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Factors Limiting Exercise Tolerance in Chronic Lung Diseases

Ioannis Vogiatzis, Spyros Zakynthinos

10.1002/cphy.c110015

Source: Volume 2, Issue 3, July 2012

Published online: July 2012

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.

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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. (325); •: Wagner (322); ⧫: Dantzker and D'Alonzo (61); ▴: Stewart and Lewis (294); ▵: Agusti et al. (8); ○: Dantzker et al. (62); ▿: D'Alonzo et al. (59). Adapted, with permission, from Agusti et al. (9).
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. (325); •: Wagner (322); ▾: Agusti et al. (8); ▪: Dantzker and D'Alonzo (61); ▴: Stewart et al. (294); ▵: Agusti et al. (10); ○: Dantzker et al. (62); ▿: D'Alonzo et al. (59); Ñ: Vogiatzis et al. (316); *: Oelberg et al. (233). Adapted, with permission, from Agusti et al. (9).
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 (61); ▾: PVD, Dantzker et al. (62) •: PVD, D'Alonzo et al. (59); ▴: ILD, Acusti et al. (10); ○: Healthy subjects, Wagner et al. (325). Adapted, with permission, from Agusti et al. (9). 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. (325); ILD (hach‐line squares]: Agusti et al. (10); COPD (dotted‐line squares): Agusti et al. (8); PVD (vertical‐line squares): D'Alonzo et al. (59). Adapted, with permission, from Agusti et al. (9).
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. (30). (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. (106).
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. (216). 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 (160).
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. (318).
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. (318).
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. (226).
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. (206).
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. (50). (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. (50). (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. (50)
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. (178).
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. (178).


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. (325); •: Wagner (322); ⧫: Dantzker and D'Alonzo (61); ▴: Stewart and Lewis (294); ▵: Agusti et al. (8); ○: Dantzker et al. (62); ▿: D'Alonzo et al. (59). Adapted, with permission, from Agusti et al. (9).



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. (325); •: Wagner (322); ▾: Agusti et al. (8); ▪: Dantzker and D'Alonzo (61); ▴: Stewart et al. (294); ▵: Agusti et al. (10); ○: Dantzker et al. (62); ▿: D'Alonzo et al. (59); Ñ: Vogiatzis et al. (316); *: Oelberg et al. (233). Adapted, with permission, from Agusti et al. (9).



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 (61); ▾: PVD, Dantzker et al. (62) •: PVD, D'Alonzo et al. (59); ▴: ILD, Acusti et al. (10); ○: Healthy subjects, Wagner et al. (325). Adapted, with permission, from Agusti et al. (9). 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. (325); ILD (hach‐line squares]: Agusti et al. (10); COPD (dotted‐line squares): Agusti et al. (8); PVD (vertical‐line squares): D'Alonzo et al. (59). Adapted, with permission, from Agusti et al. (9).



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. (30). (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. (106).



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. (216). 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 (160).



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. (318).



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. (318).



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. (226).



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. (206).



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. (50). (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. (50). (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. (50)



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. (178).



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. (178).

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Article Title: Factors Limiting Exercise Tolerance in Chronic Lung Diseases
 

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