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IntroductionSeveral studies report that pulmonary oxygen uptake (V̇O 2 ) at the respiratory compensation point (RCP) is equivalent to the V̇O 2 at critical power (CP), suggesting that the variables can be used interchangeably to demarcate the threshold between heavy and severe intensity domains. However, if RCP is a valid surrogate for CP, their values should correspond even when assessed in patients with chronic obstructive pulmonary disease (COPD) in whom the "normal" mechanisms linking CP and RCP are impeded. The aim of this study was to compare V̇O 2 at CP with V̇O 2 at RCP in patients with COPD.MethodsTwenty-two COPD patients (14 male/8 female; forced expiratory volume in 1 s, 46% ± 17% pred) performed ramp-incremental cycle ergometry to intolerance (5-10 W·min -1 ) for the determination of gas exchange threshold (GET) and RCP. CP was calculated from the asymptote of the hyperbolic power-duration relationship from 3-5 constant-power exercise tests to intolerance. CP was validated with a 20-min constant-power ride.ResultsGET was identified in 20 of 22 patients at a V̇O 2 of 0.93 ± 0.18 L·min -1 (75% ± 13% V̇O 2peak ), whereas RCP was identified in just 3 of 22 patients at a V̇O 2 of 1.40 ± 0.39 L·min -1 (85% ± 2% V̇O 2peak ). All patients completed constant-power trials with no difference in peak physiological responses relative to ramp-incremental exercise ( P > 0.05). CP was 46 ± 22 W, which elicited a V̇O 2 of 1.04 ± 0.29 L·min -1 (90% ± 9% V̇O 2peak ) during the validation ride. The difference in V̇O 2 at 15 and 20 min of the validation ride was 0.00 ± 0.04 L, which was not different from a hypothesized mean of 0 ( P = 0.856), thereby indicating a V̇O 2 steady state.ConclusionsIn COPD patients, who present with cardiopulmonary and/or respiratory-mechanical dysfunction, CP can be determined in the absence of RCP. Accordingly, CP and RCP are not equivalent in this group.

Bronchodilation is known to increase forced expiratory volume in 1 s (FEV1) and reduce hyperinflation in COPD. In a randomized controlled trial, we investigated whether combined inhaled long-acting β-agonist and muscarinic antagonist would alleviate maximal voluntary neuromuscular performance fatigue or enhance maximal muscle activation during cycling in patients with COPD. Despite increased FEV1, combination bronchodilator therapy did not reduce neuromuscular performance fatigue or enhance muscle activity or exercise tolerance in patients with mild-to-severe COPD.

Introduction: Autonomic dysfunction is common in chronic obstructive pulmonary disease (COPD), and worse autonomic function may be a marker of risk for acute exacerbations of COPD (AECOPD). Heart rate variability (HRV) is a measure of autonomic function. Our objective was to test whether lower (worse) HRV is a risk factor for AECOPD. Methods: We measured standard deviation of normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) on 10-second electrocardiograms (ECGs) performed at screening and day 42 in participants in the Beta Blockers for the Prevention of Acute Exacerbations of COPD trial ( BLOCK-COPD), a placebo-controlled trial of metoprolol for prevention of AECOPD. We used Cox-proportional hazards models to test if these HRV measures were associated with risk of any AECOPD, and separately, hospitalized AECOPD. We tested associations using baseline HRV measures and incorporating HRV measures from day 42 as a time-varying covariate. We also tested for interactions with metoprolol assignment. Results: Of 532 trial participants, 529 (forced expiratory volume in 1 second [FEV(1) ]41 ± 16.3 % predicted) were included in this analysis. We did not find a significant association between HRV measures and risk of AECOPD when all participants were analyzed together. There was a significant interaction between RMSSD and assignment to metoprolol on time to first hospitalized AECOPD; in the placebo group greater RMSSD was associated with a lower risk of hospitalized AECOPD (adjusted hazard ratio0.71, 95% confidence interval: 0.52 to 0.96, per 10 ms increase) but there was no association in the metoprolol group. Conclusions: Autonomic dysfunction as measured by HRV may be a risk factor for AECOPD. Future studies should analyze longer HRV recordings and their performance in broader samples of people with COPD, including those on beta-blockers.

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

INTRODUCTION: The COPD Biomarkers Qualification Consortium (CBQC) was formed under COPD Foundation management, with the goal of qualifying biomarkers and clinical outcome assessments through established regulatory processes for chronic obstructive pulmonary disease (COPD). Within CBQC, a working group evaluated opportunities for qualification of an exercise endurance measure. In a recent publication (Chronic Obstr Pulm Dis. 2022; 9[2]:252-265), we described a conceptual framework establishing exercise endurance's direct relationship to an individual with COPD's experience of physical functioning in daily life, and that increase in exercise endurance is a patient-centered, meaningful treatment benefit. We further proposed endurance time during constant work rate cycle ergometery (CWRCE) as a useful efficacy endpoint in clinical therapeutic intervention trials. In this current publication, we describe the process of assembling an integrated database of endurance time responses to interventions in COPD.METHODS: We sought participant-level data from published studies incorporating CWRCE as an outcome measure. A literature search screened 2993 publications and identified 553 studies for assessment. Two interventions had sufficient data across studies to warrant data extraction: bronchodilators and rehabilitative exercise training. Investigators were contacted and requested to provide participant-by-participant data from their published studies.RESULTS: The final dataset included data from 8 bronchodilator studies (2166) participants and 15 exercise training studies (3488 participants). The database includes 71 variables per participant, comprising demographic, pulmonary function, and detailed physiologic response data. This paper provides a detailed description of the analysis population, while analysis supporting the validation/qualification process and addressing other scientific questions will be described in subsequent publications.

We investigated whether dual bronchodilator therapy (glycopyrrolate/formoterol fumarate; GFF; Bevespi Aerosphere) would increase exercise tolerance during a high-intensity constant work rate exercise test (CWRET) and the relative contributions of dead space ventilation (VD/VT) and dynamic hyperinflation (change in inspiratory capacity) to exercise limitation in chronic obstructive pulmonary disease (COPD). In all, 48 patients with COPD (62.9 ± 7.6 yrs; 33 male; GOLD spirometry stage 1/2/3/4, n = 2/35/11/0) performed a randomized, double blind, placebo (PL) controlled, two-period crossover, single-center trial. Gas exchange and inspiratory capacity (IC) were assessed during cycle ergometry at 80% incremental exercise peak work rate. Transcutaneous PCO2 (TcPCO2) measurement was used for VD/VT estimation. Baseline postalbuterol forced expiratory volume in 1 s (FEV1) was 1.86 ± 0.58 L (63.6% ± 13.9 predicted). GFF increased FEV1 by 0.18 ± 0.21 L relative to placebo (PL; P < 0.001). CWRET endurance time was greater after GFF vs. PL (383 ± 184 s vs. 328 ± 115 s; difference 55 ± 125 s; P = 0.013; confidence interval: 20–90 s), a 17% increase. IC on GFF was above placebo IC at all time points and fell less with GFF vs. PL (P ≤ 0.0001). Isotime tidal volume (1.54 ± 0.50 vs. 1.47 ± 0.45 L; P = 0.022) and ventilation (52.9 ± 19.9 vs. 51.0 ± 18.9 L/min; P = 0.011) were greater, and respiratory rate was unchanged (34.9 ± 9.2 vs. 35.1 ± 8.0 br/min, P = 0.865). Isotime VD/VT did not differ between groups (GFF 0.28 ± 0.08 vs. PL 0.27 ± 0.09; P = 0.926). GFF increased exercise tolerance in patients with COPD, and the increase was accompanied by attenuated dynamic hyperinflation without altering VD/VT. NEW & NOTEWORTHY This study was a randomized clinical trial (NCT03081156) that collected detailed physiology data to investigate the effect of dual bronchodilator therapy on exercise tolerance in COPD, and additionally to determine the relative contributions of changes in dead space ventilation (VD/VT) and dynamic hyperinflation to alterations in exercise limitation. We utilized a unique noninvasive method to assess VD/VT (transcutaneous carbon dioxide, TcPCO2) and found that dual bronchodilators yielded a moderate improvement in exercise tolerance. Importantly, attenuation of dynamic hyperinflation rather than change in dead space ventilation was the most important contributor to exercise tolerance improvement.

Gas exchange inefficiency and dynamic hyperinflation contributes to exercise limitation in chronic obstructive pulmonary disease (COPD). It is also characterized by an elevated fraction of physiolo...

Background Many patients with pulmonary embolism (PE) report dyspnea on exertion following long-term treatment. Increased physiological dead space proportion (VD/VT) and decreased cardiac stroke volume reserve may distinguish persistent effects of PE itself from symptoms reflecting comorbid conditions or deconditioning. Methods This retrospective study analyzed a consecutive series of incremental symptom-limited cardiopulmonary exercise tests that had been ordered to evaluate persistent dyspnea on exertion following long-term treatment for acute PE. Physiological VD/VT was determined at anaerobic threshold from exhaled CO2 and transcutaneous Pco2 (validated against Paco2 measurements). Cardiac stroke volume reserve was estimated at rest and at anaerobic threshold by using oxygen consumption/pulse and previously validated estimates of the arteriovenous oxygen content difference. Results Cardiopulmonary exercise tests were performed on 40 patients with post-PE dyspnea. In 65.0% (95% CI, 50.2-79.8), VD/VT at anaerobic threshold was abnormally elevated, stroke volume reserve was decreased, or both defects occurred. VD/VT at anaerobic threshold was abnormally elevated (≥ 0.27) in 35.0% (95% CI, 20.2-49.8). VD/VT at anaerobic threshold significantly correlated with the extent of unmatched perfusion defects on subsequent ventilation-perfusion scans (P = .0085). In 55.0% (95% CI, 39.6-70.4), stroke volume reserve at anaerobic threshold was abnormally decreased (≤ 128% of the resting value). Both defects were present in 25.0% (95% CI, 11.6-38.4). Conclusions Increased VD/VT at anaerobic threshold and decreased stroke volume reserve during exercise are common among patients with dyspnea on exertion after long-term treatment of PE. The defects can be disclosed noninvasively by using cardiopulmonary exercise testing.

RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVES: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV(1)% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV(1) was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas

Dongxing Zhao,1,2 Asghar Abbasi,1 Richard Casaburi,1 Alessandra Adami,3 Nicholas B Tiller,1 Wei Yuan,1,4 Christopher Yee,5 Nicholas G Jendzjowsky,1 David M MacDonald,6,7 Ken M Kunisaki,6,7 William W Stringer,1 Janos Porszasz,1 Barry J Make,8 Russell P Bowler,8 Harry B Rossiter1 On behalf of the COPDGene Investigators1Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China; 3Department of Kinesiology, University of Rhode Island, Kingston, RI, USA; 4Respiratory Medicine Department, Beijing Friendship Hospital Affiliated of Capital Medical University, Beijing, 100050, People’s Republic of China; 5MemorialCare Long Beach Medical Center, Long Beach, CA, USA; 6Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN, USA; 7Minneapolis VA Health Care System, Minneapolis, MN, USA; 8National Jewish Health, Denver, CO, USACorrespondence: Harry B Rossiter Email hrossiter@ucla.eduBackground: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?.Study Design and Methods: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations.Results: HRR after 6MWT (bt/min) was categorized in quintiles: ≤ 5 (23.0% of participants), 6– 10 (20.7%), 11– 15 (18.9%), 16– 22 (18.5%) and ≥ 23 (18.9%). Compared to HRR≤ 5, HRR≥ 11 was associated with (p< 0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV1%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV1%pred and negatively associated with airway wall thickness. An optimal HRR ≤ 10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58– 0.66) for identifying FEV1< 30%pred. HRR≥ 11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤ 10 bt/min was associated with (p< 0.001): ≥ 2 exacerbations in the previous year (OR=1.76[1.33– 2.34]); CAT≥ 10 (OR=1.42[1.18– 1.71]); mMRC≥ 2 (OR=1.42[1.19– 1.69]); GOLD 4 (OR=1.98[1.44– 2.73]) and GOLD D (OR=1.51[1.18– 1.95]). HRR≤ 10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07– 3.12], P=0.027).Conclusion: HRR≤ 10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤ 10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.Keywords: autonomic dysfunction, chest computed tomography, COPD exacerbation, exercise, spirometry

Supplemental long-term oxygen therapy (LTOT) is a well-established therapy that improves mortality in patients with chronic obstructive pulmonary disease (COPD) with resting hypoxemia. In the large number of patients with COPD who do not have severe resting hypoxemia but who desaturate with exercise, the clinical benefits that can be obtained by supplemental O2 therapy during exercise is an area of interest and active research. A summary of current evidence for benefits of supplemental O2 therapy and a review of physiologic mechanisms underlying published observations are reviewed in this article.

BackgroundBody composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined.Research questionIs the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?Study design and methodsParticipants with complete data for at least one visit in the COPDGene study (n= 9,268) and the ECLIPSE study (n= 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation.ResultsBoth cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1%(95%CI, 2.4%-3.7%; P< .001) in COPDGene, and 2.4%(95%CI, 0.9%-4.0%; P< .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA.InterpretationLongitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p, Haemoglobin is nonlinearly associated with clinical outcomes in COPD, with increased morbidity at either extreme of the observed range, suggesting that therapeutic correction of anaemia might be most beneficial if targeting normal haemoglobin values https://bit.ly/3ovl7Lt

Gas exchange inefficiency and dynamic hyperinflation contributes to exercise limitation in chronic obstructive pulmonary disease (COPD). It is also characterized by an elevated fraction of physiological dead space (V

Gas exchange inefficiency and dynamic hyperinflation contributes to exercise limitation in chronic obstructive pulmonary disease (COPD). It is also characterized by an elevated fraction of physiological dead space (VD/VT). Noninvasive methods for accurate VD/VT assessment during exercise in patients are lacking. The current study sought to compare transcutaneous PCO2 (TcPCO2) with the gold standard—arterial PCO2 (PaCO2)—and other available methods (end tidal CO2 and the Jones equation) for estimating VD/VT during incremental exercise in COPD. Ten COPD patients completed a symptom limited incremental cycle exercise. TcPCO2 was measured by a heated electrode on the ear-lobe. Radial artery blood was collected at rest, during unloaded cycling (UL) and every minute during exercise and recovery. Ventilation and gas exchange were measured breath-by-breath. Bland-Altman analysis examined agreement of PCO2 and VD/VT calculated using PaCO2, TcPCO2, end-tidal PCO2 (PETCO2) and estimated PaCO2 by the Jones equation (PaCO2-Jones). Lin’s Concordance Correlation Coefficient (CCC) was assessed. 114 measurements were obtained from the 10 COPD subjects. The bias between TcPCO2 and PaCO2 was 0.86 mmHg with upper and lower limit of agreement ranging −2.28 mmHg to 3.99 mmHg. Correlation between TcPCO2 and PaCO2 during rest and exercise was r2=0.907 (p D/VT using TcPCO2 vs. PaCO2 was r2=0.958 (p 2-Jones and PETCO2 vs. PaCO2 were r2=0.755, 0.755, (p D/VT calculation (r2=0.793, 0.610; p 2 to reflect PaCO2 and calculate VD/VT during rest and exercise, but not in recovery, in COPD patients, enabling improved accuracy of noninvasive assessment of gas exchange inefficiency during incremental exercise testing.

Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov

Author(s): Adami, Alessandra; Corvino, Rogerio B; Calmelat, Robert A; Porszasz, Janos; Casaburi, Richard; Rossiter, Harry B | Abstract: IntroductionSkeletal muscle atrophy, weakness, mitochondrial loss, and dysfunction are characteristics of chronic obstructive pulmonary disease (COPD). It remains unclear whether muscle dysfunction occurs in both upper and lower limbs, because findings are inconsistent in the few studies where upper and lower limb muscle performance properties were compared within an individual. This study determined whether muscle oxidative capacity is low in upper and lower limbs of COPD patients compared with controls.MethodsOxidative capacity of the forearm and medial gastrocnemius was measured using near-infrared spectroscopy to determine the muscle O2 consumption recovery rate constant (k, min) in 20 COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2/3/4, n = 7/7/6) and 20 smokers with normal spirometry (CON). Muscle k is linearly proportional to oxidative capacity. Steps per day and vector magnitude units per minute (VMU·min) were assessed using triaxial accelerometry. Differences between group and limb were assessed by two-way ANOVA.ResultsThere was a significant main effect of group (F = 11.2, ηp = 0.13, P = 0.001): k was lower in both upper and lower limb muscles in COPD (1.01 ± 0.17 and 1.05 ± 0.24 min) compared with CON (1.29 ± 0.49 and 1.54 ± 0.60 min). There was no effect on k of limb (F = 1.8, ηp = 0.02, P = 0.18) or group-limb interaction (P = 0.35). (VMU·min) was significantly lower in COPD (-38%; P = 0.042). Steps per day did not differ between COPD (4738 ± 3194) and CON (6372 ± 2107; P = 0.286), although the difference exceeded a clinically important threshold (g600-1100 steps per day).ConclusionsCompared with CON, muscle oxidative capacity was lower in COPD in both upper (-20%) and lower (-30%) limbs. These data suggest that mitochondrial loss in COPD is not isolated to locomotor muscles.

Introduction: COPD causes inflammation and alters circulating immune cell populations. In health, exercise mobilizes immune cells and promotes anti-inflammation. Aim: To determine the change in circulating immune cell subtypes in response to exercise in COPD and controls. Methods: Age- and sex-matched ex-smokers with (n=5) and without (n=4) COPD performed a single bout of high-intensity interval exercise (10x 1 min at 120% peak work rate, 2 min recovery). Venous blood was collected at baseline (BSL) and post-exercise (0, 30 and 120 min) to quantify 12 immune cell subtypes using multicolor flow cytometry. Two-way ANOVA (Dunnett’s posthoc) assessed the effects of time x group. Results: Leukocytes were increased (p Conclusion Exercise-induced leukocytosis was not different between COPD and controls. Exercise predominantly altered lymphoid cell fractions in both groups. However, exercise-induced increases in NK and TReg subtypes were absent in COPD. These data suggest that the potentially beneficial effects of exercise on immunosurveilance are attenuated in COPD. Support: TRDRP 28FT-001

Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lu...

Oxygen uptake slow component (VO2sc) is associated with lactate accumulation, likely a contribution of poorly oxidative muscle fibers. We aimed to test the hypothesis that higher muscle tension du...

This substudy of a large, randomized, controlled trial (NCT01072396) examined tiotropium (18 μg qd) effects on dynamic hyperinflation during constant work rate treadmill exercise. Areas-under-the-spontaneous expiratory flow-volume (SEFV)-curves were compared in 20 COPD patients and 16 age-matched untreated controls, using rectangular area ratio (RAR) between peak intrabreath and end-expiratory flow. Seven patients exhibited SEFV curve concavity with RAR ≤ 0.5 (RAR low ) in ≥1 test without tiotropium; (mean ± SD FEV 1 : 1.60 ± 0.59 L; 63.4 ± 14.0%predicted). In RAR low patients, tiotropium increased end-exercise inspiratory capacity (IC, 2.10 ± 0.05 vs. 1.89 ± 0.05 L, tiotropium vs. placebo; p = 0.045) and RAR (0.57 ± 0.02 vs. 0.53 ± 0.02; p 0.5 (n = 13; RAR high ), had higher screening FEV 1 (2.15 ± 0.47 L; 79.6 ± 10.1%predicted) versus RAR low patients and no difference in end-exercise IC and RAR between tiotropium and placebo (IC: 2.24 ± 0.03 vs. 2.17 ± 0.03 L; RAR: 0.63 ± 0.005 vs. 0.62 ± 0.005). RAR and%predicted IC at peak exercise were positively correlated in RAR low patients (R 2 = 0.43, p = 0.0002). Tiotropium increased exercise RAR in GOLD 1-2 patients with SEFV curve concavity.

Contains fulltext : 194255.pdf (Publisher’s version ) (Open Access) BACKGROUND: Emphysema has considerable variability in its regional distribution. Craniocaudal emphysema distribution is an important predictor of the response to lung volume reduction. However, there is little consensus regarding how to define upper lobe-predominant and lower lobe-predominant emphysema subtypes. Consequently, the clinical and genetic associations with these subtypes are poorly characterized. METHODS: We sought to identify subgroups characterized by upper-lobe or lower-lobe emphysema predominance and comparable amounts of total emphysema by analyzing data from 9,210 smokers without alpha-1-antitrypsin deficiency in the Genetic Epidemiology of COPD (COPDGene) cohort. CT densitometric emphysema was measured in each lung lobe. Random forest clustering was applied to lobar emphysema variables after regressing out the effects of total emphysema. Clusters were tested for association with clinical and imaging outcomes at baseline and at 5-year follow-up. Their associations with genetic variants were also compared. RESULTS: Three clusters were identified: minimal emphysema (n = 1,312), upper lobe-predominant emphysema (n = 905), and lower lobe-predominant emphysema (n = 796). Despite a similar amount of total emphysema, the lower-lobe group had more severe airflow obstruction at baseline and higher rates of metabolic syndrome compared with subjects with upper-lobe predominance. The group with upper-lobe predominance had greater 5-year progression of emphysema, gas trapping, and dyspnea. Differential associations with known COPD genetic risk variants were noted. CONCLUSIONS: Subgroups of smokers defined by upper-lobe or lower-lobe emphysema predominance exhibit different functional and radiological disease progression rates, and the upper-lobe predominant subtype shows evidence of association with known COPD genetic risk variants. These subgroups may be useful in the development of personalized treatments for COPD.

Contains fulltext : 220761.pdf (Publisher’s version ) (Open Access) Rationale: The decades-long progression of chronic obstructive pulmonary disease (COPD) renders identifying different trajectories of disease progression challenging.Objectives: To identify subtypes of patients with COPD with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference" (SuStaIn) and to evaluate the utility of SuStaIn for patient stratification in COPD.Methods: We applied SuStaIn to cross-sectional computed tomography imaging markers in 3,698 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-4 patients and 3,479 controls from the COPDGene (COPD Genetic Epidemiology) study to identify subtypes of patients with COPD. We confirmed the identified subtypes and progression patterns using ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data.Measurements and Main Results: We identified two trajectories of disease progression in COPD: a "Tissue-->Airway" subtype (n = 2,354, 70.4%), in which small airway dysfunction and emphysema precede large airway wall abnormalities, and an "Airway-->Tissue" subtype (n = 988, 29.6%), in which large airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r = -0.16 [P < 0.001] in the Tissue-->Airway group; r = -0.14 [P = 0.011] in the Airway-->Tissue group). SuStaIn placed 30% of smokers with normal lung function at elevated stages, suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up.Conclusions: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One third of healthy smokers have detectable imaging changes, suggesting a new biomarker of "early COPD."

Rationale: A positive bronchodilator response (BDR) according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines require both 200 ml and 12% increase in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) after bronchodilator inhalation. This dual criterion is insensitive in those with high or low FEV1. Objectives: To establish BDR criteria with volume or percentage FEV1 change. Methods: The largest FEV1 and FVC were identified fromthree pre- and three post-bronchodilator maneuvers in COPDGene (Genetic Epidemiology of COPD) participants. A total of 7,741 individuals with coefficient of variation less than 15% for both FEV1 and FVC formed bronchodilator categories of FEV1 response: negative (0.00% to 0.00 L to 9.00% to 16.00% to 0.16 L to 26.00% or >0.26 L). These response size categories are based on empirical limits considering average FEV1 increase of approximately 160 ml and the clinically important difference for FEV1. To compare flow and volume response characteristics, BDR-FEV1 category assignments were applied for the BDR-FVC response. Results: Twenty percent met mild and 31% met moderate or marked BDR-FEV1 criteria, whereas 12% met mild and 33% met moderate or marked BDR-FVC criteria. In contrast, only 20.6% met ATS/ERS positive criteria. Compared with the negative BDR-FEV1 category, the minimal, mild, moderate, and marked BDR-FEV1 categories were associated with greater 6-minute-walk distance and lower St. George's Respiratory Questionnaire and modified Medical Research Council dyspnea scale scores. Compared with negative BDR, moderate and marked BDR-FEV1 categories were associated with fewer exacerbations, and minimal BDR was associated with lower computed tomography airway wall thickness. Compared with the negative category, all BDR-FVC categories were associated with increasing emphysema percentage and gas trapping percentage. Moderate and marked BDR-FVC categories were associated with higher St. George's Respiratory Questionnaire scores but fewer exacerbations and lower dyspnea scores. Conclusions: BDR grading by FEV1 volume or percentage response identified subjects otherwise missed by ATS/ERS criteria. BDR grades were associated with functional exercise performance, quality of life, exacerbation frequency, dyspnea, and radiological airway measures. BDR grades in FEV1 and FVC indicate different clinical and radiological characteristics. United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) National Center for Advancing Translational Sciences through UCLA CTSI Grant