Comprehensive Physiology Wiley Online Library

Factors Limiting Exercise Tolerance in Chronic Lung Diseases

Full Article on Wiley Online Library



Abstract

The major limitation to exercise performance in patients with chronic lung diseases is an issue of great importance since identifying the factors that prevent these patients from carrying out activities of daily living provides an important perspective for the choice of the appropriate therapeutic strategy. The factors that limit exercise capacity may be different in patients with different disease entities (i.e., chronic obstructive, restrictive or pulmonary vascular lung disease) or disease severity and ultimately depend on the degree of malfunction or miss coordination between the different physiological systems (i.e., respiratory, cardiovascular and peripheral muscles). This review focuses on patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pulmonary vascular disease (PVD). ILD and PVD are included because there is sufficient experimental evidence for the factors that limit exercise capacity and because these disorders are representative of restrictive and pulmonary vascular disorders, respectively. A great deal of emphasis is given, however, to causes of exercise intolerance in COPD mainly because of the plethora of research findings that have been published in this area and also because exercise intolerance in COPD has been used as a model for understanding the interactions of different pathophysiologic mechanisms in exercise limitation. As exercise intolerance in COPD is recognized as being multifactorial, the impacts of the following factors on patients’ exercise capacity are explored from an integrative physiological perspective: (i) imbalance between the ventilatory capacity and requirement; (ii) imbalance between energy demands and supplies to working respiratory and peripheral muscles; and (iii) peripheral muscle intrinsic dysfunction/weakness. © 2012 American Physiological Society. Compr Physiol 2:1779‐1817, 2012.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Conceptual framework of factors limiting exercise tolerance in COPD. (A) Mismatch of ventilatory capacity and ventilatory demand/workload. Ventilatory capacity is reduced in patients with COPD and is thus insufficient to match the ventilatory requirement and increased workload. Such a mismatch leads to intense dyspnea sensations. PEEP, positive end‐expiratory pressure; , dead space/tidal volume. (B) Reduced O2 delivery to respiratory and locomotor muscles. During intense exercise, the perfusion to locomotor and respiratory muscles provides insufficient O2 to meet the demands. Under these circumstances an autonomic reflex has been proposed to adjust the relative distribution of blood flow to respiratory and locomotor muscles. During exercise with expiratory flow limitation, the expiratory muscles may develop increased pressure in an attempt to increase flow, which may result in a Valsalva‐like maneuver decreasing venous return and pulmonary capillary blood volume, thereby further impairing energy delivery to the working muscles. Reduced oxygen delivery to working locomotor muscles may terminate exercise because of exaggerated leg discomfort. Ppl, Pleural pressure; Pab, abdominal pressure; Palv, alveolar pressure. (C) Peripheral muscle dysfunction. Systemic and/or muscle inflammation and oxidative stress can independently trigger muscle dysfunction by acting on mitochondria and myofilament properties. Inflammation and oxidative stress are interrelated mechanisms that could create a closed loop of persistence and amplification of the skeletal muscle abnormalities in patients with COPD. Ultimately peripheral muscle dysfunction can limit exercise tolerance due to leg muscle fatigue and accompanied increased leg discomfort.

Figure 2. Figure 2.

Dynamic regulation of lung volumes during exercise in chronic lung diseases. Behavior of dynamically operating lung volumes as a function of minute ventilation during exercise of increasing intensity in: a young male athlete (A), an age‐matched healthy elderly individual (B), a patient with severe chronic obstructive pulmonary disease (COPD) (C), a patient with moderate interstitial lung disease (ILD) (D) and a patient with pulmonary vascular disease (PVD) (E). Note the reduced peak ventilation, severe constraints on tidal volume () expansion, diminished resting and dynamic inspiratory capacity (IC) and inspiratory reserve volume (IRV) in COPD, PVD and ILD compared with healthy people. In COPD, tidal volume restriction is the result of static and dynamic lung hyperinflation (increased end‐expiratory lung volume, EELV). Residual volume (RV) is also increased in COPD. In ILD and PVD, tidal volume restriction is related to reduced total lung capacity (TLC), IRV, EELV and RV.

Figure 3. Figure 3.

Arterial oxygen and carbon dioxide tension during exercise in chronic lung diseases. Arterial oxygen tension (Pao2) and carbon dioxide tension (PaCO2) as a function of oxygen uptake at rest and exercise in: COPD (A and B); ILD (C and D); PVD (E and F). Exercise usually causes Pao2 to fall in all three diseases. PaCO2 often rises in COPD but falls or does not change in ILD and PVD. □: Healthy subjects, Wagner et al. (); •: Wagner (); ⧫: Dantzker and D'Alonzo (); ▴: Stewart and Lewis (); ▵: Agusti et al. (); ○: Dantzker et al. (); ▿: D'Alonzo et al. (). Adapted, with permission, from Agusti et al. ().

Figure 4. Figure 4.

Minute ventilation and cardiac output during exercise in chronic lung diseases. Minute ventilation (VE) and cardiac output as a function of oxygen uptake at rest and during exercise in patients with COPD (A and B); ILD (C and D); PVD (E and F). □: Healthy subjects, Wagner et al. (); •: Wagner (); ▾: Agusti et al. (); ▪: Dantzker and D'Alonzo (); ▴: Stewart et al. (); ▵: Agusti et al. (); ○: Dantzker et al. (); ▿: D'Alonzo et al. (); Ñ: Vogiatzis et al. (); *: Oelberg et al. (). Adapted, with permission, from Agusti et al. ().

Figure 5. Figure 5.

Pulmonary artery pressure and pulmonary vascular resistance during exercise in patients with chronic lung diseases. (A) Mean pulmonary artery pressure as a function of cardiac output in normal subjects and in patients with COPD, ILD, and PVD. There is elevated mean pulmonary pressure at rest and during exercise. ▪: COPD. Dantzker and D'Alonzo (); ▾: PVD, Dantzker et al. () •: PVD, D'Alonzo et al. (); ▴: ILD, Acusti et al. (); ○: Healthy subjects, Wagner et al. (). Adapted, with permission, from Agusti et al. (). Mean total pulmonary vascular resistance at rest (B) and during exercise (C) in normal subjects and in patients with COPD, ILD, and PVD. Contrary to normal subjects, patients with lung disease do not decrease pulmonary vascular resistance during exercise. Normal (open squares): Wagner et al. (); ILD (hach‐line squares]: Agusti et al. (); COPD (dotted‐line squares): Agusti et al. (); PVD (vertical‐line squares): D'Alonzo et al. (). Adapted, with permission, from Agusti et al. ().

Figure 6. Figure 6.

Quadriceps muscle strength and fiber type‐I distribution as a function of FEV1 percentage of predicted value in COPD (A) (r = 0.55, p < 0.0005). Adapted, with permission, from Bernard et al. (). (B) Relationships between vastus lateralis fiber type‐I distribution and FEV1 percentage of predicted value (r = 0.56, p < 0.001). Adapted, with permission, from Gosker et al. ().

Figure 7. Figure 7.

Breathing variables during incremental exercise in COPD patients and healthy age‐matched subjects. Dyspnea intensity (A), breathing frequency (B), operating lung volumes (D), and effort‐displacement ratio (E) shown in patients with COPD and age‐matched healthy individuals during incremental exercise. Dyspnea intensity is greater and breathing pattern is relatively rapid and shallow in COPD compared with healthy subjects (A, B). In COPD, tidal volume () takes up a larger proportion of the reduced inspiratory capacity (IC) at any given ventilation (D); mechanical constraints on tidal volume expansion are additionally compounded because of dynamic hyperinflation during exercise (D). In COPD compared with healthy subjects, tidal inspiratory pressure swings expressed as a fraction of their maximal force‐generating capacity (Pes/PImax) are greater and the response expressed as a fraction of the predicted vital capacity (VC) is reduced, that is, the effort‐displacement ratio is increased (E). TLC, total lung capacity; F, breathing frequency. Adapted and modified, with permission, from O'Donnell et al. (). The relationship between minute ventilation and whole‐body oxygen consumption and its respiratory and nonrespiratory energy expenditure components are shown for control‐healthy subjects (C) and COPD patients (F) during incremental exercise. Adapted and modified, with permission, from Levison and Cherniack ().

Figure 8. Figure 8.

Effect of heliox breathing on respiratory muscle load and power during exercise in COPD. (A) Total respiratory muscle power, (B) rib cage muscle power, (C) pressure‐time product for the diaphragm (PTPdi), (D) peak expiratory gastric pressure, (E) tidal excursion in transdiaphragmatic pressure (ΔPdi), and (F) pressure‐time product for expiratory abdominal muscles (PTPab) recorded at different fractions of peak work rate (WRpeak) during exercise whilst breathing normoxic heliox (open triangles) or room air (filled triangles). Asterisks denote significant differences between exercise whilst breathing heliox versus exercise in room air at an identical fraction of peak work rate, whereas crosses denote significant differences compared to exercise at 100% WRpeak in room air. Adapted, with permission, from Vogiatzis et al. ().

Figure 9. Figure 9.

Effect of heliox breathing on central hemodynamic responses during exercise in COPD. (A) cardiac output, (B) stroke volume, (C) arterial oxygen content (CaO2), (D) heart rate, (E) systemic vascular conductance, and (F) systemic oxygen delivery measured at different fractions of peak work rate (WRpeak) during exercise whilst breathing normoxic heliox (open triangles) or room air (filled triangles). Asterisks denote significant differences between exercise whilst breathing heliox versus exercise in room air at an identical fraction of WRpeak. Adapted, with permission, from Vogiatzis et al. ().

Figure 10. Figure 10.

Ventilatory and gas exchange responses during incremental exercise in chronic lung diseases. Typical exercise responses in COPD (▵) interstitial lung disease (ILD: •), PVD (▪) as well as healthy age‐matched subjects (‐‐‐‐‐) for: (A) dyspnea; (B) dead space ()/tidal volume () ratio; (C) cardiac frequency (fc); (D) ventilation; (E) arterial oxygen tension; (F) arterial carbon dioxide tension; (G) oxygen uptake; and (H) respiratory frequency (fR). Responses plotted as a function of oxygen uptake (o2), or work rate or tidal volume as a percentage of predicted vital capacity (VC). Adapted, with permission, from O’ Donnell et al. ().

Figure 11. Figure 11.

Power output and minute ventilation as a function of exercise endurance time in COPD. The power output endurance time relationship in response to four progressively intense exercise loads (WR1: ∼80% max; WR2: ∼90% max; WR3: ∼90%‐110% max; WR4: ∼110%‐130% max) and its determinants in healthy control matched by age subjects (left panels, A and C) and COPD patients (right panels, B and D). Note the different range of values for the power axes in the two groups. (A and B) Patients’ ventilation was not significantly different from the maximum voluntary capacity (MVC) at all intensities, whereas ventilation was an inverse function of endurance time in the control subjects. Adapted, with permission, from Neder et al. ().

Figure 12. Figure 12.

On‐transient kinetic responses during constant‐load exercise in COPD. (A) Pulmonary oxygen uptake kinetics (o2) kinetics at the onset of heavy‐intensity exercise in a patient with COPD (closed circles) and a representative age‐matched healthy individual (open circles). Note the slower kinetics [higher time constant (τ) of the “primary” component] in the COPD patient compared with the control subject. Adapted, with permission, from Chiappa et al. (). (B) Cardiac output (Qt) adjustment at the onset of heavy‐intensity exercise in a patient with COPD (closed circles) and a representative age‐matched control (open circles). Note the slower “central” cardiovascular adaptation to exercise [higher time constant (τ) of the “primary” component] in the COPD patient compared with the control subject. Adapted, with permission, from Chiappa et al. (). (C) Changes in quadriceps muscle deoxyhemoglobin [HHb] measured by near‐infrared spectroscopy at the onset of heavy‐intensity exercise in a patient with COPD (closed circles) and a representative age‐matched healthy individual (open circles). Values are expressed relative to the change of variation found in each test. Note the faster kinetics (lower mean response time (MRT) = τ + TD) in the COPD patient, that is, oxygen extraction rate was faster in COPD than control. Adapted, with permission, from Chiappa et al. ()

Figure 13. Figure 13.

Anaerobic threshold as a function of muscular morphology in patients with pulmonary arterial hypertension. Correlation between oxygen uptake at anaerobic threshold (AT) and (A) citrate synthase (CS) level, (B) 3‐hydroxyacyl‐CoA‐dehydrogenase (HADH) level, and (C) capillaries/type‐I fiber ratio (Cap/Type‐I) in patients with idiopathic pulmonary arterial hypertension. Adapted, with permission, from Mainguy et al. ().

Figure 14. Figure 14.

Quadriceps muscle strength in patients with pulmonary arterial hypertension. Nonvolitional (potentiated quadriceps twitches) and voluntary strength of the dominant quadriceps in patients with idiopathic pulmonary arterial hypertension (white bars) and matched sedentary controls (black bars). Adapted, with permission, from Mainguy et al. ().



Figure 1.

Conceptual framework of factors limiting exercise tolerance in COPD. (A) Mismatch of ventilatory capacity and ventilatory demand/workload. Ventilatory capacity is reduced in patients with COPD and is thus insufficient to match the ventilatory requirement and increased workload. Such a mismatch leads to intense dyspnea sensations. PEEP, positive end‐expiratory pressure; , dead space/tidal volume. (B) Reduced O2 delivery to respiratory and locomotor muscles. During intense exercise, the perfusion to locomotor and respiratory muscles provides insufficient O2 to meet the demands. Under these circumstances an autonomic reflex has been proposed to adjust the relative distribution of blood flow to respiratory and locomotor muscles. During exercise with expiratory flow limitation, the expiratory muscles may develop increased pressure in an attempt to increase flow, which may result in a Valsalva‐like maneuver decreasing venous return and pulmonary capillary blood volume, thereby further impairing energy delivery to the working muscles. Reduced oxygen delivery to working locomotor muscles may terminate exercise because of exaggerated leg discomfort. Ppl, Pleural pressure; Pab, abdominal pressure; Palv, alveolar pressure. (C) Peripheral muscle dysfunction. Systemic and/or muscle inflammation and oxidative stress can independently trigger muscle dysfunction by acting on mitochondria and myofilament properties. Inflammation and oxidative stress are interrelated mechanisms that could create a closed loop of persistence and amplification of the skeletal muscle abnormalities in patients with COPD. Ultimately peripheral muscle dysfunction can limit exercise tolerance due to leg muscle fatigue and accompanied increased leg discomfort.



Figure 2.

Dynamic regulation of lung volumes during exercise in chronic lung diseases. Behavior of dynamically operating lung volumes as a function of minute ventilation during exercise of increasing intensity in: a young male athlete (A), an age‐matched healthy elderly individual (B), a patient with severe chronic obstructive pulmonary disease (COPD) (C), a patient with moderate interstitial lung disease (ILD) (D) and a patient with pulmonary vascular disease (PVD) (E). Note the reduced peak ventilation, severe constraints on tidal volume () expansion, diminished resting and dynamic inspiratory capacity (IC) and inspiratory reserve volume (IRV) in COPD, PVD and ILD compared with healthy people. In COPD, tidal volume restriction is the result of static and dynamic lung hyperinflation (increased end‐expiratory lung volume, EELV). Residual volume (RV) is also increased in COPD. In ILD and PVD, tidal volume restriction is related to reduced total lung capacity (TLC), IRV, EELV and RV.



Figure 3.

Arterial oxygen and carbon dioxide tension during exercise in chronic lung diseases. Arterial oxygen tension (Pao2) and carbon dioxide tension (PaCO2) as a function of oxygen uptake at rest and exercise in: COPD (A and B); ILD (C and D); PVD (E and F). Exercise usually causes Pao2 to fall in all three diseases. PaCO2 often rises in COPD but falls or does not change in ILD and PVD. □: Healthy subjects, Wagner et al. (); •: Wagner (); ⧫: Dantzker and D'Alonzo (); ▴: Stewart and Lewis (); ▵: Agusti et al. (); ○: Dantzker et al. (); ▿: D'Alonzo et al. (). Adapted, with permission, from Agusti et al. ().



Figure 4.

Minute ventilation and cardiac output during exercise in chronic lung diseases. Minute ventilation (VE) and cardiac output as a function of oxygen uptake at rest and during exercise in patients with COPD (A and B); ILD (C and D); PVD (E and F). □: Healthy subjects, Wagner et al. (); •: Wagner (); ▾: Agusti et al. (); ▪: Dantzker and D'Alonzo (); ▴: Stewart et al. (); ▵: Agusti et al. (); ○: Dantzker et al. (); ▿: D'Alonzo et al. (); Ñ: Vogiatzis et al. (); *: Oelberg et al. (). Adapted, with permission, from Agusti et al. ().



Figure 5.

Pulmonary artery pressure and pulmonary vascular resistance during exercise in patients with chronic lung diseases. (A) Mean pulmonary artery pressure as a function of cardiac output in normal subjects and in patients with COPD, ILD, and PVD. There is elevated mean pulmonary pressure at rest and during exercise. ▪: COPD. Dantzker and D'Alonzo (); ▾: PVD, Dantzker et al. () •: PVD, D'Alonzo et al. (); ▴: ILD, Acusti et al. (); ○: Healthy subjects, Wagner et al. (). Adapted, with permission, from Agusti et al. (). Mean total pulmonary vascular resistance at rest (B) and during exercise (C) in normal subjects and in patients with COPD, ILD, and PVD. Contrary to normal subjects, patients with lung disease do not decrease pulmonary vascular resistance during exercise. Normal (open squares): Wagner et al. (); ILD (hach‐line squares]: Agusti et al. (); COPD (dotted‐line squares): Agusti et al. (); PVD (vertical‐line squares): D'Alonzo et al. (). Adapted, with permission, from Agusti et al. ().



Figure 6.

Quadriceps muscle strength and fiber type‐I distribution as a function of FEV1 percentage of predicted value in COPD (A) (r = 0.55, p < 0.0005). Adapted, with permission, from Bernard et al. (). (B) Relationships between vastus lateralis fiber type‐I distribution and FEV1 percentage of predicted value (r = 0.56, p < 0.001). Adapted, with permission, from Gosker et al. ().



Figure 7.

Breathing variables during incremental exercise in COPD patients and healthy age‐matched subjects. Dyspnea intensity (A), breathing frequency (B), operating lung volumes (D), and effort‐displacement ratio (E) shown in patients with COPD and age‐matched healthy individuals during incremental exercise. Dyspnea intensity is greater and breathing pattern is relatively rapid and shallow in COPD compared with healthy subjects (A, B). In COPD, tidal volume () takes up a larger proportion of the reduced inspiratory capacity (IC) at any given ventilation (D); mechanical constraints on tidal volume expansion are additionally compounded because of dynamic hyperinflation during exercise (D). In COPD compared with healthy subjects, tidal inspiratory pressure swings expressed as a fraction of their maximal force‐generating capacity (Pes/PImax) are greater and the response expressed as a fraction of the predicted vital capacity (VC) is reduced, that is, the effort‐displacement ratio is increased (E). TLC, total lung capacity; F, breathing frequency. Adapted and modified, with permission, from O'Donnell et al. (). The relationship between minute ventilation and whole‐body oxygen consumption and its respiratory and nonrespiratory energy expenditure components are shown for control‐healthy subjects (C) and COPD patients (F) during incremental exercise. Adapted and modified, with permission, from Levison and Cherniack ().



Figure 8.

Effect of heliox breathing on respiratory muscle load and power during exercise in COPD. (A) Total respiratory muscle power, (B) rib cage muscle power, (C) pressure‐time product for the diaphragm (PTPdi), (D) peak expiratory gastric pressure, (E) tidal excursion in transdiaphragmatic pressure (ΔPdi), and (F) pressure‐time product for expiratory abdominal muscles (PTPab) recorded at different fractions of peak work rate (WRpeak) during exercise whilst breathing normoxic heliox (open triangles) or room air (filled triangles). Asterisks denote significant differences between exercise whilst breathing heliox versus exercise in room air at an identical fraction of peak work rate, whereas crosses denote significant differences compared to exercise at 100% WRpeak in room air. Adapted, with permission, from Vogiatzis et al. ().



Figure 9.

Effect of heliox breathing on central hemodynamic responses during exercise in COPD. (A) cardiac output, (B) stroke volume, (C) arterial oxygen content (CaO2), (D) heart rate, (E) systemic vascular conductance, and (F) systemic oxygen delivery measured at different fractions of peak work rate (WRpeak) during exercise whilst breathing normoxic heliox (open triangles) or room air (filled triangles). Asterisks denote significant differences between exercise whilst breathing heliox versus exercise in room air at an identical fraction of WRpeak. Adapted, with permission, from Vogiatzis et al. ().



Figure 10.

Ventilatory and gas exchange responses during incremental exercise in chronic lung diseases. Typical exercise responses in COPD (▵) interstitial lung disease (ILD: •), PVD (▪) as well as healthy age‐matched subjects (‐‐‐‐‐) for: (A) dyspnea; (B) dead space ()/tidal volume () ratio; (C) cardiac frequency (fc); (D) ventilation; (E) arterial oxygen tension; (F) arterial carbon dioxide tension; (G) oxygen uptake; and (H) respiratory frequency (fR). Responses plotted as a function of oxygen uptake (o2), or work rate or tidal volume as a percentage of predicted vital capacity (VC). Adapted, with permission, from O’ Donnell et al. ().



Figure 11.

Power output and minute ventilation as a function of exercise endurance time in COPD. The power output endurance time relationship in response to four progressively intense exercise loads (WR1: ∼80% max; WR2: ∼90% max; WR3: ∼90%‐110% max; WR4: ∼110%‐130% max) and its determinants in healthy control matched by age subjects (left panels, A and C) and COPD patients (right panels, B and D). Note the different range of values for the power axes in the two groups. (A and B) Patients’ ventilation was not significantly different from the maximum voluntary capacity (MVC) at all intensities, whereas ventilation was an inverse function of endurance time in the control subjects. Adapted, with permission, from Neder et al. ().



Figure 12.

On‐transient kinetic responses during constant‐load exercise in COPD. (A) Pulmonary oxygen uptake kinetics (o2) kinetics at the onset of heavy‐intensity exercise in a patient with COPD (closed circles) and a representative age‐matched healthy individual (open circles). Note the slower kinetics [higher time constant (τ) of the “primary” component] in the COPD patient compared with the control subject. Adapted, with permission, from Chiappa et al. (). (B) Cardiac output (Qt) adjustment at the onset of heavy‐intensity exercise in a patient with COPD (closed circles) and a representative age‐matched control (open circles). Note the slower “central” cardiovascular adaptation to exercise [higher time constant (τ) of the “primary” component] in the COPD patient compared with the control subject. Adapted, with permission, from Chiappa et al. (). (C) Changes in quadriceps muscle deoxyhemoglobin [HHb] measured by near‐infrared spectroscopy at the onset of heavy‐intensity exercise in a patient with COPD (closed circles) and a representative age‐matched healthy individual (open circles). Values are expressed relative to the change of variation found in each test. Note the faster kinetics (lower mean response time (MRT) = τ + TD) in the COPD patient, that is, oxygen extraction rate was faster in COPD than control. Adapted, with permission, from Chiappa et al. ()



Figure 13.

Anaerobic threshold as a function of muscular morphology in patients with pulmonary arterial hypertension. Correlation between oxygen uptake at anaerobic threshold (AT) and (A) citrate synthase (CS) level, (B) 3‐hydroxyacyl‐CoA‐dehydrogenase (HADH) level, and (C) capillaries/type‐I fiber ratio (Cap/Type‐I) in patients with idiopathic pulmonary arterial hypertension. Adapted, with permission, from Mainguy et al. ().



Figure 14.

Quadriceps muscle strength in patients with pulmonary arterial hypertension. Nonvolitional (potentiated quadriceps twitches) and voluntary strength of the dominant quadriceps in patients with idiopathic pulmonary arterial hypertension (white bars) and matched sedentary controls (black bars). Adapted, with permission, from Mainguy et al. ().

References
 1.ATS statement: Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159: S1‐S40, 1999.
 2. ATS statement: Guidelines for the six‐minute walk test. Am J Respir Crit Care Med 166: 111‐117, 2002.
 3. ATS/ACCP: Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167: 211‐277, 2003.
 4. Aaron EA, Seow KC, Johnson BD, Dempsey JA. Oxygen cost of exercise hyperpnea: Implications for performance. J Appl Physiol 72: 1818‐1825, 1992.
 5. Aguggini G, Clement MG, Widdicombe JG. Lung reflexes affecting the larynx in the pig, and the effect of pulmonary microembolism. Q J Exp Physiol 72: 95‐104, 1987.
 6. Agusti AG. Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2: 367‐370; discussion 371‐362, 2005.
 7. Agusti AG, Barbera JA. Contribution of multiple inert gas elimination technique to pulmonary medicine. 2. Chronic pulmonary diseases: Chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Thorax 49: 924‐932, 1994.
 8. Agusti AG, Barbera JA, Roca J, Wagner PD, Guitart R, Rodriguez‐Roisin R. Hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary disease. Chest 97: 268‐275, 1990.
 9. Agusti AG, Cotes J, Wagner PD. Responses to exercise in lung diseases. In: Roca J, Whipp BJ, editors. European Respiratory Monograph. UK: ERS Journals, 1997, p. 32‐50.
 10. Agusti AG, Roca J, Gea J, Wagner PD, Xaubet A, Rodriguez‐Roisin R. Mechanisms of gas‐exchange impairment in idiopathic pulmonary fibrosis. Am Rev Respir Dis 143: 219‐225, 1991.
 11. Agusti AG, Roca J, Rodriguez‐Roisin R, Xaubet A, Agusti‐Vidal A. Different patterns of gas exchange response to exercise in asbestosis and idiopathic pulmonary fibrosis. Eur Respir J 1: 510‐516, 1988.
 12. Agusti AG, Sauleda J, Miralles C, Gomez C, Togores B, Sala E, Batle S, Busquets X. Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 166: 485‐489, 2002.
 13. Agusti C, Xaubet A, Agusti AG, Roca J, Ramirez J, Rodriguez‐Roisin R. Clinical and functional assessment of patients with idiopathic pulmonary fibrosis: Results of a 3‐year follow‐up. Eur Respir J 7: 643‐650, 1994.
 14. Aliverti A, Cala SJ, Duranti R, Ferrigno G, Kenyon CM, Pedotti A, Scano G, Sliwinski P, Macklem PT, Yan S. Human respiratory muscle actions and control during exercise. J Appl Physiol 83: 1256‐1269, 1997.
 15. Aliverti A, Macklem PT. How and why exercise is impaired in COPD. Respiration 68: 229‐239, 2001.
 16. Aliverti A, Macklem PT. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol 105: 749‐751, 2008.
 17. Aliverti A, Rodger K, Dellaca RL, Stevenson N, Lo Mauro A, Pedotti A, Calverley PM. Effect of salbutamol on lung function and chest wall volumes at rest and during exercise in COPD. Thorax 60: 916‐924, 2005.
 18. Aliverti A, Stevenson N, Dellaca RL, Lo Mauro A, Pedotti A, Calverley PM. Regional chest wall volumes during exercise in chronic obstructive pulmonary disease. Thorax 59: 210‐216, 2004.
 19. Allaire J, Maltais F, Doyon JF, Noel M, LeBlanc P, Carrier G, Simard C, Jobin J. Peripheral muscle endurance and the oxidative profile of the quadriceps in patients with COPD. Thorax 59: 673‐678, 2004.
 20. Altose MD, McCauley WC, Kelsen SG, Cherniack NS. Effects of hypercapnia and inspiratory flow‐resistive loading on respiratory activity in chronic airways obstruction. J Clin Invest 59: 500‐507, 1977.
 21. Amann M, Regan MS, Kobitary M, Eldridge MW, Boutellier U, Pegelow DF, Dempsey JA. Impact of pulmonary system limitations on locomotor muscle fatigue in patients with COPD. Am J Physiol Regul Integr Comp Physiol 299: R314‐R324, 2010.
 22. Athanasopoulos D, Louvaris Z, Cherouveim E, Andrianopoulos V, Roussos C, Zakynthinos S, Vogiatzis I. Expiratory muscle loading increases intercostal muscle blood flow during leg exercise in healthy humans. J Appl Physiol 109: 388‐395, 2010.
 23. Austrian R, McClement J, Renzetti AJ, Donald K, Riley R, Cournand A. Clinical and physiologic features of some types of pulmonary diseases with impairment of alveolar‐capillary diffusion: The syndrome of “alveolar‐capillary block.” Am J Med 11: 667‐685, 1951.
 24. Babb TG, Viggiano R, Hurley B, Staats B, Rodarte JR. Effect of mild‐to‐moderate airflow limitation on exercise capacity. J Appl Physiol 70: 223‐230, 1991.
 25. Barbera JA, Roca J, Ramirez J, Wagner PD, Ussetti P, Rodriguez‐Roisin R. Gas exchange during exercise in mild chronic obstructive pulmonary disease: Correlation with lung structure. Am Rev Respir Dis 144: 520‐525, 1991.
 26. Barreiro E, Rabinovich R, Marin‐Corral J, Barbera JA, Gea J, Roca J. Chronic endurance exercise induces quadriceps nitrosative stress in patients with severe COPD. Thorax 64: 13‐19, 2009.
 27. Baughman P, Gerson M, Bosken C. Right and left ventricular function at rest and with exercise in patients with sarcoidosis. Chest 85: 301‐306, 1984.
 28. Begin P, Grassino A. Inspiratory muscle dysfunction and chronic hypercapnia in chronic obstructive pulmonary disease. Am Rev Respir Dis 143: 905‐912, 1991.
 29. Belman M, Botnick W, Shin J. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 153: 967‐975, 1996.
 30. Bernard S, LeBlanc P, Whittom F, Carrier G, Jobin J, Belleau R, Maltais F. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 158: 629‐634, 1998.
 31. Berton DC, Barbosa PB, Takara LS, Chiappa GR, Siqueira AC, Bravo DM, Ferreira LF, Neder JA. Bronchodilators accelerate the dynamics of muscle O2 delivery and utilisation during exercise in COPD. Thorax 65: 588‐593, 2010.
 32. Biolo G, Toigo G, Ciocchi B, Situlin R, Iscra F, Gullo A, Guarnieri G. Metabolic response to injury and sepsis: Changes in protein metabolism. Nutrition 13: 52S‐57S, 1997.
 33. Booth F, Gollnick P. Effects of disease on the structure and function of skeletal muscle. Med Sci Sports Exerc 15: 415‐420, 1983.
 34. Boots AW, Haenen GR, Bast A. Oxidant metabolism in chronic obstructive pulmonary disease. Eur Respir J Suppl 46: 14S‐27S, 2003.
 35. Borghi‐Silva A, Carrascosa C, Oliveira CC, Barroco AC, Berton DC, Vilaca D, Lira‐Filho EB, Ribeiro D, Nery LE, Neder JA. Effects of respiratory muscle unloading on leg muscle oxygenation and blood volume during high‐intensity exercise in chronic heart failure. Am J Physiol Heart Circ Physiol 294: H2465‐H2472, 2008.
 36. Bridevaux PO, Gerbase MW, Probst‐Hensch NM, Schindler C, Gaspoz JM, Rochat T. Long‐term decline in lung function, utilisation of care and quality of life in modified GOLD stage 1 COPD. Thorax 63: 768‐774, 2008.
 37. Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax 61: 17‐22, 2006.
 38. Broussard SR, McCusker RH, Novakofski JE, Strle K, Shen WH, Johnson RW, Freund GG, Dantzer R, Kelley KW. Cytokine‐hormone interactions: Tumor necrosis factor alpha impairs biologic activity and downstream activation signals of the insulin‐like growth factor I receptor in myoblasts. Endocrinology 144: 2988‐2996, 2003.
 39. Buck M, Chojkier M. Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J 15: 1753‐1765, 1996.
 40. Bush A, Busst C. Cardiovascular function at rest and on exercise in patients with cryptogenic fibrosing alveolitis. Thorax 43: 276‐283, 1988.
 41. Caron MA, Debigare R, Dekhuijzen PN, Maltais F. Comparative assessment of the quadriceps and the diaphragm in patients with COPD. J Appl Physiol 107: 952‐961, 2009.
 42. Casaburi R. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Med Sci Sports Exerc 33: S662‐S670, 2001.
 43. Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 127: 809‐817, 2005.
 44. Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner C, Wasserman K. Reduction in exercise lactic acidosis and ventilation as a result of exercise training in obstructive lung disease. Am Rev Respir Dis 143: 9‐18, 1991.
 45. Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF, Wasserman K. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Respir Dis 143: 9‐18, 1991.
 46. Wasserman K. Exercise tolerance in the pulmonary patient. In: Casaburi R, Petty TL, editors. Principles and practice of pulmonary rehabilitation. Philadelphia: Saunders, 1993a, p. 115‐123.
 47. Barstow TJ, Casaburi R. Ventilatory control in lung disease. In: Casaburi R, Petty TL, editors. Principles and Practice of Pulmonary Rehabilitation. Philadelphia: Saunders, 1993b, p. 50‐65.
 48. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body‐mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 350: 1005‐1012, 2004.
 49. Cherniack RM, Colby TV, Flint A, Thurlbeck WM, Waldron JA Jr, Ackerson L, Schwarz MI, King TE Jr. Correlation of structure and function in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 151: 1180‐1188, 1995.
 50. Chiappa GR, Borghi‐Silva A, Ferreira LF, Carrascosa C, Oliveira CC, Maia J, Gimenes AC, Queiroga F Jr, Berton D, Ferreira EM, Nery LE, Neder JA. Kinetics of muscle deoxygenation are accelerated at the onset of heavy‐intensity exercise in patients with COPD: Relationship to central cardiovascular dynamics. J Appl Physiol 104: 1341‐1350, 2008.
 51. Chiappa GR, Queiroga F Jr, Meda E, Ferreira LF, Diefenthaeler F, Nunes M, Vaz MA, Machado MC, Nery LE, Neder JA. Heliox improves oxygen delivery and utilization during dynamic exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 179: 1004‐1010, 2009.
 52. Chrystyn H, Mulley BA, Peake MD. Dose response relation to oral theophylline in severe chronic obstructive airways disease. BMJ 297: 1506‐1510, 1988.
 53. Coggan AR, Spina RJ, King DS, Rogers MA, Brown M, Nemeth PM, Holloszy JO. Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women. J Gerontol 47: B71‐B76, 1992.
 54. Couillard A, Prefaut C. From muscle disuse to myopathy in COPD: Potential contribution of oxidative stress. Eur Respir J 26: 703‐719, 2005.
 55. Coyle EF, Martin WH 3rd, Bloomfield SA, Lowry OH, Holloszy JO. Effects of detraining on responses to submaximal exercise. J Appl Physiol 59: 853‐859, 1985.
 56. Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA. Interstitial lung diseases of unknown cause. Disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 310: 235‐244, 1984.
 57. Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA. Interstitial lung diseases of unknown cause: Disorders characterized by chronic inflammation of the lower respiratory tract (first of two parts). N Engl J Med 310: 154‐166, 1984.
 58. D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M. Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 115: 343‐349, 1991.
 59. D'Alonzo GE, Gianotti LA, Pohil RL, Reagle RR, DuRee SL, Fuentes F, Dantzker DR. Comparison of progressive exercise performance of normal subjects and patients with primary pulmonary hypertension. Chest 92: 57‐62, 1987.
 60. Dantzker DR, Bower JS. Pulmonary vascular tone improves VA/Q matching in obliterative pulmonary hypertension. J Appl Physiol 51: 607‐613, 1981.
 61. Dantzker DR, D'Alonzo GE. The effect of exercise on pulmonary gas exchange in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 134: 1135‐1139, 1986.
 62. Dantzker DR, D'Alonzo GE, Bower JS, Popat K, Crevey BJ. Pulmonary gas exchange during exercise in patients with chronic obliterative pulmonary hypertension. Am Rev Respir Dis 130: 412‐416, 1984.
 63. de Godoy I, Donahoe M, Calhoun WJ, Mancino J, Rogers RM. Elevated TNF‐alpha production by peripheral blood monocytes of weight‐losing COPD patients. Am J Respir Crit Care Med 153: 633‐637, 1996.
 64. De Troyer A, Leeper JB, McKenzie DK, Gandevia SC. Neural drive to the diaphragm in patients with severe COPD. Am J Respir Crit Care Med 155: 1335‐1340, 1997.
 65. Debigare R, Cote CH, Hould FS, LeBlanc P, Maltais F. In vitro and in vivo contractile properties of the vastus lateralis muscle in males with COPD. Eur Respir J 21: 273‐278, 2003.
 66. Debigare R, Maltais F. Last Word on Point: Counterpoint: The major limitation to exercise performance in COPD is (1) inadequate energy supply to the respiratory and locomotor muscles, (2) lower limb muscle dysfunction, and (3) dynamic hyperinflation. J Appl Physiol 105: 764, 2008.
 67. Debigare R, Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol 105: 751‐753; discussion 755‐757, 2008.
 68. Deboeck G, Niset G, Lamotte M, Vachiery JL, Naeije R. Exercise testing in pulmonary arterial hypertension and in chronic heart failure. Eur Respir J 23: 747‐751, 2004.
 69. Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid‐induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 153: 1958‐1964, 1996.
 70. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 150: 11‐16, 1994.
 71. Deesomchok A, Webb KA, Forkert L, Lam YM, Ofir D, Jensen D, O'Donnell DE. Lung hyperinflation and its reversibility in patients with airway obstruction of varying severity. COPD 7: 428‐437, 2010.
 72. DeLorey DS, Babb TG. Progressive mechanical ventilatory constraints with aging. Am J Respir Crit Care Med 160: 169‐177, 1999.
 73. DeLorey DS, Paterson DH, Kowalchuk JM. Effects of ageing on muscle O2 utilization and muscle oxygenation during the transition to moderate‐intensity exercise. Appl Physiol Nutr Metab 32: 1251‐1262, 2007.
 74. Dempsey JA, Harms CA, Ainsworth DM. Respiratory muscle perfusion and energetics during exercise. Med Sci Sports Exerc 28: 1123‐1128, 1996.
 75. Deschenes D, Pepin V, Saey D, LeBlanc P, Maltais F. Locus of symptom limitation and exercise response to bronchodilation in chronic obstructive pulmonary disease. J Cardiopulm Rehabil Prev 28: 208‐214, 2008.
 76. DeTroyer A, Pride N. The Chest Wall and Respiratory Muscles in Chronic Obstructive Pulmonary Disease. New York: Marcel Dekker, 1995.
 77. Di Carlo A, De Mori R, Martelli F, Pompilio G, Capogrossi MC, Germani A. Hypoxia inhibits myogenic differentiation through accelerated MyoD degradation. J Biol Chem 279: 16332‐16338, 2004.
 78. Di Francia M, Barbier D, Mege J, Orehek J. Tumor necrosis factoralpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 150: 1453‐1455, 1994.
 79. Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic‐Emil J, Lisboa C. Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest. Eur Respir J 16: 269‐275, 2000.
 80. Dillard TA, Piantadosi S, Rajagopal KR. Prediction of ventilation at maximal exercise in chronic airflow obstruction. Am Rev Respir Dis 132: 230‐235, 1985.
 81. Dodd DS, Brancatisano T, Engel LA. Chest wall mechanics during exercise in patients with severe chronic air‐flow obstruction. Am Rev Respir Dis 129: 33‐38, 1984.
 82. Doucet M, Debigare R, Joanisse DR, Cote C, Leblanc P, Gregoire J, Deslauriers J, Vaillancourt R, Maltais F. Adaptation of the diaphragm and the vastus lateralis in mild‐to‐moderate COPD. Eur Respir J 24: 971‐979, 2004.
 83. Eklund A, Broman L, Broman M, Holmgren A. V/Q and alveolar gas exchange in pulmonary sarcoidosis. Eur Respir J 2: 135‐144, 1989.
 84. Eliason G, Abdel‐Halim S, Arvidsson B, Kadi F, Piehl‐Aulin K. Physical performance and muscular characteristics in different stages of COPD. Scand J Med Sci Sports 19: 865‐870, 2009.
 85. Engelen M, Schols A, Does J. Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema. Am J Respir Crit Care Med 161: 98‐103, 2000.
 86. Engelen M, Schols A, Does J. Skeletal muscle weakness is associated with wasting of extremity fat‐free mass but not with airflow obstruction in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 71: 733‐738, 2000.
 87. Engelen MP, Schols AM, Baken WC, Wesseling GJ, Wouters EF. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in outpatients with COPD. Eur Respir J 7: 1793‐1797, 1994.
 88. Enson Y, Thomas HM 3rd, Bosken CH, Wood JA, Leroy EC, Blanc WA, Wigger HJ, Harvey RM, Cournand A. Pulmonary hypertension in interstitial lung disease: Relation of vascular resistance to abnormal lung structure. Trans Assoc Am Physicians 88: 248‐255, 1975.
 89. Escribano PM, Sanchez MA, de Atauri MJ, Frade JP, Garcia IM. Lung function testing in patients with pulmonary arterial hypertension. Arch Bronconeumol 41: 380‐384, 2005.
 90. Ferrazza A, Martolini D, Valli G, Pallange P. Cardiopulmonary exercise testing in the functional and prognostic evaluation of patients with pulmonary diseases. Respiration 77: 3‐17, 2009.
 91. Fiaccadori E, Coffrini E, Fracchia C, Rampulla C, Montagna T, Borghetti A. Hypophosphatemia and phosphorus depletion in respiratory and peripheral muscles of patients with respiratory failure due to COPD. Chest 105: 1392‐1398, 1994.
 92. Fiaccadori E, Coffrini E, Ronda N, Vezzani A, Cacciani G, Fracchia C, Rampulla C, Borghetti A. Hypophosphatemia in course of chronic obstructive pulmonary disease. Prevalence, mechanisms, and relationships with skeletal muscle phosphorus content. Chest 97: 857‐868, 1990.
 93. Fiaccadori E, Zambrelli P, Tortorella G. Physiopathology of respiratory muscles in malnutrition. Minerva Anestesiol 61: 93‐99, 1995.
 94. Franssen FM, Wouters EF, Schols AM. The contribution of starvation, deconditioning and ageing to the observed alterations in peripheral skeletal muscle in chronic organ diseases. Clin Nutr 21: 1‐14, 2002.
 95. Fulmer JD, Roberts WC, von Gal ER, Crystal RG. Morphologic‐physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis. J Clin Invest 63: 665‐676, 1979.
 96. Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deckers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke‐Zaba J. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The task force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Eur Heart J 25: 2243‐2278, 2004.
 97. Gallagher C. Exercise and chronic obstructive pulmonary disease. Med Clin North Am 74: 619‐641, 1990.
 98. Gallagher C. Exercise limitation and clinical exercise testing in chronic obstructive pulmonary disease. Clin Chest Med 15: 305‐326, 1994.
 99. Garcia‐Aymerich J, Serra I, Gomez FP, Farrero E, Balcells E, Rodriguez DA, de Batlle J, Gimeno E, Donaire‐Gonzalez D, Orozco‐Levi M, Sauleda J, Gea J, Rodriguez‐Roisin R, Roca J, Agusti AG, Anto JM. Physical activity and clinical and functional status in COPD. Chest 136: 62‐70, 2009.
 100. Gibson GJ, Pride NB. Pulmonary mechanics in fibrosing alveolitis: The effects of lung shrinkage. Am Rev Respir Dis 116: 637‐647, 1977.
 101.Global Initiative for Chronic Obstructive Lung Disease G. Executive Summary: Global Strategy for Diagnosis, Management, and Prevention of COPD. Medical Communication Resourches Inc, 2009, p. 1‐47.
 102. Gosker HR, Hesselink MK, Duimel H, Ward KA, Schols AM. Reduced mitochondrial density in the vastus lateralis muscle of patients with COPD. Eur Respir J 30: 73‐79, 2007.
 103. Gosker HR, Kubat B, Schaart G, van der Vusse GJ, Wouters EF, Schols AM. Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease. Eur Respir J 22: 280‐285, 2003.
 104. Gosker HR, van Mameren H, van Dijk PJ, Engelen MP, van der Vusse GJ, Wouters EF, Schols AM. Skeletal muscle fibre‐type shifting and metabolic profile in patients with chronic obstructive pulmonary disease. Eur Respir J 19: 617‐625, 2002.
 105. Gosker HR, Wouters EF, van der Vusse GJ, Schols AM. Skeletal muscle dysfunction in chronic obstructive pulmonary disease and chronic heart failure: Underlying mechanisms and therapy perspectives. Am J Clin Nutr 71: 1033‐1047, 2000.
 106. Gosker HR, Zeegers MP, Wouters EF, Schols AM. Muscle fibre‐type shifting in the vastus lateralis of patients with COPD is associated with disease severity: A systematic review and meta‐analysis. Thorax 62: 944‐949, 2007.
 107. Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med Sci Sports Exerc 153: 976‐980, 1996.
 108. Grimby G, Bunn J, Mead J. Relative contribution of rib cage and abdomen to ventilation during exercise. J Appl Physiol 24: 159‐166, 1968.
 109. Guenette JA, Vogiatzis I, Zakynthinos S, Athanasopoulos D, Koskolou M, Golemati S, Vasilopoulou M, Wagner HE, Roussos C, Wagner PD, Boushel R. Human respiratory muscle blood flow measured by near‐infrared spectroscopy and indocyanine green. J Appl Physiol 104: 1202‐1210, 2008.
 110. Guttadauria M, Ellman H, Kaplan D. Progressive systemic sclerosis: Pulmonary involvement. Clin Rheum Dis 5: 151‐166, 1979.
 111. Haddad F, Zaldivar F, Cooper DM, Adams GR. IL‐6‐induced skeletal muscle atrophy. J Appl Physiol 98: 911‐917, 2005.
 112. Hall‐Angeras M, Angeras M, Zamir O, Hasselgren P, Fischer J. Interaction between corticosterone and tumor necrosis factor stimulated protein breakdown in rat skeletal muscle similar to sepsis. Surgery 108: 440‐466, 1990.
 113. Hamer J. Cause of low arterial oxygen saturation in pulmonary fibrosis. Thorax 507‐514, 1964.
 114. Hamilton AL, Killian KJ, Summers E, Jones NL. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 152: 2021‐2031, 1995.
 115. Hamilton AL, Killian KJ, Summers E, Jones NL. Symptom intensity and subjective limitation to exercise in patients with cardiorespiratory disorders. Chest 110: 1255‐1263, 1996.
 116. Harms CA. Does gender affect pulmonary function and exercise capacity? Respir Physiol Neurobiol 151: 124‐131, 2006.
 117. Harms CA, Babcock MA, McClaran SR, Pegelow DF, Nickele GA, Nelson WB, Dempsey JA. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol 82: 1573‐1583, 1997.
 118. Harris‐Eze AO, Sridhar G, Clemens RE, Gallagher CG, Marciniuk DD. Oxygen improves maximal exercise performance in interstitial lung disease. Am J Respir Crit Care Med 150: 1616‐1622, 1994.
 119. Harris‐Eze AO, Sridhar G, Clemens RE, Zintel TA, Gallagher CG, Marciniuk DD. Role of hypoxemia and pulmonary mechanics in exercise limitation in interstitial lung disease. Am J Respir Crit Care Med 154: 994‐1001, 1996.
 120. Hawrylkiewicz I, Izdebska‐Makosa Z, Grebska E, Zielinski J. Pulmonary haemodynamics at rest and on exercise in patients with idiopathic pulmonary fibrosis. Bull Eur Physiopathol Respir 18: 403‐410, 1982.
 121. Hiraga T, Maekura R, Okuda Y, Okamoto T, Hirotani A, Kitada S, Yoshimura K, Yokota S, Ito M, Ogura T. Prognostic predictors for survival in patients with COPD using cardiopulmonary exercise testing. Clin Physiol Funct Imaging 23: 324‐331, 2003.
 122. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD‐related hospitalizations in the United States, 1979 to 2001. Chest 128: 2005‐2011, 2005.
 123. Holverda S, Gan CT, Marcus JT, Postmus PE, Boonstra A, Vonk‐Noordegraaf A. Impaired stroke volume response to exercise in pulmonary arterial hypertension. J Am Coll Cardiol 47: 1732‐1733, 2006.
 124. Hopkinson NS, Tennant RC, Dayer MJ, Swallow EB, Hansel TT, Moxham J, Polkey MI. A prospective study of decline in fat free mass and skeletal muscle strength in chronic obstructive pulmonary disease. Respir Res 8: 25, 2007.
 125. Hoppeler H, Vogt M, Weibel ER, Fluck M. Response of skeletal muscle mitochondria to hypoxia. Exp Physiol 88: 109‐119, 2003.
 126. Howald H, Hoppeler H, Claassen H, Mathieu O, Straub R. Influences of endurance training on the ultrastructural composition of the different muscle fiber types in humans. Pflugers Arch 403: 369‐376, 1985.
 127. Howald H, Pette D, Simoneau JA, Uber A, Hoppeler H, Cerretelli P. Effect of chronic hypoxia on muscle enzyme activities. Int J Sports Med 11(Suppl 1): S10‐S14, 1990.
 128. Hughes J, Lockwood D, Jones H, Clark R. DLCO/Q and diffusion limitation at rest and on exercise in patients with interstitial fibrosis. Respir Physiol 83: 155‐166, 1991.
 129. Hultman E, Del Canale S, Sjoholm H. Effect of induced metabolic acidosis on intracellular pH, buffer capacity and contraction force of human skeletal muscle. Clin Sci (Lond) 69: 505‐510, 1985.
 130. Hunter RB, Stevenson E, Koncarevic A, Mitchell‐Felton H, Essig DA, Kandarian SC. Activation of an alternative NF‐kappaB pathway in skeletal muscle during disuse atrophy. FASEB J 16: 529‐538, 2002.
 131. Hyatt RE. Expiratory flow limitation. J Appl Physiol 55: 1‐7, 1983.
 132. Jackman RW, Kandarian SC. The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol 287: C834‐C843, 2004.
 133. Jackson MJ, O'Farrell S. Free radicals and muscle damage. Br Med Bull 49: 630‐641, 1993.
 134. Jakobsson P, Jorfeldt L, Henriksson J. Metabolic enzyme activity in the quadriceps femoris muscle in patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 151: 374‐377, 1995.
 135. Janicki JS. Influence of the pericardium and ventricular interdependence on left ventricular diastolic and systolic function in patients with heart failure. Circulation 81: III15‐III20, 1990.
 136. Jernudd‐Wilhelmsson Y, Hornblad Y, Hedenstierna G. Ventilation‐perfusion relationships in interstitial lung disease. Eur J Respir Dis 68: 39‐49, 1986.
 137. Jezek V, Michalnanik A, Fucik J, Ramaisl R. Long‐term development of pulmonary arterial pressure in diffuse interstitial lung fibrosis. Prog Respir Res 20: 170‐175, 1985.
 138. Johnson BD, Badr MS, Dempsey JA. Impact of the aging pulmonary system on the response to exercise. Clin Chest Med 15: 229‐246, 1994.
 139. Johnson BD, Reddan WG, Pegelow DF, Seow KC, Dempsey JA. Flow limitation and regulation of functional residual capacity during exercise in a physically active aging population. Am Rev Respir Dis 143: 960‐967, 1991.
 140. Johnson BD, Reddan WG, Seow KC, Dempsey JA. Mechanical constraints on exercise hyperpnea in a fit aging population. Am Rev Respir Dis 143: 968‐977, 1991.
 141. Jörgensen K, Houltz E, Westfelt U, Nilsson F, Schersten H, Ricksten SE. Effects of lung volume reduction surgery on left ventricular diastolic filling and dimensions in patients with severe emphysema. Chest 124: 1863‐1870, 2003.
 142. Jörgensen K, Muller MF, Nel J, Upton RN, Houltz E, Ricksten SE. Reduced intrathoracic blood volume and left and right ventricular dimensions in patients with severe emphysema: An MRI study. Chest 131: 1050‐1057, 2007.
 143. Kelsen SG, Ference M, Kapoor S. Effects of prolonged undernutrition on structure and function of the diaphragm. J Appl Physiol 58: 1354‐1359, 1985.
 144. Killian KJ. Limitation to muscular activity in chronic obstructive pulmonary disease. Eur Respir J 24: 6‐7, 2004.
 145. Killian KJ, Summers E, Jones NL, Campbell EJ. Dyspnea and leg effort during incremental cycle ergometry. Am Rev Respir Dis 145: 1339‐1345, 1992.
 146. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: Scoring system and survival model. Am J Respir Crit Care Med 164: 1171‐1181, 2001.
 147. Knochel JP. Neuromuscular manifestations of electrolyte disorders. Am J Med 72: 521‐535, 1982.
 148. Koechlin C, Maltais F, Saey D, Michaud A, LeBlanc P, Hayot M, Prefaut C. Hypoxaemia enhances peripheral muscle oxidative stress in chronic obstructive pulmonary disease. Thorax 60: 834‐841, 2005.
 149. Laghi F, Jubran A, Topeli A, Fahey PJ, Garrity ER Jr, Arcidi JM, de Pinto DJ, Edwards LC, Tobin MJ. Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 157: 475‐483, 1998.
 150. Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: aging arteries: A “set up” for vascular disease. Circulation 107: 139‐146, 2003.
 151. Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part II: The aging heart in health: Links to heart disease. Circulation 107: 346‐354, 2003.
 152. Langen RC, Van Der Velden JL, Schols AM, Kelders MC, Wouters EF, Janssen‐Heininger YM. Tumor necrosis factor‐alpha inhibits myogenic differentiation through MyoD protein destabilization. FASEB J 18: 227‐237, 2004.
 153. Laude EA, Duffy NC, Baveystock C, Dougill B, Campbell MJ, Lawson R, Jones PW, Calverley PM. The effect of helium and oxygen on exercise performance in chronic obstructive pulmonary disease: A randomized crossover trial. Am J Respir Crit Care Med 173: 865‐870, 2006.
 154. Laveneziana P, Palange P, Ora J, Martolini D, O'Donnell DE. Bronchodilator effect on ventilatory, pulmonary gas exchange, and heart rate kinetics during high‐intensity exercise in COPD. Eur J Appl Physiol 107: 633‐643, 2009.
 155. Laveneziana P, Parker CM, O'Donnell DE. Ventilatory constraints and dyspnea during exercise in chronic obstructive pulmonary disease. Appl Physiol Nutr Metab 32: 1225‐1238, 2007.
 156. Laveneziana P, Valli G, Onorati P, Paoletti P, Ferrazza AM, Palange P. Effect of heliox on heart rate kinetics and dynamic hyperinflation during high‐intensity exercise in COPD. Eur J Appl Physiol 111: 225‐234, 2010.
 157. Levine S, Gregory C, Nguyen T, Shrager J, Kaiser L, Rubinstein N, Dudley G. Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD. J Appl Physiol 92: 1205‐1213, 2002.
 158. Levine S, Kaiser L, Leferovich J, Tikunov B. Cellular adaptations in the diaphragm in chronic obstructive pulmonary disease. N Engl J Med 337: 1799‐1806, 1997.
 159. Levine S, Nguyen T, Friscia M, Zhu J, Szeto W, Kucharczuk JC, Tikunov BA, Rubinstein NA, Kaiser LR, Shrager JB. Parasternal intercostal muscle remodeling in severe chronic obstructive pulmonary disease. J Appl Physiol 101: 1297‐1302, 2006.
 160. Levison H, Cherniack RM. Ventilatory cost of exercise in chronic obstructive pulmonary disease. J Appl Physiol 25: 21‐27, 1968.
 161. Li YP, Schwartz RJ, Waddell ID, Holloway BR, Reid MB. Skeletal muscle myocytes undergo protein loss and reactive oxygen‐mediated NF‐kappaB activation in response to tumor necrosis factor alpha. FASEB J 12: 871‐880, 1998.
 162. Light R, Mahutte C, Brown S. Etiology of carbon dioxide retention at rest and during exercise in chronic airflow obstruction. Chest 94: 61‐67, 1988.
 163. Light RW, Mintz HM, Linden GS, Brown SE. Hemodynamics of patients with severe chronic obstructive pulmonary disease during progressive upright exercise. Am Rev Respir Dis 130: 391‐395, 1984.
 164. Llesuy S, Evelson P, Gonzalez‐Flecha B, Peralta J, Carreras MC, Poderoso JJ, Boveris A. Oxidative stress in muscle and liver of rats with septic syndrome. Free Radic Biol Med 16: 445‐451, 1994.
 165. Llovera M, Garcia‐Martinez C, Agell N, Lopez‐Soriano F, Argiles J. TNF can directly induce the expression of ubiquitin‐dependent proteolytic system in rat soleus muscles. Biochem Biophys Res Commun 230: 238‐241, 1997.
 166. Loring SH, Garcia‐Jacques M, Malhotra A. Pulmonary characteristics in COPD and mechanisms of increased work of breathing. J Appl Physiol 107: 309‐314, 2009.
 167. Lupi‐Herrera E, Seoane M, Verdejo J, Gomez A, Sandoval J, Barrios R, Martinez W. Hemodynamic effects of hydralazine in interstitial lung disease patients with cor pulmonale. Chest 87: 564‐573, 1985.
 168. MacIntyre NR. Mechanisms of functional loss in patients with chronic lung disease. Respir Care 53: 1177‐1184, 2008.
 169. MacIntyre NR, Leatherman NE. Mechanical loads on the ventilatory muscles: A theoretical analysis. Am Rev Respir Dis 139: 968‐973, 1989.
 170. Macklem PT. Exercise in COPD: Damned if you do and damned if you don't. Thorax 60: 887‐888, 2005.
 171. Mador M, Bozkanat E, Kufel T. Quadriceps fatigue after cycle exercise in patients with COPD compared with healthy control subjects. Chest 123: 1104‐1111, 2003.
 172. Mador MJ, Deniz O, Aggarwal A, Kufel TJ. Quadriceps fatigability after single muscle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 168: 102‐108, 2003.
 173. Mador MJ, Kufel TJ, Pineda L. Quadriceps fatigue after cycle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161: 447‐453, 2000.
 174. Mador MJ, Kufel TJ, Pineda LA, Sharma GK. Diaphragmatic fatigue and high‐intensity exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161: 118‐123, 2000.
 175. Mador MJ, Kufel TJ, Pineda LA, Steinwald A, Aggarwal A, Upadhyay AM, Khan MA. Effect of pulmonary rehabilitation on quadriceps fatiguability during exercise. Am J Respir Crit Care Med 163: 930‐935, 2001.
 176. Magee F, Wright JL, Wiggs BR, Pare PD, Hogg JC. Pulmonary vascular structure and function in chronic obstructive pulmonary disease. Thorax 43: 183‐189, 1988.
 177. Mahler DA, Brent BN, Loke J, Zaret BL, Matthay RA. Right ventricular performance and central circulatory hemodynamics during upright exercise in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 130: 722‐729, 1984.
 178. Mainguy V, Maltais F, Saey D, Gagnon P, Martel S, Simon M, Provencher S. Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension. Thorax 65: 113‐117, 2010.
 179. Malaguti C, Nery LE, Dal Corso S, Napolis L, De Fuccio MB, Castro M, Neder JA. Scaling skeletal muscle function to mass in patients with moderate‐to‐severe COPD. Eur J Appl Physiol 98: 482‐488, 2006.
 180. Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, Kesten S, O'Donnell D. Improvements in symptom‐limited exercise performance over 8 h with once‐daily tiotropium in patients with COPD. Chest 128: 1168‐1178, 2005.
 181. Maltais F, LeBlanc P, Whittom F, Simard C, Marquis K, Belanger M, Breton MJ, Jobin J. Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD. Thorax 55: 848‐853, 2000.
 182. Maltais F, Simard AA, Simard C, Jobin J, Desgagnes P, LeBlanc P. Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am J Respir Crit Care Med 153: 288‐293, 1996.
 183. Maltais F, Simon M, Jobin J, Desmeules M, Sullivan MJ, Belanger M, Leblanc P. Effects of oxygen on lower limb blood flow and O2 uptake during exercise in COPD. Med Sci Sports Exerc 33: 916‐922, 2001.
 184. Maltais F, Sullivan MJ, LeBlanc P, Duscha BD, Schachat FH, Simard C, Blank JM, Jobin J. Altered expression of myosin heavy chain in the vastus lateralis muscle in patients with COPD. Eur Respir J 13: 850‐854, 1999.
 185. Mannix ET, Manfredi F, Farber MO. Elevated O2 cost of ventilation contributes to tissue wasting in COPD. Chest 115: 708‐713, 1999.
 186. Marcinek DJ, Schenkman KA, Ciesielski WA, Lee D, Conley KE. Reduced mitochondrial coupling in vivo alters cellular energetics in aged mouse skeletal muscle. J Physiol 569: 467‐473, 2005.
 187. Marciniuk DD, Sridhar G, Clemens RE, Zintel TA, Gallagher CG. Lung volumes and expiratory flow limitation during exercise in interstitial lung disease. J Appl Physiol 77: 963‐973, 1994.
 188. Marciniuk DD, Watts RE, Gallagher CG. Dead space loading and exercise limitation in patients with interstitial lung disease. Chest 105: 183‐189, 1994.
 189. Markowitz DH, Systrom DM. Diagnosis of pulmonary vascular limit to exercise by cardiopulmonary exercise testing. J Heart Lung Transplant 23: 88‐95, 2004.
 190. Martinez FJ, de Oca MM, Whyte RI, Stetz J, Gay SE, Celli BR. Lung‐volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 155: 1984‐1990, 1997.
 191. Matthay RA, Arroliga AC, Wiedemann HP, Schulman DS, Mahler DA. Right ventricular function at rest and during exercise in chronic obstructive pulmonary disease. Chest 101: 255S‐262S, 1992.
 192. Matthay RA, Berger HJ, Davies RA, Loke J, Mahler DA, Gottschalk A, Zaret BL. Right and left ventricular exercise performance in chronic obstructive pulmonary disease: Radionuclide assessment. Ann Intern Med 93: 234‐239, 1980.
 193. McLees B, Fulmer J, Adair N, Roberts W, Crystal R. Correlative studies of pulmonary hypertension in idiopathic pulmonary fibrosis. Am Rev Respir Dis 115: 354A, 1977.
 194. McParland C, Mink J, Gallagher CG. Respiratory adaptations to dead space loading during maximal incremental exercise. J Appl Physiol 70: 55‐62, 1991.
 195. Melot C, Naeije R, Mols P, Vandenbossche JL, Denolin H. Effects of nifedipine on ventilation/perfusion matching in primary pulmonary hypertension. Chest 83: 203‐207, 1983.
 196. Meyer FJ, Lossnitzer D, Kristen AV, Schoene AM, Kubler W, Katus HA, Borst MM. Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension. Eur Respir J 25: 125‐130, 2005.
 197. Mitch WE, Goldberg AL. Mechanisms of muscle wasting: The role of the ubiquitin‐proteasome pathway. N Engl J Med 335: 1897‐1905, 1996.
 198. Mitch WE, Medina R, Grieber S, May RC, England BK, Price SR, Bailey JL, Goldberg AL. Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate‐dependent pathway involving ubiquitin and proteasomes. J Clin Invest 93: 2127‐2133, 1994.
 199. Mohsenifar Z, Lee SM, Diaz P, Criner G, Sciurba F, Ginsburg M, Wise RA. Single‐breath diffusing capacity of the lung for carbon monoxide: A predictor of Pao2, maximum work rate, and walking distance in patients with emphysema. Chest 123: 1394‐1400, 2003.
 200. Montes de Oca M, Celli BR. Respiratory muscle recruitment and exercise performance in eucapnic and hypercapnic severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161: 880‐885, 2000.
 201. Montes de Oca M, Torres SH, De Sanctis J, Mata A, Hernandez N, Talamo C. Skeletal muscle inflammation and nitric oxide in patients with COPD. Eur Respir J 26: 390‐397, 2005.
 202. Morrison DA, Adcock K, Collins CM, Goldman S, Caldwell JH, Schwarz MI. Right ventricular dysfunction and the exercise limitation of chronic obstructive pulmonary disease. J Am Coll Cardiol 9: 1219‐1229, 1987.
 203. Mostert R, Goris A, Weling‐Scheepers C, Wouters EF, Schols AM. Tissue depletion and health related quality of life in patients with chronic obstructive pulmonary disease. Respir Med 94: 859‐867, 2000.
 204. Mountain R, Zwillich C, Weil J. Hypoventilation in obstructive lung disease: The role of familial factors. N Engl J Med 298: 521‐525, 1978.
 205. Naeije R. Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2: 20‐22, 2005.
 206. Neder JA, Jones PW, Nery LE, and Whipp BJ. Determinants of the exercise endurance capacity in patients with chronic obstructive pulmonary disease: The power‐duration relationship. Am J Respir Crit Care Med 162: 497‐504, 2000.
 207. Nery LE, Wasserman K, Andrews JD, Huntsman DJ, Hansen JE, Whipp BJ. Ventilatory and gas exchange kinetics during exercise in chronic airways obstruction. J Appl Physiol 53: 1594‐1602, 1982.
 208. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5‐year survival than airway obstruction in patients with COPD. Chest 121: 1434‐1440, 2002.
 209. Nishiyama O, Taniguchi H, Kondoh Y, Kimura T, Ogawa T, Watanabe F, Arizono S. Quadriceps weakness is related to exercise capacity in idiopathic pulmonary fibrosis. Chest 127: 2028‐2033, 2005.
 210. Nixon PA, Orenstein DM, Kelsey SF, Doershuk CF. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med 327: 1785‐1788, 1992.
 211. O'Donnell D. Exercise Limitation and Clinical Exercise Testing in Chronic Obstructive Pulmonary Disease. Basle: Karger, 2002.
 212. O'Donnell DE. Breathlessness in patients with chronic airflow limitation: Mechanisms and management. Chest 106: 904‐912, 1994.
 213. O'Donnell DE. Exertional breathlessness in chronic respiratory disease. In: Mahler DA, editor. Dyspnea. New York: Marcel Dekker, 1998, p. 99‐147.
 214. O'Donnell DE. Exercise limitation and clinical exercise testing in chronic obstructive pulmonary disease. In: Weisman I, Zeballos R, editors. Progress in Respiratory Research. Basel: Karger, 2002, p. 138‐158.
 215. O'Donnell DE, Bertley J, Webb K, Conlan A. Mechanisms of relief of exertional breathlessness following unilateral bullectomy and lung volume reduction surgery in advanced chronic airflow limitation. Chest 110: 18‐27, 1996.
 216. O'Donnell DE, Bertley JC, Chau LK, Webb KA. Qualitative aspects of exertional breathlessness in chronic airflow limitation: Pathophysiologic mechanisms. Am J Respir Crit Care Med 155: 109‐115, 1997.
 217. O'Donnell DE, Chau LK, Webb KA. Qualitative aspects of exertional dyspnea in patients with interstitial lung disease. J Appl Physiol 84: 2000‐2009, 1998.
 218.O’Donnell DE, D’Arsigny C, Fitzpatrick M, Webb KA. Exercise hypercapnia in advanced chronic obstructive pulmonary disease: The role of lung hyperinflation. Am J Respir Crit Care Med 166: 663‐668, 2002.
 219. O'Donnell DE, D'Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163: 892‐898, 2001.
 220. O'Donnell DE, Fitzpatrick M. Physiology of Interstitial Lung Disease. Hamilton: Decker, 2003.
 221.O’Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 23: 832‐840, 2004.
 222. O'Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 158: 1557‐1565, 1998.
 223. O'Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160: 542‐549, 1999.
 224. O'Donnell DE, Laveneziana P, Ora J, Webb KA, Lam YM, Ofir D. Evaluation of acute bronchodilator reversibility in patients with symptoms of GOLD stage I COPD. Thorax 64: 216‐223, 2009.
 225.O’Donnell DE, McGuire M, Samis L, Webb K. Effects of general exercise training on ventilatory and peripheral muscle strength and endurance in chronic airflow limitation. Am J Respir Crit Care Med 157: 1489‐1497, 1998.
 226. O'Donnell DE, Ofir D, Laveneziana P. Patterns of cardiopulmonary response to exercise in lung diseases. In: Ward SA, Palange P, editors. European Respiratory Monograph. United Kingdom: European Respiratory Society, 2007, p. 69‐92.
 227. O'Donnell DE, Revill S, Webb K. Dynamic hyperinflation and exercise intolerance in COPD. Am J Respir Crit Care Med 164: 770‐777, 2001.
 228. O'Donnell DE, Sanii R, Younes M. Improvements in exercise endurance in patients with chronic airflow limitation using CPAP. Am Rev Respir Dis 138: 1510‐1514, 1988.
 229. O'Donnell DE, Webb K. Exercise, Chapter 18. In: Calverley P, MacNee W, Rennard S, Pride N, editors. Chronic Obstructive Lung Disease (2nd ed). London: Edward Arnold, 2003, p. 243‐269.
 230. O'Donnell DE, Webb KA. Breathlessness in patients with severe chronic airflow limitation: Physiologic correlations. Chest 102: 824‐831, 1992.
 231. O'Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation: The role of lung hyperinflation. Am Rev Respir Dis 148: 1351‐1357, 1993.
 232. O'Donnell DE, Webb KA. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol 105: 753‐755; discussion 755‐757, 2008.
 233. Oelberg DA, Kacmarek RM, Pappagianopoulos PP, Ginns LC, Systrom DM. Ventilatory and cardiovascular responses to inspired He‐O2 during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 158: 1876‐1882, 1998.
 234. Oelberg DA, Medoff BD, Markowitz DH, Pappagianopoulos PP, Ginns LC, Systrom DM. Systemic oxygen extraction during incremental exercise in patients with severe chronic obstructive pulmonary disease. Eur J Appl Physiol Occup Physiol 78: 201‐207, 1998.
 235. Ofir D, Laveneziana P, Webb KA, Lam YM, O'Donnell DE. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177: 622‐629, 2008.
 236. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in chronic obstructive pulmonary disease: Role of exercise capacity and health status. Am J Respir Crit Care Med 167: 544‐549, 2003.
 237. Oga T, Nissimura K, Tsukino M, Hajiro T, Ikeda A, Mishima M. Relationship between different indices of exercise capacity and clinical measures in patients with chronic obstructive pulmonary disease. Heart Lung 31: 374‐381, 2002.
 238. Onorati P, Antonucci R, Valli G, Berton E, De Marco F, Serra P, Palange P. Non‐invasive evaluation of gas exchange during a shuttle walking test vs. a 6‐min walking test to assess exercise tolerance in COPD patients. Eur J Appl Physiol 89: 331‐336, 2003.
 239. Openbrier DR, Irwin MM, Rogers RM, Gottlieb GP, Dauber JH, Van Thiel DH, Pennock BE. Nutritional status and lung function in patients with emphysema and chronic bronchitis. Chest 83: 17‐22, 1983.
 240. Orth TA, Allen JA, Wood JG, Gonzalez NC. Exercise training prevents the inflammatory response to hypoxia in cremaster venules. J Appl Physiol 98: 2113‐2118, 2005.
 241. Oswald‐Mammosser M, Apprill M, Bachez P, Ehrhart M, Weitzenblum E. Pulmonary hemodynamics in chronic obstructive pulmonary disease of the emphysematous type. Respiration 58: 304‐310, 1991.
 242. Ottenheijm CA, Heunks LM, Hafmans T, van der Ven PF, Benoist C, Zhou H, Labeit S, Granzier HL, Dekhuijzen PN. Titin and diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173: 527‐534, 2006.
 243. Ottenheijm CA, Heunks LM, Sieck GC, Zhan WZ, Jansen SM, Degens H, de Boo T, Dekhuijzen PN. Diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 172: 200‐205, 2005.
 244. Palange P, Galassetti P, Mannix ET, Farber MO, Manfredi F, Serra P, Carlone S. Oxygen effect on O2 deficit and VO2 kinetics during exercise in obstructive pulmonary disease. J Appl Physiol 78: 2228‐2234, 1995.
 245. Palange P, Valli G, Onorati P, Antonucci R, Paoletti P, Rosato A, Manfredi F, Serra P. Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients. J Appl Physiol 97: 1637‐1642, 2004.
 246. Palange P, Ward S, Carlsen K, Casaburi R, Gallagher C, Gosselink R, O'Donnell D, Puente‐Maestu L, Schols A, Singh S, Whipp B. Recommendation on the use of exercise testing in clinical practice. Eur Respir J 29: 185‐209, 2007.
 247. Petrof BJ, Calderini E, Gottfried SB. Effect of CPAP on respiratory effort and dyspnea during exercise in severe COPD. J Appl Physiol 69: 179‐188, 1990.
 248. Phipps B, Wong B, Chang CH, Dunn M. Unexplained severe pulmonary hypertension in the older age group. Chest 84: 399‐402, 1983.
 249. Pinto‐Plata VM, Celli‐Cruz RA, Vassaux C, Torre‐Bouscoulet L, Mendes A, Rassulo J, Celli BR. Differences in cardiopulmonary exercise test results by American Thoracic Society/European Respiratory Society‐Global Initiative for chronic obstructive lung disease stage categories and gender. Chest 132: 1204‐1211, 2007.
 250. Polkey MI, Green M, Moxham J. Measurement of respiratory muscle strength. Thorax 50: 1131‐1135, 1995.
 251. Potter WA, Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitation during exercise in patients with obstructive lung disease. J Clin Invest 50: 910‐919, 1971.
 252. Pride N, Macklem P. Lung Mechanics in Disease. USA: Bethesda, 1986.
 253. Puente‐Maestu L, Perez‐Parra J, Godoy R, Moreno N, Tejedor A, Gonzalez‐Aragoneses F, Bravo JL, Alvarez FV, Camano S, Agusti A. Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients. Eur Respir J 33: 1045‐1052, 2009.
 254. Puente‐Maestu L, Tena T, Trascasa C, Perez‐Parra J, Godoy R, Garcia MJ, Stringer WW. Training improves muscle oxidative capacity and oxygenation recovery kinetics in patients with chronic obstructive pulmonary disease. Eur J Appl Physiol 88: 580‐587, 2003.
 255. Rabinovich RA, Bastos R, Ardite E, Llinas L, Orozco‐Levi M, Gea J, Vilaro J, Barbera JA, Rodriguez‐Roisin R, Fernandez‐Checa JC, Roca J. Mitochondrial dysfunction in COPD patients with low body mass index. Eur Respir J 29: 643‐650, 2007.
 256. Rabinovich RA, Figueras M, Ardite E, Carbo N, Troosters T, Filellaz X, Barbera JA, Fernandez‐Checa JC, Argiles JM, Roca J. Increased tumour necrosis factor‐a plasma levels during moderate‐intensity exercise in COPD patients. Eur Respir J 21: 789‐794, 2003.
 257. Raguso CA, Guinot SL, Janssens JP, Kayser B, Pichard C. Chronic hypoxia: Common traits between chronic obstructive pulmonary disease and altitude. Curr Opin Clin Nutr Metab Care 7: 411‐417, 2004.
 258. Rahman I, Skwarska E, MacNee W. Attenuation of oxidant/antioxidant imbalance during treatment of exacerbations of chronic obstructive pulmonary disease. Thorax 52: 565‐568, 1997.
 259. Revill SM, Morgan MD, Singh SJ, Williams J, Hardman AE. The endurance shuttle walk: A new field test for the assessment of endurance capacity in chronic obstructive pulmonary disease. Thorax 54: 213‐222, 1999.
 260. Ribera F, N'Guessan B, Zoll J, Fortin D, Serrurier B, Mettauer B, Bigard X, Ventura‐Clapier R, Lampert E. Mitochondrial electron transport chain function is enhanced in inspiratory muscles of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 167: 873‐879, 2003.
 261. Rice AJ, Thornton AT, Gore CJ, Scroop GC, Greville HW, Wagner H, Wagner PD, Hopkins SR. Pulmonary gas exchange during exercise in highly trained cyclists with arterial hypoxemia. J Appl Physiol 87: 1802‐1812, 1999.
 262. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, Levy PC, Reid LM, Vreim CE, Williams GW. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 107: 216‐223, 1987.
 263. Richardson RS, Knight DR, Poole DC, Kurdak SS, Hogan MC, Grassi B, Wagner PD. Determinants of maximal exercise VO2 during single leg knee‐extensor exercise in humans. Am J Physiol 268: H1453‐H1461, 1995.
 264. Richardson RS, Leek BT, Gavin TP, Haseler LJ, Mudaliar SR, Henry R, Mathieu‐Costello O, Wagner PD. Reduced mechanical efficiency in chronic obstructive pulmonary disease but normal peak VO2 with small muscle mass exercise. Am J Respir Crit Care Med 169: 89‐96, 2004.
 265. Richardson RS, Sheldon J, Poole DC, Hopkins SR, Ries AL, Wagner PD. Evidence of skeletal muscle metabolic reserve during whole‐body exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159: 881‐885, 1999.
 266. Riley M, Porszasz J, Engelen M, Wasserman K. Gas exchange response to continuous incremental cycle ergometry exercise in primary pulmonary hypertension in humans. Eur J Appl Physiol 83: 63‐70, 2000.
 267. Roca J, Weisman I, Marciniuk D, Martinez F, Sciurba F, Sue D, Myers J. Guidelines for interpretation. In: Roca J, Whipp BJ, editors. European Respiratory Monograph. United Kingdom: European Respiratory Society, 1997, p. 88‐114.
 268. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 307: 786‐797, 1982.
 269. Rubin L. Current concepts: Primary pulmonary hypertension. N Engl J Med 336: 111‐117, 1997.
 270. Rubin LJ, Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 302: 69‐73, 1980.
 271. Russell JA, Kindig CA, Behnke BJ, Poole DC, Musch TI. Effects of aging on capillary geometry and hemodynamics in rat spinotrapezius muscle. Am J Physiol Heart Circ Physiol 285: H251‐H258, 2003.
 272. Saey D, Cote CH, Mador MJ, Laviolette L, LeBlanc P, Jobin J, Maltais F. Assessment of muscle fatigue during exercise in chronic obstructive pulmonary disease. Muscle Nerve 34: 62‐71, 2006.
 273. Saey D, Debigare R, LeBlanc P, Mador MJ, Cote CH, Jobin J, Maltais F. Contractile leg fatigue after cycle exercise: A factor limiting exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 168: 425‐430, 2003.
 274. Saey D, Michaud A, Couillard A, Cote CH, Mador MJ, LeBlanc P, Jobin J, Maltais F. Contractile fatigue, muscle morphometry, and blood lactate in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 171: 1109‐1115, 2005.
 275. Sala E, Roca J, Marrades RM, Alonso J, Gonzalez De Suso JM, Moreno A, Barbera JA, Nadal J, de Jover L, Rodriguez‐Roisin R, Wagner PD. Effects of endurance training on skeletal muscle bioenergetics in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159: 1726‐1734, 1999.
 276. Saumon G, Georges R, Loiseau A, Turiaf J. Membrane‐diffusing capacity and pulmonary capillary blood volume. Prog Respir Res 8: 198‐212, 1975.
 277. Scano G, Spinelli A, Duranti R, Gorini M, Gigliotti F, Goti P, Milic‐Emili J. Carbon dioxide responsiveness in COPD patients with and without chronic hypercapnia. Eur Respir J 8: 78‐85, 1995.
 278. Schols A, Buurman W, Staal‐van den Brekel A, Dentener M, Wouters E. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 51: 819‐824, 1996.
 279. Schols AM. Nutritional and metabolic modulation in chronic obstructive pulmonary disease management. Eur Respir J Suppl 46: 81‐86, 2003.
 280. Schols AM. Nutritional modulation as part of the integrated management of chronic obstructive pulmonary disease. Proc Nutr Soc 62: 783‐791, 2003.
 281. Schols AM, Broekhuizen R, Weling‐Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr 82: 53‐59, 2005.
 282. Schols AM, Soeters PB, Dingemans AM, Mostert R, Frantzen PJ, Wouters EF. Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 147: 1151‐1156, 1993.
 283. Serres I, Gautier V, Varray A, Prefaut C. Impaired skeletal muscle endurance related to physical inactivity and altered lung function in COPD patients. Chest 113: 900‐905, 1998.
 284. Sheel AW, Derchak PA, Morgan BJ, Pegelow DF, Jacques AJ, Dempsey JA. Fatiguing inspiratory muscle work causes reflex reduction in resting leg blood flow in humans. J Physiol 537: 277‐289, 2001.
 285. Sieck G, Johnson B. Metabolic and Structural Alterations in Skeletal Muscle with Hypoxia. New York: Marcel Dekker, 1996.
 286. Similowski T, Yan S, Gauthier AP, Macklem PT, Bellemare F. Contractile properties of the human diaphragm during chronic hyperinflation. N Engl J Med 325: 917‐923, 1991.
 287. Simon M, LeBlanc P, Jobin J, Desmeules M, Sullivan MJ, Maltais F. Limitation of lower limb VO(2) during cycling exercise in COPD patients. J Appl Physiol 90: 1013‐1019, 2001.
 288. Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE. Development of a shuttle walking test of disability in patients with chronic airways obstruction. Thorax 47: 1019‐1024, 1992.
 289. Slutsky R, Hooper W, Ackerman W, Ashburn W, Gerber K, Moser K, Karliner J. Evaluation of left ventricular function in chronic pulmonary disease by exercise gated equilibrium radionuclide angiography. Am Heart J 101: 414‐420, 1981.
 290. Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan‐Ramirez G, Bogaerts P, Bouillon R, Decramer M. Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF‐I. Thorax 58: 752‐756, 2003.
 291. Spruit MA, Gosselink R, Troosters T, Kasran A, Van Vliet M, Decramer M. Low‐grade systemic inflammation and the response to exercise training in patients with advanced COPD. Chest 128: 3183‐3190, 2005.
 292. Stathokostas L, Jacob‐Johnson S, Petrella RJ, Paterson DH. Longitudinal changes in aerobic power in older men and women. J Appl Physiol 97: 781‐789, 2004.
 293. Stendig‐Lingberg G, Bergstrom J, Hultmam E. Hypomagnesium and muscle electrolytes and metabolites. Acta Med Scand 201: 273‐280, 1997.
 294. Stewart RI, Lewis CM. Cardiac output during exercise in patients with COPD. Chest 89: 199‐205, 1986.
 295. Stubbing DG, Pengelly LD, Morse JL, Jones NL. Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol 49: 511‐515, 1980.
 296. Sturani C, Papiris S, Galavotti V, Gunella G. Pulmonary vascular responsiveness at rest and during exercise in idiopathic pulmonary fibrosis: Effects of oxygen and nifedipine. Respiration 50: 117‐129, 1986.
 297. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 104: 429‐435, 2001.
 298. Sun XG, Hansen JE, Oudiz RJ, Wasserman K. Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol 41: 1028‐1035, 2003.
 299. Systrom D, Cockrill B, Hales C. Role of cardiopulmonary exercise testing in patients with pulmonary vascular disease. In: Weisman I, Zeballos R, editors. Clinical Exercise Testing. Basel: Karger, 2002, p. 200‐204.
 300. Systrom DM, Pappagianopoulos P, Fishman RS, Wain JC, Ginns LC. Determinants of abnormal maximum oxygen uptake after lung transplantation for chronic obstructive pulmonary disease. J Heart Lung Transplant 17: 1220‐1230, 1998.
 301. Tantucci C, Duguet A, Similowski T, Zelter M, Derenne JP, Milic‐Emili J. Effect of salbutamol on dynamic hyperinflation in chronic obstructive pulmonary disease patients. Eur Respir J 12: 799‐804, 1998.
 302. Taylor BJ, Johnson BD. The pulmonary circulation and exercise responses in the elderly. Semin Respir Crit Care Med 31: 528‐538, 2010.
 303. Thannickal VJ. The paradox of reactive oxygen species: Injury, signaling, or both? Am J Physiol Lung Cell Mol Physiol 284: L24‐L25, 2003.
 304. Tiao G, Fagan J, Samuels N, James J, Hudson K, Lieberman M. Sepsis stimulates nonlyosomal, energy‐dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle. J Clin Invest 94: 2255‐2264, 1994.
 305. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst 89: 1763‐1773, 1997.
 306. Tolep K, Higgins N, Muza S, Criner G, Kelsen SG. Comparison of diaphragm strength between healthy adult elderly and young men. Am J Respir Crit Care Med 152: 677‐682, 1995.
 307. Troosters T, Vilaro J, Rabinovich R, Casas A, Barbera JA, Rodriguez‐Roisin R, Roca J. Physiological responses to the 6‐min walk test in patients with chronic obstructive pulmonary disease. Eur Respir J 20: 564‐569, 2002.
 308. Turner JM, Mead J, Wohl ME. Elasticity of human lungs in relation to age. J Appl Physiol 25: 664‐671, 1968.
 309. Uenami A, Mizuno T, Chiba H, Ohno M, Wakino K, Sawada Y, Ohno J, Kume K. Exercise tolerance in mitral stenosis and chronic obstructive pulmonary disease: Evaluation by anaerobic threshold and radionuclide ventriculography. J Cardiogr 16: 301‐308, 1986.
 310. Van't Hul A, Harlaar J, Gosselink R, Hollander P, Postmus P, Kwakkel G. Quadriceps muscle endurance in patients with chronic obstructive pulmonary disease. Muscle Nerve 29: 267‐274, 2004.
 311. Van Gammeren D, Damrauer JS, Jackman RW, Kandarian SC. The IkappaB kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy. FASEB J 23: 362‐370, 2009.
 312. Vassilakopoulos T, Roussos C, Zakynthinos S. The immune response to resistive breathing. Eur Respir J 24: 1033‐1043, 2004.
 313. Vaz M, Thangam S, Prabhu A, Sheety P. Maximal voluntary contraction as a functional indicator of adult chronic undernutrition. Br J Nutr 76: 9‐15, 1996.
 314. Vizza CD, Lynch JP, Ochoa LL, Richardson G, Trulock EP. Right and left ventricular dysfunction in patients with severe pulmonary disease. Chest 113: 576‐583, 1998.
 315. Vogiatzis I, Aliverti A, Golemati S, Georgiadou O, Lomauro A, Kosmas E, Kastanakis E, Roussos C. Respiratory kinematics by optoelectronic plethysmography during exercise in men and women. Eur J Appl Physiol 93: 581‐587, 2005.
 316. Vogiatzis I, Athanasopoulos D, Habazettl H, Aliverti A, Louvaris Z, Cherouveim E, Wagner H, Roussos C, Wagner PD, Zakynthinos S. Intercostal Muscle Blood Flow Limitation During Exercise in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 182: 1105‐1113, 2010.
 317. Vogiatzis I, Georgiadou O, Golemati S, Aliverti A, Kosmas E, Kastanakis E, Geladas N, Koutsoukou A, Nanas S, Zakynthinos S, Roussos C. Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary disease. Thorax 60: 723‐729, 2005.
 318. Vogiatzis I, Habazettl H, Aliverti A, Athanasopoulos D, Louvaris Z, Lomauro A, Wagner HE, Roussos C, Wagner PD, Zakynthinos SG. Effect of helium breathing on intercostal and quadriceps muscle blood flow during exercise in COPD patients. Am J Physiol Regul Integr Comp Physiol 300: R1549‐R1559, 2011.
 319. Vogiatzis I, Simoes DC, Stratakos G, Kourepini E, Terzis G, Manta P, Athanasopoulos D, Roussos C, Wagner PD, Zakynthinos S. Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD. Eur Respir J 36: 301‐310, 2010.
 320. Vogiatzis I, Stratakos G, Athanasopoulos D, Georgiadou O, Golemati S, Koutsoukou A, Weisman I, Roussos C, Zakynthinos S. Chest wall volume regulation during exercise in COPD patients with GOLD stages II to IV. Eur Respir J 32: 42‐52, 2008.
 321. Wagner PD. Determinants of maximal oxygen transport and utilization. Annu Rev Physiol 58: 21‐50, 1996.
 322. Wagner PD. Ventilation‐perfusion inequality and gas exchange during exercise in lung disease. In: Dempsey JA, Reed C, editors. Muscular Exercise and the Lung. Madison, WI: Wisconsin Press, 1977, p. 345‐356.
 323. Wagner PD. Possible mechanisms underlying the development of cachexia in COPD. Eur Respir J 31: 492‐501, 2008.
 324. Wagner PD, Dantzker DR, Dueck R, de Polo JL, Wasserman K, West JB. Distribution of ventilation‐perfusion ratios in patients with interstitial lung disease. Chest 69: 256‐257, 1976.
 325. Wagner PD, Gale GE, Moon RE, Torre‐Bueno JE, Stolp BW, Saltzman HA. Pulmonary gas exchange in human exercising at sea level and simulated altitude. J Appl Physiol 61: 260‐270, 1986.
 326. Walsh J, Webber C, Fahey P Jr, Sharp J. Structural change of the thorax in chronic obstructive pulmonary disease. J Appl Physiol 72: 1270‐1278, 1992.
 327. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Exercise testing and interpretation: An overview. In: Weinberg WR, editor. Principles of Exercise Testing and Interpretation (4th ed). Philadelphia, USA: Williams & Wilkins; Baltimore: Lippincott, 2005, p. 1‐9.
 328. Watz H, Waschki B, Boehme C, Claussen M, Meyer T, Magnussen H. Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: A cross‐sectional study. Am J Respir Crit Care Med 177: 743‐751, 2008.
 329. Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with COPD. Eur Respir J 33: 262‐272, 2009.
 330. Weitzenblum E, Ehrhart M, Rasaholinjanahary J, Hirth C. Pulmonary hemodynamics in idiopathic pulmonary fibrosis and other interstitial pulmonary diseases. Respiration 44: 118‐127, 1983.
 331. Wensel R, Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, Sharma R, Hummel M, Hetzer R, Ewert R. Assessment of survival in patients with primary pulmonary hypertension: Importance of cardiopulmonary exercise testing. Circulation 106: 319‐324, 2002.
 332. West JB. State of the art: Ventilation‐perfusion relationships. Am Rev Respir Dis 116: 919‐943, 1977.
 333. Whipp BJ, Wagner PD, Agusti A. Determinants of the physiological systems responses to muscular exercise in healthy subjects. In: Roca J, Whipp BJ, editors. European Respiratory Monograph. United Knigdom: European Respiratory Society, 2007, p. 30‐34.
 334. Whittom F, Jobin J, Simard PM, Leblanc P, Simard C, Bernard S, Belleau R, Maltais F. Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Med Sci Sports Exerc 30: 1467‐1474, 1998.
 335. Widimsky J, Riedel M, Stonek V. Central hemodynamics during exercise in patients with restrictive pulmonary disease. Bull Eur Physiopathol Respir 13: 369‐379, 1977.
 336. Wijnhoven JH, Janssen AJ, van Kuppevelt TH, Rodenburg RJ, Dekhuijzen PN. Metabolic capacity of the diaphragm in patients with COPD. Respir Med 100: 1064‐1071, 2006.
 337. Williams TJ, Patterson GA, McClean PA, Zamel N, Maurer JR. Maximal exercise testing in single and double lung transplant recipients. Am Rev Respir Dis 145: 101‐105, 1992.
 338. Wust RC, Degens H. Factors contributing to muscle wasting and dysfunction in COPD patients. Int J Chron Obstruct Pulmon Dis 2: 289‐300, 2007.
 339. Wuyam B, Payen JF, Levy P, Bensaidane H, Reutenauer H, Le Bas JF, Benabid AL. Metabolism and aerobic capacity of skeletal muscle in chronic respiratory failure related to chronic obstructive pulmonary disease. Eur Respir J 5: 157‐162, 1992.
 340. Yan S, Kaminski D, Sliwinski P. Reliability of inspiratory capacity for estimating end‐expiratory lung volume changes during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 156: 55‐59, 1997.
 341. Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben‐Neriah Y. Identification of the receptor component of the IkappaBalpha‐ubiquitin ligase. Nature 396: 590‐594, 1998.
 342. Yernault JC, de Jonghe M, de Coster A, Englert M. Pulmonary mechanics in diffuse fibrosing alveolitis. Bull Physiopathol Respir (Nancy) 11: 231‐244, 1975.
 343. Younes M. Determinants of Thoracic Excursion During Exercise. New York: Marcel Dekker, 1991.

Related Articles:

Action of the Respiratory Muscles
Respiratory Muscle Coordination
Static Distribution of Lung Volumes
Relationship Between Neuromuscular Respiratory Drive and Ventilatory Output
Respiratory Muscle Energetics
Lung Mechanics in Disease
Airway, Lung, and Respiratory Muscle Function During Exercise
Determinants of Gas Exchange and Acid–Base Balance During Exercise
Cardiac Output During Exercise: Contributions of the Cardiac, Circulatory, and Respiratory Systems
Integration of Cardiovascular Control Systems in Dynamic Exercise
Control of Blood Flow to Cardiac and Skeletal Muscle During Exercise
Respiratory Control During Exercise

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Ioannis Vogiatzis, Spyros Zakynthinos. Factors Limiting Exercise Tolerance in Chronic Lung Diseases. Compr Physiol 2012, 2: 1779-1817. doi: 10.1002/cphy.c110015