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Background: Exertional dyspnea increases when the mechanical output of the respiratory muscles becomes uncoupled from increases in neural respiratory drive. Combining measurements of inspiratory constraints and ventilatory inefficiency may better uncover the role of mechanical-ventilatory abnormalities on exertional dyspnea than the currently-recommended approach, i.e., a low breathing reserve., Methods: We determined the presence of a low breathing reserve (1-(peak ventilation (V̇E)/estimated maximal voluntary ventilation) x 100 < 15%), critical inspiratory constraints (tidal volume (VT)/exercise inspiratory capacity (IC dyn ) > 0.7) and ventilatory inefficiency (V̇E/CO 2 output (V̇CO 2 ) nadir>34) in 284 subjects (161 males) with "disproportionate dyspnea" (N = 148), "dyspnea with multiple potential causes" (N = 93) and "dyspnea without an apparent cause., Results: The agreement between breathing reserve and assessment of inspiratory constraints was only "fair" (kappa [confidence interval (CI)] = 0.264 [0.169-0.358]). Attainment of critical inspiratory constraints and an upward inflection in dyspnea ratings systematically preceded a low breathing reserve. Of note, ~55% (93/167) of subjects with normal breathing reserve showed critical inspiratory constraints despite largely preserved lung function. Regardless of the breathing reserve, subjects showing critical inspiratory constraints and/or poor ventilatory efficiency reported higher dyspnea and more impaired exercise tolerance compared to their counterparts (p < 0.05). Poor ventilatory efficiency strongly predicted a high dyspnea/work rate in subjects without critical inspiratory constraints regardless of the breathing reserve (odds ratio [95% CI] = 4.21 [2.01-6.42; p < 0.001)., Conclusion: An integrated analysis of inspiratory constraints and ventilatory inefficiency is key to uncover physiological abnormalities germane to dyspnea in clinical populations in whom the origins of this distressing symptom are uncertain., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Hyperinflation has been associated with negative cardiocirculatory consequences in patients with chronic obstructive pulmonary disease (COPD). These abnormalities are likely to worsen when the demands for O 2 increase, e.g., under the stress of exercise. Thus, pharmacologically-induced lung deflation may improve cardiopulmonary interactions and exertional cardiac output leading to higher limb muscle blood flow and oxygenation in hyperinflated patients with COPD., Methods: 20 patients (residual volume = 201.6 ± 63.6% predicted) performed endurance cardiopulmonary exercise tests (75% peak) 1 h after placebo or tiotropium/olodaterol 5/5 μg via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Cardiac output was assessed by signal-morphology impedance cardiography. Near-infrared spectroscopy determined quadriceps blood flow (indocyanine green dye) and intra-muscular oxygenation., Results: Tiotropium/olodaterol was associated with marked lung deflation (p < 0.01): residual volume decreased by at least 0.4 L in 14/20 patients (70%). The downward shift in the resting static lung volumes was associated with less exertional inspiratory constraints and dyspnoea thereby increasing exercise endurance by ~50%. Contrary to our premises, however, neither central and peripheral hemodynamics nor muscle oxygenation improved after active intervention compared to placebo. These results were consistent with those found in a subgroup of patients showing the largest decrements in residual volume (p < 0.05)., Conclusions: The beneficial effects of tiotropium/olodaterol on resting and operating lung volumes are not translated into enhanced cardiocirculatory responses to exertion in hyperinflated patients with COPD. Improvement in exercise tolerance after dual bronchodilation is unlikely to be mechanistically linked to higher muscle blood flow and/or O 2 delivery., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Cardiovascular diseases play a major role in morbidity and mortality in the earlier stages of COPD. We hypothesized that systemic vascular dysfunction would be present even in patients who are currently considered at "low-risk" for negative cardiovascular outcomes, i.e., those with largely preserved FEV 1 , few exacerbations and only mild burden of respiratory symptoms (GOLD spirometric grade 1, clinical group A)., Methods: 16 patients (FEV 1  = 86 ± 13%) and 16 age- and gender-matched controls underwent measurements of: a) central arterial stiffness by pulse wave velocity, b) brachial flow-mediated dilation and c) forearm muscle oxygenation by near-infrared spectroscopy. Computed tomography quantified emphysema (% of low attenuation areas (LAA)) and airway disease., Results: Patients and controls were well matched for key clinical variables including co-morbidities burden. Thirteen patients presented with more than 5% LAA: emphysema extension was negatively related to transfer factor for carbon monoxide (TL CO ) (r = -0.63; p = .01). Compared to controls, patients had higher central arterial stiffness, lower normalized (to shear stress) flow-mediated dilation, delayed time to peak flow-mediated dilation and poorer muscle oxygenation (p < .05). TL CO and emphysema, but not airway disease, were significantly related to each of these functional abnormalities (r values ranging from 0.51 to 0.66; p < .05)., Conclusion: Systemic vascular dysfunction is present in the earlier stages of COPD, particularly in patients with greater emphysema burden and low TL CO . Regardless FEV 1 , patients showing those structural and functional abnormalities might be at higher risk of negative events thereby deserving closer follow-up for early detection of cardiovascular disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: It is currently unclear whether the additive effects of a long-acting beta(2)-agonist (LABA) and the antimuscarinic tiotropium bromide (TIO) on resting lung function are translated into lower operating lung volumes and improved exercise tolerance in patients with chronic obstructive pulmonary disease (COPD)., Methods: On a double-blind and cross-over study, 33 patients (FEV(1) = 47.4 +/- 12.9% predicted) were randomly allocated to 2-wk formoterol fumarate 12 microg twice-daily (FOR) plus TIO 18 microg once-daily or FOR plus placebo (PLA). Inspiratory capacity (IC) was obtained on constant-speed treadmill tests to the limit of tolerance (Tlim)., Results: FOR-TIO was superior to FOR-PLA in increasing post-treatment FEV(1) and Tlim (1.34 +/- 0.42 L vs. 1.25 +/- 0.39 L and 124 +/- 27% vs. 68 +/- 14%, respectively; p < 0.05). FOR-TIO slowed the rate of decrement in exercise IC compared to FOR-PLA (Deltaisotime-rest = -0.27 +/- 0.40 L vs. -0.45 +/- 0.36 L, p < 0.05). In addition, end-expiratory lung volume (% total lung capacity) was further reduced with FOR-TIO (p < 0.05). Of note, patients showing greater increases in Tlim with FOR-TIO (16/26, 61.6%) had more severe airways obstruction and lower exercise capacity at baseline. Improvement in Tlim with FOR-TIO was also related to larger increases in FEV(1) (p < 0.05)., Conclusions: Compared to FOR monotherapy, FOR-TIO further improved effort-induced dynamic hyperinflation and exercise endurance in patients with moderate-to-severe COPD. These beneficial consequences were more likely to be found in severely-disabled patients with larger resting functional responses to the combination therapy., Trial Registration: Clinicaltrials.gov Identifier: NCT00680056 [ClinicalTrials.gov].