DLCO and VC responses to exercise in mild COPD. Sixteen mild COPD participants and 13 age-, gender-, and height-matched controls completed DLCO maneuvers at rest and during exercise in the upright and supine position. The multiple [Formula: see text]-DLCO method was used to determine DLCO, VC, and membrane diffusion capacity (DM). All three variables were adjusted for alveolar volume (DLCOAdj, VCAdj, and DMAdj). The supine position reduced alveolar volume similarly in both groups, but oxygen consumption and cardiac output were unaffected. DLCOAdj, DMAdj, and VCAdj were all lower in COPD. These same variables all increased with upright and supine exercise in both groups. DLCOAdj was unaffected by the supine position. VCAdj increased in the supine position similarly in both groups. DMAdj was reduced in the supine position in both groups. While the supine position increased exercise VCAdj in COPD, the increase was of similar magnitude to healthy controls; therefore, exercise VC remained blunted in COPD. The persistent reduction in exercise DLCO and VC when supine suggests that pulmonary vascular destruction is a contributing factor to the blunted DLCO and VC response to exercise in mild COPD. NEW & NOTEWORTHY Patients with mild chronic obstructive pulmonary disease demonstrate a combination of reversible pulmonary microvascular dysfunction and irreversible pulmonary microvascular destruction.

Key points Precapillary gas exchange for oxygen has been documented in both humans and animals. It has been suggested that, if precapillary gas exchange occurs to a greater extent for inert gases than for oxygen, shunt and its effects on arterial oxygenation may be underestimated by the multiple inert gas elimination technique (MIGET). We evaluated fractional precapillary gas exchange in canines for O2 and two inert gases, sulphur hexafluoride and ethane, by measuring these gases in the proximal pulmonary artery, distal pulmonary artery (1 cm proximal to the wedge position) and systemic artery. Some 12-19% of pulmonary gas exchange occurred within small (1.7 mm in diameter or larger) pulmonary arteries and this was quantitatively similar for oxygen, sulphur hexafluoride and ethane. Under these experimental conditions, this suggests only minor effects of precapillary gas exchange on the magnitude of calculated shunt and the associated effect on pulmonary gas exchange estimated by MIGET. Abstract Some pulmonary gas exchange is known to occur proximal to the pulmonary capillary, although the magnitude of this gas exchange is uncertain, and it is unclear whether oxygen and inert gases are similarly affected. This has implications for measuring shunt and associated gas exchange consequences. By measuring respiratory and inert gas levels in the proximal pulmonary artery (P), a distal pulmonary artery 1 cm proximal to the wedge position (using a 5-F catheter) (D) and a systemic artery (A), we evaluated precapillary gas exchange in 27 paired samples from seven anaesthetized, ventilated canines. Fractional precapillary gas exchange (F) was quantified for each gas as F = (P - D)/(P - A). The lowest solubility inert gases, sulphur hexafluoride (SF6 ) and ethane were used because, with higher solubility gases, the P-A difference is sufficiently small that experimental error prevents accurate assessment of F. Distal samples (n = 12) with oxygen (O2 ) saturation values that were (within experimental error) equal to or above systemic arterial values, suggestive of retrograde capillary blood aspiration, were discarded, leaving 15 for analysis. D was significantly lower than P for SF6 (D/P = 88.6 ± 18.1%; P = 0.03) and ethane (D/P = 90.6 ± 16.0%; P = 0.04), indicating partial excretion of inert gas across small pulmonary arteries. Distal pulmonary arterial O2 saturation was significantly higher than proximal (74.1 ± 6.8% vs. 69.0 ± 4.9%; P = 0.03). Fractional precapillary gas exchange was similar for SF6 , ethane and O2 (0.12 ± 0.19, 0.12 ± 0.20 and 0.19 ± 0.26, respectively; P = 0.54). Under these experimental conditions, 12-19% of pulmonary gas exchange occurs within the small pulmonary arteries and the extent is similar between oxygen and inert gases.

Background Extreme preterm birth confers risk of long-term impairments in lung function and exercise capacity. There are limited data on the factors contributing to exercise limitation following extreme preterm birth. This study examined respiratory mechanics and ventilatory response during exercise in a large cohort of children born extremely preterm (EP). Methods This cohort study included children 8–12 years of age who were born EP (≤28 weeks gestation) between 1997 and 2004 and treated in a large regionalised neonatal intensive care unit in western Canada. EP children were divided into no/mild bronchopulmonary dysplasia (BPD) (ie, supplementary oxygen or ventilation ceased before 36 weeks gestational age; n=53) and moderate/severe BPD (ie, continued supplementary oxygen or ventilation at 36 weeks gestational age; n=50). Age-matched control children (n=65) were born at full term. All children attempted lung function and cardiopulmonary exercise testing measurements. Results Compared with control children, EP children had lower airway flows and diffusion capacity but preserved total lung capacity. Children with moderate/severe BPD had evidence of gas trapping relative to other groups. The mean difference in exercise capacity (as measured by oxygen uptake (VO 2 )% predicted) in children with moderate/severe BPD was −18±5% and −14±5.0% below children with no/mild BPD and control children, respectively. Children with moderate/severe BPD demonstrated a potentiated ventilatory response and greater prevalence of expiratory flow limitation during exercise compared with other groups. Resting lung function did not correlate with exercise capacity. Conclusions Expiratory flow limitation and an exaggerated ventilatory response contribute to respiratory limitation to exercise in children born EP with moderate/severe BPD.

KEY POINTS Imaging techniques such as contrast echocardiography suggest that anatomical intra-pulmonary arteriovenous anastomoses (IPAVAs) are present at rest and are recruited to a greater extent in conditions such as exercise. IPAVAs have the potential to act as a shunt, although gas exchange methods have not demonstrated significant shunt in the normal lung. To evaluate this discrepancy, we compared anatomical shunt with 25-µm microspheres to contrast echocardiography, and gas exchange shunt measured by the multiple inert gas elimination technique (MIGET). Intra-pulmonary shunt measured by 25-µm microspheres was not significantly different from gas exchange shunt determined by MIGET, suggesting that MIGET does not underestimate the gas exchange consequences of anatomical shunt. A positive agitated saline contrast echocardiography score was associated with anatomical shunt measured by microspheres. Agitated saline contrast echocardiography had high sensitivity but low specificity to detect a ≥1% anatomical shunt, frequently detecting small shunts inconsequential for gas exchange. ABSTRACT The echocardiographic visualization of transpulmonary agitated saline microbubbles suggests that anatomical intra-pulmonary arteriovenous anastomoses are recruited during exercise, in hypoxia, and when cardiac output is increased pharmacologically. However, the multiple inert gas elimination technique (MIGET) shows insignificant right-to-left gas exchange shunt in normal humans and canines. To evaluate this discrepancy, we measured anatomical shunt with 25-µm microspheres and compared the results to contrast echocardiography and MIGET-determined gas exchange shunt in nine anaesthetized, ventilated canines. Data were acquired under the following conditions: (1) at baseline, (2) 2 µg kg-1 min-1 i.v. dopamine, (3) 10 µg kg-1 min-1 i.v. dobutamine, and (4) following creation of an intra-atrial shunt (in four animals). Right to left anatomical shunt was quantified by the number of 25-µm microspheres recovered in systemic arterial blood. Ventilation-perfusion mismatch and gas exchange shunt were quantified by MIGET and cardiac output by direct Fick. Left ventricular contrast scores were assessed by agitated saline bubble counts, and separately by appearance of 25-µm microspheres. Across all conditions, anatomical shunt measured by 25-µm microspheres was not different from gas exchange shunt measured by MIGET (microspheres: 2.3 ± 7.4%; MIGET: 2.6 ± 6.1%, P = 0.64). Saline contrast bubble score was associated with microsphere shunt (ρ = 0.60, P

Purpose Some patients with chronic obstructive pulmonary disease (COPD) fail to achieve health benefits with pulmonary rehabilitation (PR). Exercise intensity and load represent stimulus for adaptation but it is unclear whether inappropriate exercise intensity and/or load are affected by severity of COPD, which may affect health benefits. The purpose was to determine whether COPD severity and/or the severity of pulmonary limitation to exercise (PLE) impacted exercising intensity or load and whether resultant intensity/load affected health outcomes derived from PR. Methods Patients with COPD (n = 58, age = 67 ± 7 y, forced expiratory volume in the first second of expiration [FEV1] % predicted = 52 ± 21%) were recruited upon referral to PR. Primary health outcomes evaluated were 6-min walk distance and St George's Respiratory Questionnaire. Patients were stratified for disease severity using Global Initiative for Obstructive Lung Disease (GOLD) staging and PLE severity by change in inspiratory capacity during exercise. Exercise intensity and load were calculated from daily exercise records. Results Participants achieved comparable training duration and load regardless of GOLD severity. Patients with more severe PLE achieved greater training duration (more severe: 546 ± 143 min., less severe: 451 ± 109 min., P = .036), and relative training load (more severe: 2200.8 ± 595.3 kcal, less severe: 1648.3 ± 597.8 kcal, P = .007). Greater overall training load was associated with greater improvements in 6-min walk distance (r = 0.24, P = .035). No significant relationships were observed between PLE, GOLD severity, training parameters, and St George's Respiratory Questionnaire response. Conclusions Improvements in exercise tolerance can be explained by achieving greater training loads, demonstrating the importance of appropriate training load to maximize health outcomes in PR.

During a 10 km run at race pace, changes in lower extremity mechanics have been reported in male runners however mechanical changes over 10 km in female runners is unknown. Thus we aimed to examine running mechanics in females during a simulated 10 km race on a treadmill. Nine female distance runners (age: 32.1±4.2 yrs; ht: 166.7 ± 7.4 cm; wt: 57.8 ± 7.0 kg; VO 2max = 3.24 ± 0.50 L/min) completed graded exercise testing (Day 1); 10km time trial (Day 2); and simulated 10km treadmill run (DAY 3; 95 % of running velocity from Day 2 time-trial). Mechanical data sampled at 120Hz using a 6-camera optoelectronic motion capture system and effort (Rating of Perceived Exertion - RPE) were measured at 50, 1450, 2950, 4450, 5950, 7450, 8950 and 9950 metres. Maximum voluntary contraction of knee extensors was measured pre-post. Seven participants decreased MVC (1-21% decrease) and RPE increased from 12 (50m) to 19 (9950m). Step frequency decreased 3 steps/min (p

Carotid chemoreceptor (CC) inhibition reduces sympathetic nervous outflow in exercising dogs and humans. We sought to determine if CC suppression increases muscle blood flow in humans during exercise and hypoxia. Healthy subjects (N = 13) were evaluated at rest and during constant-work leg extension exercise while exposed to either normoxia or hypoxia (inspired O(2) tension, F(IO(2)), ≈ 0.12, target arterial O(2) saturation = 85%). Subjects breathed hyperoxic gas (F(IO(2)) ≈ 1.0) and/or received intravenous dopamine to inhibit the CC while femoral arterial blood flow data were obtained continuously with pulsed Doppler ultrasound. Exercise increased heart rate, mean arterial pressure, femoral blood flow and conductance compared to rest. Transient hyperoxia had no significant effect on blood flow at rest, but increased femoral blood flow and conductance transiently during exercise without changing blood pressure. Similarly, dopamine had no effect on steady-state blood flow at rest, but increased femoral blood flow and conductance during exercise. The transient vasodilatory response observed by CC inhibition with hyperoxia during exercise could be blocked with simultaneous CC inhibition with dopamine. Despite evidence of dopamine reducing ventilation during hypoxia, no effect on femoral blood flow, conductance or mean arterial pressure was observed either at rest or during exercise with CC inhibition with dopamine while breathing hypoxia. These findings indicate that the carotid chemoreceptor contributes to skeletal muscle blood flow regulation during normoxic exercise in healthy humans, but that the influence of the CC on blood flow regulation in hypoxia is limited.