Among patients with COPD, those with the lowest maximal inspiratory pressures experience greater breathing discomfort (dyspnea) during exercise. In such individuals, inspiratory muscle training (IMT) ...may be associated with improvement of dyspnea but the mechanisms for this are poorly understood. Therefore, we aimed to identify physiological mechanisms of improvement in dyspnea and exercise endurance following inspiratory muscle training (IMT) in patients with COPD and low maximal inspiratory pressure (Pi,max). The effects of 8 weeks of controlled IMT on respiratory muscle function, dyspnea, respiratory mechanics, and diaphragm electromyography (EMGdi) during constant-work rate cycle exercise were evaluated in patients with activity-related dyspnea (Baseline Dyspnea Index <9). Subjects were randomized to either IMT or a sham training control group (n=10 each). Twenty subjects (FEV
= 47±19 %predicted; Pi,max= -59±14 cmH
O; cycle ergometer peak work rate= 47±21 %predicted) completed the study; groups had comparable baseline lung function, respiratory muscle strength, activity-related dyspnea and exercise capacity. IMT, compared with control, was associated with greater increases in inspiratory muscle strength and endurance, with attendant improvements in exertional dyspnea and exercise endurance time (all p<0.05). After IMT, EMGdi expressed relative to its maximum (EMGdi/EMGdi,max) decreased (p<0.05) with no significant change in ventilation, tidal inspiratory pressures, breathing pattern and operating lung volumes during exercise. In conclusion, IMT improved inspiratory muscle strength and endurance in mechanically compromised patients with COPD and low Pi,max. The attendant reduction in EMGdi/EMGdi,max helped explain the decrease in perceived respiratory discomfort despite sustained high ventilation and intrinsic mechanical loading over a longer exercise duration.
The mechanisms underlying dyspnea in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are unknown.
To examine whether the relationship between inspiratory neural drive ...to the diaphragm and exertional dyspnea intensity is different in ILD and COPD, given the marked differences in static respiratory mechanics between these conditions.
We compared sensory-mechanical relationships in patients with ILD, patients with COPD, and healthy control subjects (n = 16 each) during incremental cycle exercise with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements.
In patients with mild to moderate ILD or COPD with similarly reduced inspiratory capacity, the peak oxygen uptake, work rate, and ventilation were lower (P < 0.05) than in healthy control subjects. EMGdi expressed as a percentage of the maximum (EMGdi/EMGdi,max), respiratory effort (esophageal pressure expressed as percentage of the maximum), and ventilation were higher (P < 0.05) at rest and during exercise in both patients with ILD and patients with COPD than in control subjects. Each of these measurements was similar in the ILD and COPD groups. A Vt inflection and critically reduced inspiratory reserve volume occurred at a lower (P < 0.05) ventilation in the ILD and COPD groups than in control subjects. Patients with ILD had greater diaphragmatic activity, whereas patients with COPD had greater expiratory muscle activity. The relationship between dyspnea intensity and EMGdi/EMGdi,max during exercise was similar in all three groups. In ILD and COPD, descriptors alluding to inspiratory difficulty were selected more frequently, with a greater disparity between EMGdi/EMGdi,max and Vt.
Disease-specific differences in mechanics and respiratory muscle activity did not influence the key association between dyspnea intensity and inspiratory neural drive to the diaphragm.
Several studies in mild chronic obstructive pulmonary disease (COPD) have shown a higher than normal ventilatory equivalent for carbon dioxide (Formula: see texte/Formula: see textco2) during ...exercise. Our objective was to examine pulmonary gas exchange abnormalities and the mechanisms of high Formula: see texte/Formula: see textco2 in mild COPD and its impact on dyspnea and exercise intolerance.
Twenty-two subjects (11 patients with GOLD Global Initiative for Chronic Obstructive Lung Disease grade 1B COPD, 11 age-matched healthy control subjects) undertook physiological testing and a symptom-limited incremental cycle exercise test with arterial blood gas collection.
Patients (post-bronchodilator FEV1: 94 ± 10% predicted; mean ± SD) had evidence of peripheral airway dysfunction and reduced peak oxygen uptake compared with control subjects (80 ± 18 vs. 113 ± 24% predicted; P<0.05). Arterial blood gases were within the normal range and effective alveolar ventilation was not significantly different from control subjects throughout exercise. The alveolar-arterial O2 tension gradient was elevated at rest and throughout exercise in COPD (P<0.05). Formula: see texte/Formula: see textco2, dead space to tidal volume ratio (Vd/Vt), and arterial to end-tidal CO2 difference were all higher (P<0.05) in patients with COPD than in control subjects during exercise. In patients with COPD versus control subjects, there was significant dynamic hyperinflation and greater tidal volume constraints (P<0.05). Standardized dyspnea intensity ratings were also higher (P<0.05) in patients with COPD versus control subjects in association with higher ventilatory requirements. Within all subjects, Vd/Vt correlated with the Formula: see texte/Formula: see textco2 ratio during submaximal exercise (r=0.780, P<0.001).
High Vd/Vt was the most consistent gas exchange abnormality in smokers with only mild spirometric abnormalities. Compensatory increases in minute ventilation during exercise maintained alveolar ventilation and arterial blood gas homeostasis but at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD.
The purpose of this study was to determine if a dissociation existed between respiratory drive, as estimated by diaphragmatic electromyography (EMGdi), and its pressure-generating capacity during ...exercise in mild chronic obstructive pulmonary disease (COPD) and whether this, if present, had negative sensory consequences. Subjects meeting spirometric criteria for mild COPD (n=16) and age and sex-matched controls (n=16) underwent detailed pulmonary function testing and a symptom limited cycle test while detailed ventilatory, sensory and respiratory mechanical responses were measured. Compared with controls, subjects with mild COPD had greater ventilatory requirements throughout submaximal exercise. At the highest equivalent work rate of 60 W, they had a significantly higher: total work of breathing (32±17 versus 16±7 J·min(-1); p<0.01); EMGdi (37.3±17.3 versus 17.9±11.7% of maximum; p<0.001); and EMGdi to transdiaphragmatic pressure ratio (0.87±0.38 versus 0.52±0.27; p<0.01). Dyspnoea-ventilation slopes were significantly higher in mild COPD than controls (0.17±0.12 versus 0.10±0.05; p<0.05). However, absolute dyspnoea ratings reached significant levels only at high levels of ventilation. Increased respiratory effort and work of breathing, and a wider dissociation between diaphragmatic activation and pressure-generating capacity were found at standardised work rates in subjects with mild COPD compared with controls. Despite these mechanical and neuromuscular abnormalities, significant dyspnoea was only experienced at higher work rates.
The necroptosis cell death pathway has been implicated in host defense and in the pathology of inflammatory diseases. While phosphorylation of the necroptotic effector pseudokinase Mixed Lineage ...Kinase Domain-Like (MLKL) by the upstream protein kinase RIPK3 is a hallmark of pathway activation, the precise checkpoints in necroptosis signaling are still unclear. Here we have developed monobodies, synthetic binding proteins, that bind the N-terminal four-helix bundle (4HB) “killer” domain and neighboring first brace helix of human MLKL with nanomolar affinity. When expressed as genetically encoded reagents in cells, these monobodies potently block necroptotic cell death. However, they did not prevent MLKL recruitment to the “necrosome” and phosphorylation by RIPK3, nor the assembly of MLKL into oligomers, but did block MLKL translocation tomembranes where activatedMLKL normally disrupts membranes to kill cells. An X-ray crystal structure revealed a monobodybinding site centered on the α4 helix of the MLKL 4HB domain, which mutational analyses showed was crucial for reconstitution of necroptosis signaling. These data implicate the α4 helix of its 4HB domain as a crucial site for recruitment of adaptor proteins that mediatemembrane translocation, distinct from known phospholipid binding sites.
The role of dynamic hyperinflation (DH) in exercise limitation in chronic obstructive pulmonary disease (COPD) remains to be defined. We examined DH during exercise in 105 patients with COPD (FEV(1) ...= 37 +/- 13% predicted; mean +/- SD) and studied the relationships between resting lung volumes, DH during exercise, and peak oxygen consumption (VO(2)). Patients completed pulmonary function tests and incremental cycle exercise tests. We measured the change in inspiratory capacity (Delta IC) during exercise to reflect changes in DH. During exercise, 80% of patients showed significant DH above resting values. IC decreased 0.37 +/- 0.39 L or 14 +/- 15% predicted during exercise (p < 0.0005), but with large variation in range. Delta IC correlated best with resting IC, both expressed %predicted (r = -0.50, p < 0.0005). Peak VO(2) (%predicted maximum) correlated best with the peak tidal volume attained (VT standardized as % of predicted vital capacity) (r = 0.68, p < 0.0005), which, in turn, correlated strongly with IC at peak exercise (r = 0.79, p < 0.0005) or at rest (r = 0.75, p < 0.0005). The extent of DH during exercise in COPD correlated best with resting IC. DH curtailed the VT response to exercise. This inability to expand VT in response to increasing metabolic demand contributed importantly to exercise intolerance in COPD.
Patients with chronic obstructive pulmonary disease (COPD) primarily describe their exertional dyspnea using descriptors alluding to increased effort or work of breathing and unsatisfied inspiration ...or inspiratory difficulty.
The purpose of this study was to examine the impact of changes in dynamic respiratory mechanics during incremental (INCR) and high-intensity constant work-rate (CWR) cycle exercise on the evolution of dyspnea intensity and its major qualitative dimensions in patients with moderate-to-severe COPD.
Sixteen subjects with COPD performed symptom-limited INCR and CWR cycle exercise tests. Measurements included dyspnea intensity and qualitative descriptors, breathing pattern, operating lung volumes, and esophageal pressure (Pes).
During both exercise tests, there was an inflection in the relation between tidal volume (Vt) and ventilation. This inflection occurred significantly earlier in time during CWR versus INCR exercise but at a similar ventilation, Vt, and tidal Pes swing. Beyond this inflection, there was no further change in Vt despite a continued increase in ventilation and tidal Pes. During both tests, "work and effort" was the dominant dyspnea descriptor selected up to the inflection point, whereas after this point dyspnea intensity and the selection frequency of "unsatisfied inspiration" rose sharply.
Regardless of the exercise test protocol, the inflection (or plateau) in the Vt response marked the point where dyspnea intensity rose abruptly and there was a transition in the dominant qualitative descriptor choice from "work and effort" to "unsatisfied inspiration." Intensity and quality of dyspnea evolve separately and are strongly influenced by mechanical constraints on Vt expansion during exercise in COPD.
It is not known if abnormal dynamic respiratory mechanics actually limit exercise in patients with mild chronic obstructive pulmonary disease (COPD). We reasoned that failure to increase peak ...ventilation and Vt in response to dead space (DS) loading during exercise would indicate true ventilatory limitation to exercise in mild COPD.
To compare the effects of DS loading during exercise on ventilation, breathing pattern, operating lung volumes, and dyspnea intensity in subjects with mild symptomatic COPD and age- and sex-matched healthy control subjects.
Twenty subjects with Global Initiative for Chronic Obstructive Lung Disease stage I COPD and 20 healthy subjects completed two symptom-limited incremental cycle exercise tests, in randomized order: unloaded control and added DS of 0.6 L.
Peak oxygen uptake and ventilation were significantly lower in COPD than in health by 36% and 41%, respectively. With added DS compared with control, both groups had small decreases in peak work rate and no significant increase in peak ventilation. In health, peak Vt and end-inspiratory lung volume increased significantly with DS. In contrast, the COPD group failed to increase peak end-inspiratory lung volume and had a significantly smaller increase in peak Vt during DS. At 60 W, a 50% smaller increase in Vt (P < 0.001) in response to added DS in COPD compared with health was associated with a greater increase in dyspnea intensity (P = 0.0005).
These results show that the respiratory system reached or approached its physiologic limit in mild COPD at a lower peak work rate and ventilation than in healthy participants. Clinical trial registered with www.clinicaltrials.gov (NCT 00975403).
To better understand the interrelationships among disease severity, inspiratory capacity (IC), breathing pattern, and dyspnea, we studied responses to symptom-limited cycle exercise in a large cohort ...with COPD.
Analysis was conducted on data from two previously published replicate clinical trials in 427 hyperinflated patients with COPD. Patients were divided into disease severity quartiles based on FEV(1) % predicted. Spirometry, plethysmographic lung volumes, and physiologic and perceptual responses to constant work rate (CWR) cycle exercise at 75% of the peak incremental work rate were compared.
Age, body size, and COPD duration were similar across quartiles. As the FEV(1) quartile worsened (mean, 62%, 49%, 39%, and 27% predicted), functional residual capacity increased (144%, 151%, 164%, and 185% predicted), IC decreased (86%, 81%, 69%, and 60% predicted), and peak incremental cycle work rate decreased (66%, 55%, 50%, and 44% predicted); CWR endurance time was 9.7, 9.3, 8.2, and 7.3 min, respectively. During CWR exercise, as FEV(1) quartile worsened, peak minute ventilation ($$\dot{\mathrm{V}}$$e) and tidal volume (Vt) decreased, whereas an inflection or plateau of the Vt response occurred at a progressively lower $$\dot{\mathrm{V}}$$e (P < .0005), similar percentage of peak $$\dot{\mathrm{V}}$$e (82%-86%), and similar Vt/IC ratio (73%-77%). Dyspnea intensity at this inflection point was also similar across quartiles (3.1-3.7 Borg units) but accelerated steeply to intolerable levels thereafter.
Progressive reduction of the resting IC with increasing disease severity was associated with the appearance of critical constraints on Vt expansion and a sharp increase in dyspnea to intolerable levels at a progressively lower ventilation during exercise.
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