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Background: Exertional breathlessness is a cardinal symptom of cardiorespiratory disease., Research Question: How does breathlessness abnormality, graded using normative reference equations during cardiopulmonary exercise testing (CPET), relate to self-reported and physiologic responses in people with chronic airflow limitation (CAL)?, Study Design and Methods: An analysis was done of people aged ≥ 40 years with CAL undergoing CPET in the Canadian Cohort Obstructive Lung Disease study. Breathlessness intensity ratings (Borg CR10 scale [0-10 category-ratio scale for breathlessness intensity rating]) were evaluated in relation to power output, rate of oxygen uptake, and minute ventilation at peak exercise, using normative reference equations as follows: (1) probability of breathlessness normality (probability of having an equal or greater Borg CR10 rating among healthy people; lower probability reflecting more severe breathlessness) and (2) presence of abnormal breathlessness (rating above the upper limit of normal). Associations with relevant participant-reported and physiologic outcomes were evaluated., Results: We included 330 participants (44% women): mean ± SD age, 64 ± 10 years (range, 40-89 years); FEV 1 /FVC, 57.3% ± 8.2%; FEV 1 , 75.6% ± 17.9% predicted. Abnormally low exercise capacity (peak rate of oxygen uptake < lower limit of normal) was present in 26%. Relative to peak power output, rate of oxygen uptake, and minute ventilation, abnormally high breathlessness was present in 26%, 25%, and 18% of participants. For all equations, abnormally high exertional breathlessness was associated with worse lung function, exercise capacity, self-reported symptom burden, physical activity, and health-related quality of life; and greater physiologic abnormalities during CPET., Interpretation: Abnormal breathlessness graded using CPET normative reference equations was associated with worse clinical, physiological, and functional outcomes in people with CAL, supporting construct validity of abnormal exertional breathlessness., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. B. and W. C. T. report receiving institutional funding for the CanCOLD study from AstraZeneca Canada Ltd., Boehringer Ingelheim Canada Ltd., GlaxoSmithKline Canada Ltd., Merck, Novartis Pharma Canada Inc., as well as Nycomed Canada Inc. (W. C. T.), Pfizer Canada Ltd. (W. C. T.), Trudell (J. B.), and Grifolds (J. B.). None declared (P. Z. L., M. E., H. L., D. J.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The SARS-CoV-2 pandemic has limited objective physiologic assessments. A standardized remote alternative is not currently available. "Cardiac effort" (CE), that is, the total number of heart beats divided by the 6-min walk test (6MWT) distance (beats/m), has improved reproducibility in the 6MWT and correlated with right ventricular function in pulmonary arterial hypertension., Research Question: Can a chest-based accelerometer estimate 6MWT distance remotely? Is remote cardiac effort more reproducible than 6MWT distance when compared with clinic assessment?, Study Design and Methods: This was a single-center, prospective observational study, with institutional review board approval, completed between October 2020 and April 2021. Group 1 subjects with pulmonary arterial hypertension, receiving stable therapy for > 90 days, completed four to six total 6MWTs during a 2-week period to assess reproducibility. The first and last 6MWTs were performed in the clinic; two to four remote 6MWTs were completed at each participant's discretion. Masks were not worn. BioStamp nPoint sensors (MC10) were worn on the chest to measure heart rate and accelerometry. Two blinded readers counted laps, using accelerometry data obtained on the clinic or user-defined course. Averages of clinic variables and remote variables were used for Wilcoxon matched-pairs signed rank tests, Bland-Altman plots, or Spearman correlation coefficients., Results: Estimated 6MWT distance, using the MC10, correlated strongly with directly measured 6MWT distance (r = 0.99; P < .0001; in 20 subjects). Remote 6MWT distances were shorter than clinic 6MWT distances: 405 m (330-464 m) vs 389 m (312-430 m) (P = .002). There was no difference between in-clinic and remote CE: 1.75 beats/m (1.48-2.20 beats/m) vs 1.86 beats/m (1.57-2.14 beats/m) (P = .14)., Interpretation: Remote 6MWT was feasible on a user-defined course; 6MWT distance was shorter than clinic distance. CE calculated by chest heart rate and accelerometer-estimated distance provides a reproducible remote assessment of exercise tolerance, comparable to the clinic-measured value., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure with preserved ejection fraction (HFpEF) exhibit many cardiopulmonary abnormalities that could result in V˙/Q˙ mismatch, manifesting as an increase in alveolar dead space (VD alveolar ) during exercise. Therefore, we tested the hypothesis that VD alveolar would increase during exercise to a greater extent in patients with HFpEF compared with control participants., Research Question: Do patients with HFpEF develop VD alveolar during exercise?, Study Design and Methods: Twenty-three patients with HFpEF and 12 control participants were studied. Gas exchange (ventilation [V˙ E ], oxygen uptake [V˙o 2 ], and CO 2 elimination [V˙co 2 ]) and arterial blood gases were analyzed at rest, twenty watts (20W), and peak exercise. Ventilatory efficiency (evaluated as the V˙ E /V˙co 2 slope) also was measured from rest to 20W in patients with HFpEF. The physiologic dead space (VD physiologic ) to tidal volume (VT) ratio (VD/VT) was calculated using the Enghoff modification of the Bohr equation. VD alveolar was calculated as: (VD / VT × VT) - anatomic dead space. Data were analyzed between groups (patients with HFpEF vs control participants) across conditions (rest, 20W, and peak exercise) using a two-way repeated measures analysis of variance and relationships were analyzed using Pearson correlation coefficient., Results: VD alveolar increased from rest (0.12 ± 0.07 L/breath) to 20W (0.22 ± 0.08 L/breath) in patients with HFpEF (P < .01), whereas VD alveolar did not change from rest (0.01 ± 0.06 L/breath) to 20W (0.06 ± 0.13 L/breath) in control participants (P = .19). Thereafter, VD alveolar increased from 20W to peak exercise in patients with HFpEF (0.37 ± 0.16 L/breath; P < .01 vs 20W) and control participants (0.19 ± 0.17 L/breath; P = .03 vs 20W). VD alveolar was greater in patients with HFpEF compared with control participants at rest, 20W, and peak exercise (main effect for group, P < .01). Moreover, the increase in VD alveolar correlated with the V˙ E /V˙co 2 slope (r = 0.69; P < .01), which was correlated with peak V˙o 2peak (r = 0.46; P < .01) in patients with HFpEF., Interpretation: These data suggest that the increase in V˙/Q˙ mismatch may be explained by increases in VD alveolar and that increases in VD alveolar worsens ventilatory efficiency, which seems to be a key contributor to exercise intolerance in patients with HFpEF., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

A cardiopulmonary exercise test (CPET) is ideally suited to quantify exercise tolerance and evaluate the pathophysiological mechanism(s) of dyspnea and exercise limitation in people with chronic respiratory disease. Although there are several statements on CPET and many outstanding resources detailing the cardiorespiratory and perceptual responses to exercise, limited information is available to support the health care provider in conducting a practical CPET evaluation. This article provides the health care provider with practical and timely information on how to use CPET data to understand dyspnea and exercise intolerance in people with chronic respiratory diseases. Information on CPET protocol, as well as how to evaluate maximal patient effort, peak rate of oxygen consumption, ventilatory demand, pulmonary gas exchange, ventilatory reserve, operating lung volumes, and exertional dyspnea, is presented. Two case examples are also described to highlight how these parameters are evaluated to provide a clinical interpretation of CPET data., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The adherence to and clinical efficacy of pulmonary rehabilitation in idiopathic pulmonary fibrosis (IPF), particularly in comparison with COPD, remains uncertain. The objectives of this real-world study were to compare the responses of patients with IPF with a matched group of patients with COPD undergoing the same supervised, outpatient pulmonary rehabilitation program and to determine whether pulmonary rehabilitation is associated with survival in IPF., Research Question: Do people with IPF improve to the same extent with pulmonary rehabilitation as a matched group of individuals with COPD, and are noncompletion of or nonresponse to pulmonary rehabilitation, or both, associated with 1-year all-cause mortality in IPF?, Study Design and Methods: Using propensity score matching, 163 patients with IPF were matched 1:1 with a control group of 163 patients with COPD referred for pulmonary rehabilitation. We compared between-group pulmonary rehabilitation completion rates and response. Survival status in the IPF cohort was recorded over 1 year after pulmonary rehabilitation discharge. Cox proportional hazards regression explored the association between pulmonary rehabilitation status and all-cause mortality., Results: Similar pulmonary rehabilitation completion rates (IPF, 69%; COPD, 63%; P = .24) and improvements in exercise response were observed in both groups with no significant mean between-group differences in incremental shuttle walk test (ISWT) change (mean, 2 m [95% CI, -18 to 22 m]). Pulmonary rehabilitation noncompletion (hazard ratio [HR], 5.62 [95% CI, 2.24-14.08]) and nonresponse (HR, 3.91 [95% CI, 1.54-9.93]) were associated independently with increased 1-year all-cause mortality in IPF., Interpretation: This real-word study demonstrated that patients with IPF have similar completion rates and magnitude of response to pulmonary rehabilitation compared with a matched group of patients with COPD. In IPF, noncompletion of and nonresponse to pulmonary rehabilitation were associated with increased all-cause mortality. These data reinforce the benefits of pulmonary rehabilitation in patients with IPF., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: During exercise, dynamic hyperinflation (DH), measured by a reduction in inspiratory capacity (IC), increases exertional dyspnea and reduces functional capacity in many patients with severe COPD. Although noninvasive ventilation (NIV) during exercise can improve exercise duration, the effect on DH is unclear., Research Questions: In people with COPD, resting hyperinflation, and evidence of DH during exercise, does bilevel NIV during exercise reduce DH and increase endurance time compared with exercise with no NIV, and does NIV with an individually titrated expiratory positive airway pressure (T-EPAP) reduce DH and increase exercise endurance time more than NIV with standardized EPAP (S-EPAP) of 5 cm H 2 O?, Study Design and Methods: A randomized crossover trial in which investigators and participants were blinded between NIV interventions was performed. Participants (N = 19; FEV 1 of 1.02 ± 0.24 L (39% ± 6% predicted) completed three constant work rate endurance cycle tests in random order-no NIV, NIV with S-EPAP, and NIV with T-EPAP-during exercise. Primary outcomes were isotime IC and exercise endurance time. Outcome measures from each intervention were compared at isotime and at end exercise by using a linear mixed-model analysis., Results: Compared with no NIV, isotime IC and endurance time were greater with both NIV with S-EPAP (mean difference: 95% CI, 0.19 L [0.10-0.28]; 95% CI, 153 s [24-280], respectively) and T-EPAP (95% CI, 0.22 L [0.13-0.32]; 95% CI, 145 s [28-259], respectively). There was no difference between NIV with S-EPAP and NIV with T-EPAP., Interpretation: In people with COPD and DH during exercise, NIV during exercise reduced DH and increased cycle endurance time. An S-EPAP of 5 cm H 2 O was adequate to obtain these benefits., Trial Registry: Australian New Zealand Clinical Trials Registry; No.: ACTRN12613000804785; URL: http://www.anzctr.org.au., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Right ventricular (RV) dysfunction is associated with poorer outcomes in heart failure with preserved ejection fraction (HFpEF). Although female subjects are more likely to have HFpEF, male subjects have worse prognosis and resting RV function. The contribution of dynamic RV-pulmonary arterial (RV-PA) coupling between sex and its impact on peak exercise capacity (VO 2 ) in HFpEF is not known., Research Question: The goal of this study was to investigate the differential effects of sex on RV-PA coupling during maximum incremental exercise in patients with HFpEF., Study Design and Methods: This study examined rest and exercise invasive pulmonary hemodynamics in 22 male patients with HFpEF and 27 female patients with HFpEF. To further investigate the discrepancy in RV-PA response between sex, 26 age-matched control subjects (11 male subjects and 15 female subjects) were included. Single beat analysis of RV pressure waveforms was used to determine the end-systolic elastance (Ees) and pulmonary arterial elastance. RV-PA coupling was determined as the ratio of end-systolic elastance/PA elastance., Results: Both HFpEF groups experienced decreased peak VO 2 (% predicted). However, male patients with HFpEF experienced a greater decrement in peak VO 2 compared with female patients (58 ± 16% vs 70 ± 15%; P < .05). Male patients with HFpEF had a more pronounced increase in RV afterload, Ea (1.8 ± 0.6 mm Hg/mL/m 2 vs 1.3 ± 0.4 mm Hg/mL/m 2 ; P < .05) and failed to increase RV contractility during exercise, resulting in dynamic RV-PA uncoupling (0.9 ± 0.4 vs 1.2 ± 0.4; P < .05) and subsequent reduced stroke volume index augmentation. In contrast, female patients with HFpEF were able to augment RV contractility in the face of increasing afterload, preserving RV-PA coupling during exercise., Interpretation: Male patients with HFpEF were more compromised regarding dynamic RV-PA uncoupling and reduced peak VO 2 compared with female patients. This finding was driven by both RV contractile impairment and afterload mismatch. In contrast, female patients with HFpEF had preserved RV-PA coupling during exercise and better peak exercise VO 2 compared with male patients with HFpEF., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Eccentric cycling (ECC) may be an attractive exercise method in COPD because of both low cardiorespiratory demand and perception of effort compared with conventional concentric cycling (CON) at matched mechanical loads. However, it is unknown whether ECC can be performed by individuals with COPD at an intensity able to cause sufficient metabolic stress to improve aerobic capacity., Research Question: What are the cardiopulmonary and metabolic responses to ECC in people with COPD and healthy volunteers when compared with CON at matched mechanical loads?, Study Design and Methods: Thirteen people with COPD (mean ± SD age, 64 ± 9 years; FEV 1 , 45 ± 19% predicted; BMI, 24 ± 4 kg/m 2 ; oxygen uptake at peak exercise [V̇O 2peak ], 15 ± 3 mL/kg/min) and 9 age-matched control participants (FEV 1 , 102 ± 13% predicted; BMI, 28 ± 5 kg/m 2 ; V̇O 2peak , 23 ± 5 mL/kg/min), performed up to six 4-min bouts of ECC and CON at matched mechanical loads of increasing intensity. In addition, 12 individuals with COPD underwent quadriceps muscle biopsies before and after 20 min of ECC and CON at 65% peak power., Results: At matched mechanical loads, oxygen uptake, minute ventilation, heart rate, systolic BP, respiratory exchange ratio (all P < .001), capillary lactate, perceived breathlessness, and leg fatigue (P < .05) were lower in both groups during ECC than CON. Muscle lactate content increased (P = .008) and muscle phosphocreatine decreased (P = .012) during CON in COPD, which was not evident during ECC., Interpretation: Cardiopulmonary and blood lactate responses during submaximal ECC were less compared with during CON at equivalent mechanical workloads in healthy participants and COPD patients, and this was confirmed at a muscle level in COPD patients. Submaximal ECC was well tolerated and allowed greater mechanical work at lower ventilatory cost. However, in people with COPD, a training intervention based on ECC is unlikely to stimulate cardiovascular and metabolic adaptation to the same extent as CON., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Up-to-date normative reference sets for cardiopulmonary exercise testing (CPET) are important to aid in the accurate interpretation of CPET in clinical or research settings., Research Question: This study aimed to (1) develop and externally validate a contemporary reference set for peak CPET responses in Canadian adults identified with population-based sampling; and (2) evaluate previously recommended reference equations for predicting peak CPET responses., Study Design and Methods: Participants were healthy adults who were ≥40 years old from the Canadian Cohort Obstructive Lung Disease who completed an incremental cycle CPET. Prediction models for peak CPET responses were estimated from readily available participant characteristics (age, sex, height, body mass) with the use of quantile regression. External validation was performed with a second convenience sample of healthy adults. Peak CPET parameters that were measured and predicted in the validation cohort were assessed for equivalence (two one-sided tests of equivalence for paired-samples and level of agreement (Bland-Altman analyses). Two one-sided tests of equivalence for paired samples assessed differences between responses in the derivation cohort using previously recommended reference equations., Results: Normative reference ranges (5th-95th percentiles) for 28 peak CPET parameters and prediction models for 8 peak CPET parameters were based on 173 participants (47% male) who were 64 ± 10 years old. In the validation cohort (n = 84), peak CPET responses that were predicted with the newly generated models were equivalent to the measured values. Peak cardiac parameters predicted by the previously recommended reference equations by Jones and colleagues and Hansen and colleagues were significantly higher., Interpretation: This study provides reference ranges and prediction models for peak cardiac, ventilatory, operating lung volume, gas exchange, and symptom responses to incremental CPET and presents the most comprehensive reference set to date in Canadian adults who were ≥40 years old to be identified with population-based sampling., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Exertional dyspnea is a common complaint for patients seen in pulmonary, cardiac, and general medicine clinics, and elucidating the cause is often challenging, particularly when physical examination, echocardiography, radiography, and pulmonary function test results are inconclusive. Invasive cardiopulmonary exercise testing has emerged as the gold standard test to define causes of dyspnea and exertional limitation in this population. In this review, we describe the methods for performing and interpreting invasive cardiopulmonary exercise testing, with particular attention to the hemodynamic and blood sampling data as they apply to patients being evaluated for heart failure and pulmonary hypertension., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Black smokers have earlier development of lung disease as well as poorer sleep health than whites., Research Question: In a sample of black smokers, to what extent does sleep health modify the association between smoking level and functional exercise capacity?, Design and Methods: Cross-sectional data from 209 black smokers (≥ 1 cigarette in last month), aged 40 to 65 years with no evidence of sleep-disordered breathing (apnea-hypopnea index < 15) or severe COPD (FEV 1 > 50%), were used for the current study. Self-reported smoking rate, objectively measured sleep efficiency (SE), total sleep time (TST), and the 6-min walk test (6MWT) for functional exercise capacity were the key assessments., Results: The mean age was 54.8 years (SD, 5.96), and mean cigarettes smoked per day (cpd) was 8.71 (SD, 6.78). Mean SE was 69.9% (SD, 12.3%), and mean TST was 307.99 min (SD 92.2). In adjusted linear regression models of the 6MWT (meters), TST (slope estimate, -0.14; P = .14) and SE (slope estimate, -1.0; P = .19) were negatively associated with 6MWT. The smoking rate × SE interaction was highly significant (slope estimate, 0.18; P = .007) such that in individuals who smoked ≥ 10 cpd, every additional percentage of SE garnered an additional distance of 0.83 to 6.62 m. Similarly, the smoking rate × TST interaction was significant (slope estimate, 0.019; P = .03) such that in smokers who smoked ≥ 10 cpd, every additional minute of TST garnered an additional distance of 0.04 to 0.60 m., Interpretation: Higher SE and, to a lesser extent, longer TST, in black adults who smoke ≥ 10 cpd is associated with better 6MWT performance., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03534076; URL: www.clinicaltrials.gov., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension (PH) adversely affects patient's exercise capacity in interstitial lung disease (ILD). The impact of pulmonary vascular and right ventricular (RV) dysfunction, however, has traditionally been believed to be mild and clinically relevant principally in advanced lung disease states., Research Question: The aim of this study was to evaluate the relative contributions of pulmonary mechanics, pulmonary vascular function, and RV function to the ILD exercise limit., Study Design and Methods: Forty-nine patients with ILD who underwent resting right heart catheterization followed by invasive exercise testing were evaluated. Patients with PH at rest (ILD + rPH) and with PH diagnosed exclusively during exercise (ILD + ePH) were contrasted with ILD patients without PH (ILD non-PH)., Results: Peak oxygen consumption was reduced in ILD + rPH (61 ± 10% predicted) and ILD + ePH (67 ± 13% predicted) compared with ILD non-PH (81 ± 16% predicted; P < .001 and P = .016, respectively). Each ILD hemodynamic phenotype presented distinct patterns of dynamic changes of pulmonary vascular compliance relative to pulmonary vascular resistance from rest to peak exercise. Peak RV stroke work index was increased in ILD + ePH (24.7 ± 8.2 g/m 2 per beat) and ILD + rPH (30.9 ± 6.1 g/m 2 per beat) compared with ILD non-PH (18.3 ± 6.4 g/m 2 per beat; P = .020 and P = .014). Ventilatory reserve was reduced in ILD + rPH compared with the other groups at the anaerobic threshold, but it was similar between ILD + ePH and ILD non-PH at the anaerobic threshold (0.32 ± 0.13 vs 0.30 ± 0.11; P = .921) and at peak exercise (0.70 ± 0.17 vs 0.73 ± 0.24; P = .872)., Interpretation: ILD with resting and exercise PH is associated with increased exercise RV work, reduced pulmonary vascular reserve, and reduced peak oxygen consumption. The findings highlight the role of pulmonary vascular and RV burden to ILD exercise limit., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The 6-min walk test (6MWT) is a commonly used test for the objective assessment of functional exercise capacity for the management of patients with moderate-to-severe pulmonary disease. Unlike pulmonary function testing, the 6MWT captures the often coexisting extrapulmonary manifestations of chronic respiratory disease, including cardiovascular disease, frailty, sarcopenia, and cancer. In contrast with cardiopulmonary exercise stress testing, this test does not require complex equipment or technical expertise. In this low complexity, safe test, the patient is asked to walk as far as possible along a 30-m minimally trafficked corridor for a period of 6 min with the primary outcome measure being the 6-min walk distance (6MWD) measured in meters. There has been interest in other derived indexes, such as distance-desaturation product (the product of nadir oxygen saturation and walk distance), which in small studies has been predictive of morbidity and mortality in certain chronic respiratory conditions. Special attention to methodology is required to produce reliable and reproducible results. Factors that can affect walk distance include track layout (continuous vs straight), track length, oxygen amount and portability, learning effect, and verbal encouragement. The absolute 6MWD and change in 6MWD are predictive of morbidity and mortality in patients with COPD, pulmonary arterial hypertension, and idiopathic pulmonary fibrosis and patients awaiting lung transplant, highlighting its use in management decisions and clinical trials. As of January 2018, Current Procedural Terminology code 94620 (simple pulmonary stress test) has been deleted and replaced by two new codes, 94617 and 94618. Code 94617 includes exercise test for bronchospasm including pre- and postspirometry, ECG recordings, and pulse oximetry. Code 94618, pulmonary stress testing (eg, 6MWT), includes the measurement of heart rate, oximetry, and oxygen titration when performed. If 94620 is billed after January 2018 it will not be reimbursed., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: We evaluated the prognostic meaning of the simple presence or absence of identifiable anaerobic threshold (AT) and respiratory compensation point (RCP) at cardiopulmonary exercise tests (CPETs) performed with a maximal incremental exercise protocol., Methods: In the present multicenter study, we retrospectively analyzed data in 1,995 patients with heart failure with reduced ejection fraction (HFrEF). All underwent clinical and laboratory evaluation, echocardiography, and maximal CPET at baseline. The analysis was performed according to absence of identified AT and RCP (group 1: n = 292; 15%), presence of AT but absence of identified RCP (group 2: n = 920; 46%), and presence of both AT and RCP (group 3: n = 783; 39%). The study end point was the composite of cardiovascular mortality, urgent heart transplant, and left ventricular assist device implantation., Results: Median follow-up was 2.97 years (interquartile range, 1.50-5.35 years). Eighty-seven (30%), 169 (18%), and 111 (14%) events were observed in groups 1, 2, and 3, respectively (P = .025). Compared with results in group 3 (patients with the best survival), the likelihood of reaching the study end point increased 2.7 times when neither AT nor RCP were identified (hazard ratio, 2.74) and 1.4 times when only AT was identified (hazard ratio, 1.4). Moreover, adding the presence or absence of identified AT and RCP improved the prognostic power of peak oxygen uptake because a significant reclassification was obtained., Conclusions: AT and RCP identification has a potential role in the prognostic stratification of HFrEF., (Copyright © 2019. Published by Elsevier Inc.)

Background: The BMI, obstruction, dyspnea, and exercise capacity (BODE) score is used to inform prognostic considerations for lung transplantation for COPD, but it has not been validated in this context. A large proportion of mortality in COPD is attributable to comorbidities that could preclude transplant candidacy. We hypothesized that patients with COPD who are selected as transplant candidates experience better survival than traditional interpretation of BODE scores might indicate., Methods: We performed a retrospective analysis of survival according to the BODE score for patients with COPD in the United Network of Organ Sharing (UNOS) database of lung transplantation candidates (n = 4,377) compared with the cohort of patients with COPD in which the BODE score was validated (n = 625)., Results: Median survival in the fourth quartile of BODE score was 59 months (95% CI, 51-77 months) in the UNOS cohort and 37 months (95% CI, 29-42 months) in the BODE validation cohort. In models controlling for BODE score and incorporating lung transplantation as a competing end point, the risk of death was higher in the BODE validation cohort (subhazard ratio, 4.8; 95% CI, 4.0-5.7; P < .001). The risk difference was greatest in the fourth quartile of BODE scores (SHR, 6.1; 95% CI, 4.9-7.6; P < .001)., Conclusions: Extrapolation of prognosis based on the BODE score overestimates mortality risk in lung transplantation candidates with COPD. This is likely due to a lower prevalence of comorbid conditions attributable to the lung transplantation evaluation screening process., (Published by Elsevier Inc.)

Background: Pulmonary hypertension manifests with impaired exercise capacity. Our aim was to investigate whether the mean pulmonary arterial pressure to cardiac output relationship (mPAP/CO) predicts transplant-free survival in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: Hemodynamic data according to right heart catheterization in patients with PAH and CTEPH at rest and during supine incremental cycle exercise were analyzed. Transplant-free survival and predictive value of hemodynamics were assessed by using Kaplan-Meier and Cox regression analyses., Results: Seventy patients (43 female; 54 with PAH, 16 with CTEPH; median (quartiles) age, 65 [50; 73] years; mPAP, 34 [29; 44] mm Hg; cardiac index, 2.8 [2.3; 3.5] [L/min]/m(2)) were followed up for 610 (251; 1256) days. Survival at 1, 3, 5, and 7 years was 89%, 81%, 71%, and 59%. Age, World Health Organization-functional class, 6-min walk test, and mixed-venous oxygen saturation (but not resting hemodynamics) predicted transplant-free survival. Maximal workload (hazard ratio [HR], 0.94 [95% CI, 0.89-0.99]; P = .027), peak cardiac index (HR, 0.51 [95% CI, 0.27-0.95]; P = .034), change in cardiac index, 0.25 [95% CI, 0.06-0.94]; P = .040), and mPAP/CO (HR, 1.02 [95% CI, 1.01-1.03]; P = .003) during exercise predicted survival. Values for mPAP/CO predicted 3-year transplant-free survival with an area under the curve of 0.802 (95% CI, 0.66-0.95; P = .004)., Conclusions: In this collective of patients with PAH or CTEPH, the pressure-flow relationship during exercise predicted transplant-free survival and correlated with established markers of disease severity and outcome. Right heart catheterization during exercise may provide important complementary prognostic information in the management of pulmonary hypertension., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The impact of bronchoscopic lung volume reduction (BLVR) on physiologic responses to exercise in patients with advanced emphysema remains incompletely understood. We hypothesized that effective BLVR (e-BLVR), defined as a reduction in residual volume > 350 mL, would improve cardiovascular responses to exercise and accelerate oxygen uptake (Vo₂) kinetics., Methods: Thirty-one patients (FEV1, 36% ± 9% predicted; residual volume, 219% ± 57% predicted) underwent a constant intensity exercise test at 70% peak work rate to the limit of tolerance before and after treatment bronchoscopy (n = 24) or sham bronchoscopy (n = 7). Physiologic responses in patients who had e-BLVR (n = 16) were compared with control subjects (ineffective BLVR or sham bronchoscopy; n = 15)., Results: e-BLVR reduced residual volume (-1.1 ± 0.5 L, P = .001), improved lung diffusing capacity by 12% ± 13% (P = .001), and increased exercise tolerance by 181 ± 214 s (P = .004). Vo₂ kinetics were accelerated in the e-BLVR group but remained unchanged in control subjects (Δ mean response time, -20% ± 29% vs 1% ± 25%, P = .04). Acceleration of Vo₂ kinetics was associated with reductions in heart rate and oxygen pulse response half-times by 8% (84 ± 14 to 76 ± 15 s, P = .04) and 20% (49 ± 16 to 34 ± 16 s, P = .01), respectively. There were also increases in heart rate and oxygen pulse amplitudes during the cardiodynamic phase post e-BLVR. Faster Vo₂ kinetics in the e-BLVR group were significantly correlated with reductions in residual volume (r = 0.66, P = .005) and improvements in inspiratory reserve volume (r = 0.56, P = .024) and exercise tolerance (r = 0.63, P = .008)., Conclusions: Lung deflation induced by e-BLVR accelerated exercise Vo₂ kinetics in patients with emphysema. This beneficial effect appears to be related mechanistically to an enhanced cardiovascular response to exercise, which may contribute to improved functional capacity., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: In COPD, a decreased inspiratory capacity to total lung capacity ratio (IC/TLC) is associated with dynamic hyperinflation and poor exercise capacity. The association with upper-extremity force measured by handgrip strength (HGS) and 6-min walk distance (6MWD) has not been previously described. We hypothesized that IC/TLC affects muscle strength in the upper and lower extremities, affecting HGS and 6MWD., Methods: We prospectively measured lung function, HGS, and 6MWD in 27 patients with COPD and 12 healthy nonsmokers twice, 1 year apart. The patients were classified according to level of hyperinflation: IC/TLC > 25% or IC/TLC ≤ 25%., Results: Patients with COPD had reduced lung function, static hyperinflation, and reduced HGS and 6MWD compared with the control subjects on both evaluations (P < .01). There was a statistically significant deterioration in HGS, IC/TLC, and 6MWD after 1-year follow-up in the COPD compared with the control group (P < .001). More hyperinflation (IC/TLC < 0.25) was associated with lower HGS and 6MWD (P < .001). Changes in IC/TLC correlated with changes in HGS (r = 0.429, P < .05). Multivariate analysis determined that IC/TLC is an independent factor associated with HSG and 6MWD., Conclusions: HGS and 6MWD are reduced in patients with COPD, particularly in those with hyperinflation and evidence of longitudinal deterioration not seen in control subjects. This finding suggests that resting hyperinflation may exert a detrimental effect on cardiac function and plays a role in reduced exercise performance in patients with COPD.

Background: Mechanisms of decreased exercise capacity in patients with hypertrophic cardiomyopathy (HCM) are not well understood. Sleep-disordered breathing (SDB) is a highly prevalent but treatable disorder in patients with HCM. The role of comorbid SDB in the attenuated exercise capacity in HCM has not been studied previously., Methods: Overnight oximetry, cardiopulmonary exercise testing, and echocardiographic studies were performed in consecutive patients with HCM seen at the Mayo Clinic. SDB was considered present if the oxygen desaturation index (number of ≥ 4% desaturations/h) was ≥ 10. Peak oxygen consumption (VO2 peak) (the most reproducible and prognostic measure of cardiovascular fitness) was then correlated with the presence and severity of SDB., Results: A total of 198 patients with HCM were studied (age, 53 ± 16 years; 122 men), of whom 32% met the criteria for the SDB diagnosis. Patients with SDB had decreased VO2 peak compared with those without SDB (16 mL O2/kg/min vs 21 mL O2/kg/min, P < .001). SDB remained significantly associated with VO2 peak after accounting for confounding clinical variables (P < .001) including age, sex, BMI, atrial fibrillation, and coronary artery disease., Conclusions: In patients with HCM, the presence of SDB is associated with decreased VO2 peak. SDB may represent an important and potentially modifiable contributor to impaired exercise tolerance in this unique population.

Background: Involving family as part of the patient's rehabilitation plan of care might enhance the management of COPD. The primary aim of this study was to investigate the impact of a family-based pulmonary rehabilitation (PR) program on patients and family members' coping strategies to manage COPD., Methods: Family dyads (patient and family member) were randomly assigned to family-based (experimental) or conventional (control) PR. Patients from both groups underwent exercise training three times a week and psychosocial support and education once a week, during 12 weeks. Family members of the family-based PR attended the psychosocial support and education sessions together with patients. In the conventional PR, family members did not participate. Family coping and psychosocial adjustment to illness were assessed in patients and family members of both groups. Patients' exercise tolerance, functional balance, muscle strength, and health-related quality of life were also measured. All measures were collected pre/post-program., Results: Forty-two dyads participated (patients: FEV1, 70.4% ± 22.1% predicted). Patients (P = .048) and family members (P = .004) in the family-based PR had significantly greater improvements in family coping than the control group. Family members of the family-based PR had significantly greater changes in sexual relationships (P = .026) and in psychologic distress (P = .033) compared with the control group. Patients from both groups experienced significant improvements in exercise tolerance, functional balance, knee extensors strength, and health-related quality of life after intervention (P < .001)., Conclusions: This research supports family-based PR programs to enhance coping and psychosocial adjustment to illness of the family system., Trial Registry: ClinicalTrials.gov; No.: NCT02048306; URL: www.clinicaltrials.gov.

Background: Pulmonary arterial hypertension (PAH) is a progressive disease with high rates of morbidity and mortality. Current therapies improve symptoms, functional capacity, and, in select cases, survival. Little is known about patient factors that may predict the likelihood of patient-important, clinically relevant responses to therapy such as the 6-min walk distance (6MWD) and health-related quality of life (HRQoL)., Methods: Data from the randomized clinical trial of tadalafil in PAH were used. Adjusted logistic regression models were created to examine the relationship between baseline characteristics and odds of achieving the minimal important difference (MID) in three parameters, defined as either a > 33-m increase in 6MWD, a > 5-unit increase in physical component summary score of the Medical Outcomes Study Short Form-36 (SF-36), or a > 5-unit increase in mental component summary score of the SF-36., Results: The study included 405 subjects. Younger age, male sex, lower baseline 6MWD, and disease etiology were associated with greater odds of achieving the MID for the 6-min walk test. Active treatment, younger age, and male sex were associated with greater odds of achieving the MID for the physical component summary score. Male sex was associated with greater odds of achieving the MID for the mental component summary score., Conclusions: Age, sex, baseline functional capacity, and disease etiology are variably associated with the likelihood of achieving clinically relevant responses in patient-important outcomes to PAH-specific therapy such as 6MWD and HRQoL. The increased likelihood of response in men compared with women is a novel finding and may reflect pathophysiologic differences between sexes.

Background: Programs aimed at increasing physical activity in daily life (PADL) have generated growing interest to prevent the deleterious effects of physical inactivity. Recent literature has shown that a short-term protocol using pedometers increased PADL in smokers with normal lung function. However, the long-term effects of such a protocol were not yet studied. The objective of this study was to evaluate the results of 1-year follow-up after a program aimed at increasing PADL in smokers with normal lung function., Methods: Twenty-four smokers were followed (15 men; mean [interquartile range (IQR)], 51 [41-57] years of age; BMI, 26 [22-29] kg/m2; 20 [20-30] cigarettes/d). Subjects were assessed at baseline, immediately after completion of the program, and 1 year later for PADL, lung function, 6-min walking distance (6MWD), smoking habits, quality of life, anxiety, and depression. The 5-month program used pedometers and informative booklets as interventions., Results: The gains achieved after the program were maintained in the long term: steps/d (postprogram vs 1-year follow-up, mean [IQR]: 10,572 [9,804-12,237] vs 10,438 [9,151-12,862]); 6MWD (625 [530-694] m, 88 [81-97] % predicted vs 609 [539-694] m, 89 [81-96] % predicted), anxiety (34 [26-41] points vs 35 [36-47] points) and depression (6 [2-9] points vs 5 [2-11] points) (P > .05 for all). One year after the program, 20% of the subjects had quit smoking., Conclusions: In smokers with normal lung function, improvements in daily physical activity, exercise capacity, anxiety, and depression obtained through a 5-month program aimed at increasing physical activity are sustained 1 year after completion of the program. Furthermore, such a program can contribute to smoking cessation in this population.

Background: Resting mean pulmonary artery pressure (mPAP) values between 20 and 25 mm Hg are above normal but do not fulfill the criteria for pulmonary hypertension (PH). The clinical relevance of such borderline hemodynamics is a matter of discussion., Methods: We focused on patients who underwent right-sided heart catheterization during rest and exercise for symptoms indicative of PH or due to underlying disease associated with an increased risk for pulmonary arterial hypertension and characterized the patients according to their resting mPAP. Patients with manifest PH (mPAP ≥ 25 mm Hg) were excluded., Results: We included 141 patients, 32 of whom presented with borderline hemodynamics (20 < mPAP < 25 mm Hg). Borderline patients were older (65.8 ± 12.5 years vs 57.3 ± 12.5 years, P = .001) and more often had cardiac comorbidities (53% vs 15%, P < .001) or decreased lung function (47% vs 16%, P < .001) as compared with patients with resting mPAP < 21 mm Hg. After correction for age, borderline patients had significantly increased pulmonary vascular resistance (2.7 ± 0.7 Wood units vs 1.8 ± 0.8 Wood units, P < .001) and mPAP/cardiac output (CO) and transpulmonary gradient/CO slopes (both P < .001) as well as lower peak oxygen uptake (16.9 ± 4.6 mL/min/kg vs 20.9 ± 4.7 mL/min/kg, P = .009) and 6-min walk distance (383 ± 120 m vs 448 ± 92 m, P = .001). During follow-up (4.4 ± 1.4 years), the mortality rate of borderline patients vs patients with resting mPAP < 21 mm Hg was 19% vs 4%., Conclusions: In patients undergoing right-sided heart catheterization with exclusion of manifest PH, borderline elevation of pulmonary arterial pressure is associated with cardiac and pulmonary comorbidities, decreased exercise capacity, and a poor prognosis.

Background: Patients with pulmonary arteriovenous malformations (PAVMs) are unusual because hypoxemia results from right-to-left shunting and not airway or alveolar disease. Their surprisingly well-preserved exercise capacity is not generally appreciated., Methods: To examine why exercise tolerance is preserved, cardiopulmonary exercise tests were performed while breathing room air in 21 patients with radiologically proven PAVMs, including five restudied 3 to 12 months after embolization when their PAVMs had regressed. Where physiologic matching was demonstrable, comparisons were made with 12 healthy control subjects., Results: The majority of patients achieved their predicted work rate despite a resting arterial oxygen saturation (SaO₂) of 80% to 96%. Peak work rate and oxygen consumption (VO₂) were no lower in patients with more hypoxemia. Despite higher SaO₂ following embolization (median, 96% and 90%; P = .009), patients achieved similar work rates and similar peak VO₂. Strikingly, treated patients reset to virtually identical peak oxygen pulses (ie, VO₂ per heart beat) and in many cases to the same point on the peak oxygen pulse/work rate plot. The 21 patients had increased minute ventilation (VE) for given increases in CO₂ production (VE/VCO₂ slope), but perceived dyspnea was no greater than in the 12 control subjects or in the same patients before compared to after embolization comparison. Overall, work rate and peak VO₂ were associated not with oxygenation parameters but with VE/VCO₂ slope, BMI, and anaerobic threshold., Conclusions: Patients with hypoxemia and PAVMs can maintain normal oxygen delivery/VO₂ during peak exercise. Following improvement of SaO₂ by embolization, patients appeared to reset compensatory mechanisms and, as a result, achieved similar peak VO₂ per heart beat and peak work rates.

Background: Cardiorespiratory fitness, assessed during cardiopulmonary exercise tests by peak oxygen uptake (Vo2pk), is an independent predictor of mortality in obesity. We investigated whether Vo2pk and systemic responses measured during field walking tests were similar to those measured during an incremental treadmill test (ITMT) in obese individuals with treated OSA., Methods: Individuals with treated OSA and a BMI > 30 kg/m2 were recruited. Participants completed an ITMT, two 6-min walk tests (6MWTs), and two incremental shuttle walk tests (ISWTs) on three separate days in a randomized order. Expired gas analysis was performed during all tests., Results: The study was completed by 16 patients (nine men) (mean [SD] age, 58 [12] y; BMI, 36.1 [7.6] kg/m2). There was no difference (P = .27) in Vo2pk assessed by the ITMT and the ISWT (2,266 [478] and 2,017 [561] mL/min, respectively). The Vo2pk measured by the 6MWT (1,778 [360] mL/min) was lower than that measured by the ITMT (P < .01). The limits of agreement for Vo2pk between the ISWT and the ITM were ± 730 mL/min. Cardiorespiratory responses during the ISWT and the ITMT reflected a graded response to a peak, whereas the 6MWT demonstrated a rapid rise to a plateau., Conclusions: The ISWT can be used instead of an ITMT and in preference to the 6MWT to assess cardiorespiratory fitness for a cohort of obese people with treated OSA. However, the imprecision of the agreement in Vo2pk between the ITMT and ISWT means they cannot be used interchangeably in an individual., Trial Registry: ClinicalTrials.gov; No.: NCT01930513; www.clinicaltrials.gov.

Objective: The COPD Assessment Test (CAT) has been proposed for assessing health status in COPD, but little is known about its longitudinal changes. The objective of this study was to evaluate 1-year CAT variability in patients with stable COPD and to relate its variations to changes in other disease markers., Methods: We evaluated the following variables in smokers with and without COPD at baseline and after 1 year: CAT score, age, sex, smoking status, pack-year history, BMI, modified Medical Research Council (mMRC) scale, 6-min walk distance (6MWD), lung function, BODE (BMI, obstruction, dyspnea, exercise capacity) index, hospital admissions, Hospital and Depression Scale, and the Charlson comorbidity index. In patients with COPD, we explored the association of CAT scores and 1-year changes in the studied parameters., Results: A total of 824 smokers with COPD and 126 without COPD were evaluated at baseline and 441 smokers with COPD and 66 without COPD 1 year later. At 1 year, CAT scores for patients with COPD were similar (± 4 points) in 56%, higher in 27%, and lower in 17%. Of note, mMRC scale scores were similar (± 1 point) in 46% of patients, worse in 36%, and better in 18% at 1 year. One-year CAT changes were best predicted by changes in mMRC scale scores (β-coefficient, 0.47; P < .001). Similar results were found for CAT and mMRC scale score in smokers without COPD., Conclusions: One-year longitudinal data show variability in CAT scores among patients with stable COPD similar to mMRC scale score, which is the best predictor of 1-year CAT changes. Further longitudinal studies should confirm long-term CAT variability and its clinical applicability., Trial Registry: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov.

Background: The goal of the 6-min walk test (6MWT) is to enable patients to walk "as far as possible" as a measure of their functional ability. The impact of the specific walk instructions on patient 6MWT performance is unknown., Methods: Patients with pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and other forms of interstitial lung disease (ILD) were recruited to perform four identical 6MWTs with one differing instructional phrase. The standard instruction to walk "as far as possible" was substituted in random order with "as fast as possible," "at your normal pace," or "at a leisurely pace.", Results: Twenty-four patients (10 with PAH, eight with IPF, six with other ILD) were enrolled and completed all four 6MWTs. Patients attained the greatest distance with the fast instruction, exceeding the standard instruction distance by a mean of 52.7 m (P < .001). The mean difference between the fast and standard walks was 41.5 m in the PAH group, 66.5 m in the IPF group, and 53 m in the other ILD group., Conclusions: Patients do not walk as far as they are able with the standard American Thoracic Society instruction for 6MWT. Changing the wording from "far" to "fast" may facilitate a better effort and greater distance during the test. It is possible that this modified 6MWT instruction may result in improved accuracy and reproducibility, thereby enhancing its clinical and research trial usefulness.

Endoscopic lung volume-reduction therapy for emphysema has been associated with therapeutic responses smaller in magnitude and less durable than surgical volume reduction (LVRS). Bronchoscopic emphysematous lung sealant (ELS) therapy has been shown to produce improvements in pulmonary function similar to surgery at 1 year. This case series summarizes safety and efficacy data of all patients from the initial ELS study out to 2 years. Between 1 and 2 years, there were three all-cause adverse events requiring hospitalization. One patient went on to successful lung transplant. Improvements relative to baseline in spirometry (change in FEV1: + 14.3 ± 33.1%; change in FVC: + 5.8 ± 23.2%) and diffusing capacity (change in diffusing capacity of the lung for carbon monoxide: + 10.6 ± 20.6%) were observed at 2 years. An exponential model fit to FEV₁ data at 6, 12, 18, and 24 months predicted improvements from a baseline of > 5% out to 4.1 years, similar to what has been reported following surgery. This report confirms long-term safety and efficacy following ELS therapy in advanced emphysema. Studies in a larger cohort are needed to define the role of ELS therapy in the treatment algorithm of patients with this condition.

Background: Hyperinflated patients with COPD breathe against an increased elastic load during physical activity. Arm activities are especially demanding. Some pulmonary rehabilitation programs instruct patients to inhale while raising their arms, whereas others recommend the opposite. This study aimed to determine the effect of coordinating breathing with arm movements on the endurance of a lifting task., Methods: Participants with COPD and hyperinflation completed two (high intensity and severe intensity) rhythmic, constant load-lifting tasks to intolerance (tlimit) before and after attending four "teaching" sessions. Participants were randomly assigned to one of three groups: (1) taught to inhale during the lift, (2) taught to exhale during the lift, or (3) sham (unconstrained coordination)., Results: Thirty-six participants (FEV1 % predicted [SD], 34 [13]; FEV1/FVC [SD], 33% [10%]; thoracic gas volume % predicted [SD], 179 [44]) completed the study. There was an effect of group on the change in tlimit (P<.01) regardless of task intensity (P=.47). The change in tlimit in the exhalation group was greater than in both the sham (difference [95% CI]: 2.82 [0.21-5.44] min; P<.05) and inhalation (difference [95% CI]: 3.29 [0.65-5.92] min; P<.05) groups at the high intensity. There was no difference in the change in tlimit between the inhalation and sham groups., Conclusions: A specific breathing strategy, exhalation during the lift, improved task performance. Coordinating exhalation with lifting may be of value to hyperinflated patients with COPD who are engaged in arm and shoulder training exercises or daily activities that involve arm elevation., Trial Registry: ClinicalTrials.gov; No: NCT00836108; URL: www.clinicaltrials.gov.

Background: Partial volume averaging and tilt relative to the scan plane on transverse images limit the accuracy of airway wall thickness measurements on CT scan, confounding assessment of the relationship between airway remodeling and clinical status in COPD. The purpose of this study was to assess the effect of partial volume averaging and tilt corrections on airway wall thickness measurement accuracy and on relationships between airway wall thickening and clinical status in COPD., Methods: Airway wall thickness measurements in 80 heavy smokers were obtained on transverse images from low-dose CT scan using the open-source program Airway Inspector. Measurements were corrected for partial volume averaging and tilt effects using an attenuation- and geometry-based algorithm and compared with functional status., Results: The algorithm reduced wall thickness measurements of smaller airways to a greater degree than larger airways, increasing the overall range. When restricted to analyses of airways with an inner diameter < 3.0 mm, for a theoretical airway of 2.0 mm inner diameter, the wall thickness decreased from 1.07 ± 0.07 to 0.29 ± 0.10 mm, and the square root of the wall area decreased from 3.34 ± 0.15 to 1.58 ± 0.29 mm, comparable to histologic measurement studies. Corrected measurements had higher correlation with FEV₁, differed more between BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index scores, and explained a greater proportion of FEV1 variability in multivariate models., Conclusions: Correcting for partial volume averaging improves accuracy of airway wall thickness estimation, allowing direct measurement of the small airways to better define their role in COPD.

Background: Cystic fibrosis (CF) is a genetic disorder that affects not only pulmonary function but also multiple organ systems. The fl ow-mediated dilation (FMD) test is a noninvasive assessment of endothelial function and nitric oxide bioavailability. Thus, the purpose of this study was to determine (1) whether endothelial dysfunction is present in young patients with CF and (2) whether endothelial function is associated with pulmonary function and exercise capacity., Methods: Fifteen patients with CF and 15 demographically matched control subjects participated in this study. Spirometry, brachial-artery FMD, and a maximal exercise capacity test on a cycle ergometer were performed on all subjects to determine pulmonary function, endothelial function, and exercise capacity, respectively., Results: No differences ( P . .05) in age, height, or BMI were observed between patients with CF and control subjects. FEV 1 (% predicted), FEV 1 /FVC, and forced expiratory fl ow between 25% and 75% of vital capacity were lower in patients with CF. Volume of oxygen consumption peak (absolute and relative) was similar between groups; however, volume of oxygen consumption (% predicted and mL/kg fat-free mass/min) and peak workload were significantly ( P , .05) lower in patients with CF. FMD (4.9% 2.6% vs 7.5% 3.1%; P 5 .018) was lower in patients compared with control subjects, respectively. Relationships between FMD and both pulmonary function and exercise capacity were identified., Conclusions: For the fi rst time to our knowledge, these data provide evidence of vascular endothelial dysfunction in a fairly healthy cohort of young patients with CF. In addition, our data demonstrate the complex relationships between endothelial function and both pulmonary function and exercise capacity in young patients with CF.

Background: Pulmonary hypertension (PH) restricts the ability to engage in physical activity and decreases longevity. We examined the impact of aerobic exercise training on function and quality of life in patients with World Health Organization group 1 PH., Methods: Patients were randomized to a 10-week education only (EDU) or education/exercise combined (EXE) group. The exercise program consisted of 24-30 sessions of treadmill walking for 30-45 min per session at 70% to 80% of heart rate reserve. Outcome variables included changes in 6-min walk test (6MWT) distance, time to exercise intolerance, peak work rate (WR) from a cardiopulmonary treadmill test, and quality-of-life measures, including the Short Form Health Survey, version 2 (SF-36v2) and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)., Results: Data are presented as mean SD. Twenty-three women (age, 54 11 years; BMI, 31 7 kg/m 2 ) were randomized to the EDU (n 5 13) or EXE (n 5 10) groups. Following 10 weeks of intervention, patients in the EXE group demonstrated an improvement in 6MWT distance (56 45 m; P 5 .002), increased time to exercise intolerance (1.9 1.3 min; P 5 .001), and peak WR (26 23 W; P 5 .004). Additionally, the EXE group scored significantly ( P , .050) better on six of the eight scales on SF-36v2, and fi ve of the six scales on CAMPHOR. In contrast, no significant improvement was observed for any of the outcome measures following EDU. No adverse events were noted in either group., Conclusion: Ten weeks of brisk treadmill walking improved 6MWT distance, cardiorespiratory function, and patient-reported quality of life in female patients with group 1 PH.

Background: Little is known about pulmonary vascular complications in children with sickle cell disease (SCD). We hypothesized that transfer factor (diffusing capacity of the lung for carbon monoxide [D(LCO)] ) may be used as a surrogate for the size of the pulmonary vascular bed and that pulmonary vascular abnormalities in children with SCD may limit exercise capacity., Methods: Fifty stable patients with SCD aged 10 to 18 years and 50 healthy control subjects matched for race and age were recruited. Incremental ergometer cardiopulmonary exercise testing was performed using respiratory mass spectrometry for exhaled gas analysis. A rebreathing maneuver was used to measure functional residual capacity, effective pulmonary blood fl ow (Qpeff), and D(LCO), and helium dilution was used to calculate minute ventilation, oxygen consumption, and CO 2 production., Results: In the 89 evaluable subjects, there were no ventilatory differences between SCD and control subjects. Qpeff was consistently 15% to 20% greater in subjects with SCD than control subjects at all stages, but D(LCO) corrected for both surface area and hemoglobin was only about 7% to 10% greater in subjects with SCD at all stages. As a result, the D(LCO)/Qpeff ratio was considerably lower in SCD at all stages. Arteriovenous oxygen content difference was about one-third less in SCD at all stages., Conclusions: Contrary to our hypothesis, failure to maintain a sufficient Qpeff to compensate for anemia led to exercise limitation. The ratio of pulmonary capillary blood volume to fl ow is reduced throughout, implying subtle pulmonary vascular disease; however, this was not a factor limiting exercise.

Background: COPD has been described as a risk factor for excessive expiratory tracheal collapse, but its prevalence and clinical correlates have not been fully determined. The purpose of this study is to prospectively determine the prevalence of excessive expiratory tracheal collapse among patients with COPD and to test the hypothesis that clinical and/or physiologic parameters will correlate with the presence of excessive tracheal collapse., Methods: We studied 100 adults meeting GOLD (Global Initiative for Obstructive Lung Disease) criteria for COPD, who underwent full pulmonary function tests (PFTs), 6-min walk test (6MWT), St. George's Respiratory Questionnaire (SGRQ), and low-dose CT scan at total lung capacity and during dynamic exhalation with spirometric monitoring. We examined correlations between percentage dynamic expiratory tracheal collapse and PFTs, 6MWT distance, and SGRQ scores., Results: Patients included 48 women and 52 men with mean age 65 ± 7 years, FEV₁ 64% ± 22% predicted, and percentage expiratory collapse 59% ± 19%. Twenty of 100 participants met study criteria for excessive expiratory collapse. There was no significant correlation between percentage expiratory tracheal collapse and any pulmonary function measure, total SGRQ score, or 6MWT distance. The SGRQ symptom subscale was weakly correlated with percentage collapse of the mid trachea (R = 0.215, P = .03)., Conclusions: Excessive expiratory tracheal collapse is observed in a subset of patients with COPD, but the magnitude of collapse is independent of disease severity and does not correlate significantly with physiologic parameters. Thus, the incidental identification of excessive expiratory tracheal collapse in a general COPD population may not necessarily be clinically significant.

Background: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor., Methods: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score., Results: Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of &lt; 1 mg or discontinued because of adverse events (4 m)., Conclusions: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies., Trial Registry: ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Background: The 6-min walk test, commonly used to assess exercise capacity and response to therapy in pulmonary arterial hypertension (PAH), has many well-described limitations. Sedentary time is associated with adverse cardiovascular outcomes and reduced quality of life, and measuring sedentary time and physical activity using accelerometry is another potential way to quantify exercise capacity in PAH. Whether sedentary time is different in patients with PAH vs control subjects is unknown., Methods: Physical activity was measured in 20 patients with PAH and 30 matched healthy control subjects using accelerometry for 7 consecutive days. Patients with PAH completed standard 6-min walk testing, and baseline demographics were recorded for all study participants. Total daily activity counts, sedentary time, and proportion of time at various activity levels were compared between groups., Results: Sedentary time was significantly higher in patients with PAH (mean, 92.1% daily activity; 95% CI, 89.5-94.8%) than in control subjects (mean, 79.9% daily activity; 95% CI, 76.4%-83.5%; P < .001), and all levels of physical activity were reduced in the PAH group compared with the control group ( P < .01 for all). Daily moderate to vigorous physical activity was reduced in the PAH group (7.5 min; 95% CI; 0.8-15.6 min) compared with the control group (mean, 64.7 min; 95% CI, 51.1-78.2 min; P < .001). Activity counts correlated with 6-min walk distance in the PAH group (Spearman rank correlation 5 0.72, P < .001)., Conclusions: Sedentary time is increased in patients with PAH and may lead to increased risk for metabolic and cardiovascular morbidity. Quantitation of daily activity and sedentary time using accelerometry may be a novel end point for PAH management and clinical trials.

Background: It is uncertain whether the effort and expense of performing a second walk for the 6-min walk test improves test performance. Hence, we attempted to quantify the improvement in 6-min walk distance if an additional walk were to be performed., Methods: We studied patients consecutively enrolled into the National Emphysema Treatment Trial who prior to randomization and after 6 to 10 weeks of pulmonary rehabilitation performed two 6-min walks on consecutive days (N = 396). Patients also performed two 6-min walks at 6-month follow-up after randomization to lung volume reduction surgery (n = 74) or optimal medical therapy (n = 64). We compared change in the first walk distance to change in the second, average-of-two, and best-of-two walk distances., Results: Compared with the change in the first walk distance, change in the average-of-two and best-of-two walk distances had better validity and precision. Specifically, 6 months after randomization to lung volume reduction surgery, changes in the average-of-two (r = 0.66 vs r = 0.58, P = .01) and best-of-two walk distances (r = 0.67 vs r = 0.58, P = .04) better correlated with the change in maximal exercise capacity (ie, better validity). Additionally, the variance of change was 14% to 25% less for the average-of-two walk distances and 14% to 33% less for the best-of-two walk distances than the variance of change in the single walk distance, indicating better precision., Conclusions: Adding a second walk to the 6-min walk test significantly improves its performance in measuring response to a therapeutic intervention, improves the validity of COPD clinical trials, and would result in a 14% to 33% reduction in sample size requirements. Hence, it should be strongly considered by clinicians and researchers as an outcome measure for therapeutic interventions in patients with COPD.

Background: Pulmonary hypertension (PH) is a well-recognized complication of COPD. The impact of PH on exercise tolerance is largely unknown. We evaluated and compared the circulatory and ventilatory profiles during exercise in patients with COPD without PH, with moderate PH, and with severe PH., Methods: Forty-seven patients, GOLD (Global Initiative for Chronic Obstructive Lung Disease)stages II to IV, underwent cardiopulmonary exercise testing and right-sided heart catheterization at rest and during exercise. Patients were divided into three groups based on mean pulmonary artery pressure (mPAP) at rest: no PH (mPAP, < 25 mm Hg), moderate PH (mPAP, 25-39 mm Hg),and severe PH (mPAP, ≥ 40 mm Hg). Mixed venous oxygen saturation (S VO 2 ) was used for evaluating the circulatory reserve. Pa CO 2 and the calculated breathing reserve were used for evaluation of the ventilatory reserve., Results: Patients without PH (n = 24) had an end-exercise S VO 2 of 48%± 9%, an increasing Pa CO 2 with exercise, and a breathing reserve of 22% ± 20%. Patients with moderate PH (n = 14) had an exercise S VO 2 of 40% ± 8%, an increasing Pa CO 2 , and a breathing reserve of 26% ± 15%. Patients with severe PH (n =9) had a significantly lower end-exercise S VO 2 (30% ± 6%), a breathing reserve of 37% ± 11%, and an absence of Pa CO 2 accumulation., Conclusion: Patients with severe PH showed an exhausted circulatory reserve at the end of exercise.A profile of circulatory reserve in combination with ventilatory impairments was found inpatients with COPD and moderate or no PH. The results suggest that pulmonary vasodilation might only improve exercise tolerance in patients with COPD and severe PH.

Background: Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity., Methods: Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test., Results: The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 1, 32 2, and 33 2 mL/min/kg, respectively, mean SE( P 5 .8), with ventilatory equivalents for C O 2 vs end-tidal P CO 2 , measured at the anaerobic threshold,of 0.9 0.1, 1.2 0.1, and 1.4 0.1 mm Hg, respectively ( P , .001); arterial oxygen content of 26 1, 21 2, and 16 1 mL/dL, respectively ( P , .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% 4%, 150% 5%, and 120% 3% predicted, respectively( P , .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 0.1 at sea level decreased to 3.6 0.1, 3.7 0.1, and 3.9 0.1, respectively ( P , .05) and a maximal exercise mean pulmonary arterial pressure at 56 4, 42 3, and 31 2 mm Hg, respectively ( P , .001)., Conclusions: The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume.

Background: The mechanisms through which neuromuscular electrical stimulation (NMES) training may improve limb muscle function and exercise tolerance in COPD are poorly understood. We investigated the functional and muscular effects of NMES in advanced COPD., Methods: Twenty of 22 patients with COPD were randomly assigned to NMES (n = 12) or sham (n = 8) training in a double-blind controlled study. NMES was performed on quadriceps and calf muscles, at home, 5 days per week for 6 weeks. Quadriceps and calf muscle cross-sectional area (CSA), quadriceps force and endurance, and the shuttle-walking distance with cardiorespiratory measurements were assessed before and after training. Quadriceps biopsy specimens were obtained to explore the insulin-like growth factor-1/AKT signaling pathway (70-kDa ribosomal S6 kinase [p70S6K] , atrogin-1)., Results: NMES training improved muscle CSA (P < .05), force, and endurance (P < .03) when compared with sham training. Phosphorylated p70S6K levels (anabolism) were increased after NMES as compared with sham (P = .03), whereas atrogin-1 levels (catabolism) were reduced (P = .01). Changes in quadriceps strength and ventilation during walking contributed independently to variations in walking distance after training (r = 0.77, P < .001). Gains in walking distance were related to the ability to tolerate increasing current intensities during training (r = 0.95, P < .001)., Conclusions: In patients with severe COPD, NMES improved muscle CSA. This was associated with a more favorable muscle anabolic to catabolic balance. Improvement in walking distance after NMES training was associated with gains in muscle strength, reduced ventilation during walking, and the ability to tolerate higher stimulation intensity., Trial Registry: ClinicalTrials.gov; No.: NCT00874965; URL: www.clinicaltrials.gov.

Background: There are no recommendations on how to measure arm exercise capacity in individuals with COPD. The objectives of this study were (1) to synthesize the literature on measures of arm exercise capacity in individuals with COPD, (2) to describe the psychometric properties and the target construct of each measure, and (3) to make recommendations for clinical practice and research., Methods: Studies conducted in patients with COPD that included a measure of arm exercise capacity were identified after searches of five electronic databases (PubMed, CINAHL, EMBASE, PEDro, and Cochrane Library) and reference lists of pertinent articles. One reviewer performed data extraction, and two assessed the quality of the studies that described measurement properties, using the Consensus-based Standards for the Selection of Health Status Measurement Instruments (COSMIN) checklist., Results: Of 654 reports, 41 met the study criteria. Five types of arm exercise tests were identified: arm ergometry, ring shifts, dowel lifts, proprioceptive neuromuscular facilitation, and activities of daily living. Four studies assessed the measurement properties of the unsupported upper-limb exercise test (UULEX), the 6-min pegboard and ring test (6PBRT), a test involving weight shifts, and the grocery-shelving task (GST). Validity studies were of fair to good quality, whereas reliability studies were of poor quality., Conclusions: Arm ergometry may be the best method for measuring peak supported arm exercise capacity and endurance. The UULEX, 6PBRT, and GST may better reflect activities of daily living and should be the tests of choice to measure peak unsupported arm exercise capacity (UULEX) and arm function (6PBRT and GST).

Background: Detailed description of functional exercise outcomes before and after lung transplantation is lacking. The objective of this study was to describe and compare posttransplant improvement in lung function and peak exercise parameters in patients with advanced lung disease., Methods: The study included 153 patients who underwent lung transplantation over 7 years who had complete cardiopulmonary exercise testing (CPET) and pulmonary function tests (PFTs) before and after lung transplantation. CPET and PFT within 30 months pretransplant and posttransplant were compared., Results: Pulmonary function markedly improved posttransplant as FVC increased 67%, maximum voluntary ventilation increased 91%, and FEV(1) increased 136%. However, peak oxygen consumption increased only 19%, peak CO(2) production increased 50%, and peak work increased 78%. Although transplant recipients had a 1.5- to 2.0-fold increase in exercise capacity posttransplant, peak exercise capacity remained at 50% of the predicted normal, suggesting a maximal limitation. Subgroup stratification into quartiles based on pretransplant exercise capacity revealed the greatest exercise benefit to be in the lowest functional pretransplant groups., Conclusions: Lung transplant recipients have an increase in exercise capacity that does not match the improvement in lung function, indicating that poor strength, deconditioning, or other peripheral factors play a significant role in the limitation of exercise benefit posttransplantation. Further elucidation of the mechanisms of exercise limitation may allow for improved exercise outcomes posttransplant.

Background: Patients with COPD generally have a poor peak aerobic capacity and, therefore, may experience more inconvenience during domestic activities of daily life (ADLs). Yet, task-related oxygen uptake and symptom perception during ADLs have been studied rarely in COPD. Therefore, it remains unknown whether and to what extent differences may exist in task-related oxygen uptake and symptom perception during ADLs in patients with COPD after stratification for sex; GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage; Medical Research Council (MRC) dyspnea grade; or score on the BMI, obstruction, dyspnea, exercise capacity (BODE) index., Methods: Ninety-seven patients with COPD and 20 healthy elderly subjects performed the following five self-paced domestic ADLs with 4-min rest intervals: putting on socks, shoes, and vest; folding eight towels; putting away groceries; washing four dishes, cups, and saucers; and sweeping the floor for 4 min. Task-related oxygen uptake was assessed using an Oxycon Mobile device, whereas Borg scores were used to assess task-related dyspnea and fatigue., Results: Patients with COPD used a significantly higher proportion of their peak aerobic capacity and ventilation to perform ADLs than did the healthy subjects, accompanied by higher task-related Borg dyspnea scores. Patients with GOLD stage IV, MRC dyspnea grade 5, or BODE score ≥ 6 points had the highest task-related oxygen uptake and dyspnea perception during the performance of domestic ADLs. Results showed no sex-related differences., Conclusion: Patients with COPD experience a relatively high metabolic load and symptom perception during the performance of ADLs that is not the same as seen in their healthy peers, particularly in patients with GOLD stage IV, MRC dyspnea grade 5, or BODE score ≥ 6 points.

Background: There is considerable evidence that oxidative stress is increased in patients with COPD, although little information is available about its relationship with the structural and functional alterations produced by COPD. In this study, we evaluated the relationship between 8-isoprostane in exhaled breath condensate (EBC) of stable patients with COPD and the main parameters of the disease (such as dyspnea), stages of severity, lung parenchyma densities, lung function impairment, and exercise tolerance in order to identify the predictors of airway oxidative stress., Methods: In a cross-sectional study, we included 76 men with moderate to very severe COPD. 8-Isoprostane levels in EBC were measured by enzyme immunoassay. Regional lung densities were measured by lung densitometry with high-resolution CT scanning. Arterial blood gas levels, lung volumes, and diffusing capacity were determined. Patients performed a 6-min walk test and an incremental exercise test with measurement of breathing pattern and operating lung volumes., Results: Significant severity-related differences in 8-isoprostane were identified according to the BMI, obstruction, dyspnea, and exercise (BODE) index. 8-Isoprostane levels were related to smoking intensity, lung densities in expiration, static lung volumes, PaO(2), diffusion capacity, distance walked in 6 min, peak oxygen uptake, and anaerobic threshold. Concentration of 8-isoprostane was higher in the 60 patients (79%) who developed dynamic hyperinflation than in the remaining 16 (21%) who did not. In a multivariate linear regression analysis using 8-isoprostane as a dependent variable, end-expiratory lung volume change and PaO(2) were retained in the prediction model (r(2) = 0.734, P < .001)., Conclusions: In stable patients with COPD, oxygen level and dynamic hyperinflation are related to airway oxidative stress.

Background: Impairment in pulmonary capacity due to pleural effusion compromises daily activity. Removal of fluid improves symptoms, but the impact, especially on exercise capacity, has not been determined., Methods: Twenty-five patients with unilateral pleural effusion documented by chest radiograph were included. The 6-min walk test, Borg modified dyspnea score, FVC, and FEV(1) were analyzed before and 48 h after the removal of large pleural effusions., Results: The mean fluid removed was 1,564 ± 695 mL. After the procedure, values of FVC, FEV(1), and 6-min walk distance increased (P < .001), whereas dyspnea decreased (P < .001). Statistical correlations (P < .001) between 6-min walk distance and FVC (r = 0.725) and between 6-min walk distance and FEV(1) (r = 0.661) were observed. Correlations also were observed between the deltas (prethoracentesis × postthoracentesis) of the 6-min walk test and the percentage of FVC (r = 0.450) and of FEV(1) (r = 0.472) divided by the volume of fluid removed (P < .05)., Conclusion: In addition to the improvement in lung function after thoracentesis, the benefits of fluid removal are more evident in situations of exertion, allowing better readaptation of patients to routine activities.

Background: An increased minute ventilation (VE)/carbon dioxide production (VCO2) relationship, an expression of ventilatory inefficiency (VI), is associated with increased morbidity and mortality in patients with left ventricular systolic dysfunction (LVSD). A direct link between VI and a specific cardiac abnormality has not been established., Methods: We analyzed cardiopulmonary exercise test (CPET) data from patients (N=83) with severe LVSD (ischemic and nonischemic; left ventricular ejection fraction [LVEF] 19%±7%) and at least moderate exercise intolerance. Subjects were stratified into two groups based on the (VE/VCO2 ratio at anaerobic threshold (VE/VCO2@AT) (group 1 VE/VCO2@AT≤34; group 2 VE/VCO2@AT>34). Clinical, CPET, echocardiographic, and hemodynamic data were compared between groups., Results: Group 2 subjects had lower exercise capacity (peak (VO2, 45.7%±11.8% vs 50.4±8.9% predicted; P<.05), with a significantly lower oxygen pulse (71.6%±24.5% vs 85.4±18.5% predicted) and maximum systolic BP (122±19 mm Hg vs 138±22 mm Hg; P<.001 for both), suggesting a more blunted stroke volume to exercise vs group 1. There were no differences in left ventricular (LV) size, LVEF, or mitral regurgitation between the two groups. In sharp contrast, group 2 had larger right ventricular (RV) dimensions (4.5±1.1 cm vs 3.9±0.8 cm) and more severe RV systolic dysfunction (RV fractional area change 26%±11% vs 33%±12%; tricuspid annular plane systolic excursion [TAPSE] 1.6±0.5 cm vs 2.0±0.5 cm; all P<.001) vs group 1. Multivariable analysis revealed that only TAPSE and Doppler-estimated pulmonary artery systolic pressure were independently associated with VE/VCO2@AT and the (VE/VCO2slope. The VE/VCO2@AT, VE/VCO2 slope, and TAPSE had nearly identical predictive value for death or transplant., Conclusions: The present study suggests that VI is a functional, noninvasive marker of more advanced right-sided heart dysfunction in patients with severe LVSD.