Advances in the Evaluation of Respiratory Pathophysiology during Exercise in Chronic Lung Diseases

Dyspnea and exercise limitation are among the most common symptoms experienced by patients with various chronic lung diseases and are linked to poor quality of life. Our understanding of the source and nature of perceived respiratory discomfort and exercise intolerance in chronic lung diseases has increased substantially in recent years. These new mechanistic insights are the primary focus of the current review. Cardiopulmonary exercise testing (CPET) provides a unique opportunity to objectively evaluate the ability of the respiratory system to respond to imposed incremental physiological stress. In addition to measuring aerobic capacity and quantifying an individual's cardiac and ventilatory reserves, we have expanded the role of CPET to include evaluation of symptom intensity, together with a simple “non-invasive” assessment of relevant ventilatory control parameters and dynamic respiratory mechanics during standardized incremental tests to tolerance. This review explores the application of the new advances in the clinical evaluation of the pathophysiology of exercise intolerance in chronic obstructive pulmonary disease (COPD), chronic asthma, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). We hope to demonstrate how this novel approach to CPET interpretation, which includes a quantification of activity-related dyspnea and evaluation of its underlying mechanisms, enhances our ability to meaningfully intervene to improve quality of life in these pathologically-distinct conditions.

Dyspnea and exercise limitation are among the most common symptoms experienced by patients with various chronic lung diseases and are linked to poor quality of life. Our understanding of the source and nature of perceived respiratory discomfort and exercise intolerance in chronic lung diseases has increased substantially in recent years. These new mechanistic insights are the primary focus of the current review. Cardiopulmonary exercise testing (CPET) provides a unique opportunity to objectively evaluate the ability of the respiratory system to respond to imposed incremental physiological stress. In addition to measuring aerobic capacity and quantifying an individual's cardiac and ventilatory reserves, we have expanded the role of CPET to include evaluation of symptom intensity, together with a simple "non-invasive" assessment of relevant ventilatory control parameters and dynamic respiratory mechanics during standardized incremental tests to tolerance. This review explores the application of the new advances in the clinical evaluation of the pathophysiology of exercise intolerance in chronic obstructive pulmonary disease (COPD), chronic asthma, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). We hope to demonstrate how this novel approach to CPET interpretation, which includes a quantification of activity-related dyspnea and evaluation of its underlying mechanisms, enhances our ability to meaningfully intervene to improve quality of life in these pathologically-distinct conditions.

INTRODUCTION
Dyspnea and exercise intolerance are commonly the most troublesome symptoms reported by patients with chronic pulmonary diseases and contribute significantly to poor quality of life. Moreover, dyspnea, physical inactivity and reduced peak oxygen consumption (VO 2 ) are closely inter-related and have been shown to predict earlier mortality in various chronic pulmonary diseases (Oga et al., 2003;Pinto-Plata et al., 2004;Waschki et al., 2011;Ley et al., 2016). Not surprisingly, improving dyspnea and exercise tolerance are major goals in the management of chronic lung diseases.
Exercise capacity cannot reliably be predicted in any individual based solely on careful clinical assessment or resting pulmonary function tests (O'Donnell et al., 2001). Patients with chronic dyspnea routinely avoid activities that provoke this unpleasant symptom and therefore, commonly underestimate (and under-report) true symptom severity and its negative long-term impact on exercise capacity. Cardiopulmonary exercise testing (CPET) alone provides a rigorous evaluation of the interface between respiratory impairment (caused by disease) and reduced exercise capacity in an individual under measured physiological stress. It uniquely permits an objective assessment of the integrated functions of the neurosensory, metabolic, respiratory, cardiovascular, and locomotor muscle systems to graded physical exertion.
A fact that has traditionally been overlooked in studies of exercise physiology is that the proximate limitation of exercise performance in chronic lung disease populations is very often intolerable symptoms such as dyspnea, not critical encroachment on physiological maxima of the cardiovascular and respiratory systems (Killian et al., 1992;O'Donnell and Webb, 1993;Hamilton et al., 1996). Accordingly, there is renewed interest in elucidating the underlying mechanisms of exertional dyspnea. Moreover, there is now broader acknowledgment that measurements of exertional symptoms and non-invasive dynamic respiratory mechanics are integral components of CPET (ERS Task Force et al., 2007;O'Donnell et al., 2009;Guenette et al., 2013;Puente-Maestu et al., 2016).
For the pulmonologist interested in evaluating the severity of activity-related dyspnea and in discovering its cause(s) in individual patients, we suggest a simple, ordered interrogation of perceptual and physiological responses to incremental exercise. These include: (1) perceptual responses: dyspnea (Borg) ratings as a function of increasing work rate (WR) [and/or minute ventilation (V E )]; (2) ventilatory control:V E -WR,V E -carbon dioxide production (VCO 2 ) ratio, O 2 saturation, and partial pressure of end-tidal carbon dioxide (PetCO 2 ) as a function of WR; (3) dynamic respiratory mechanics: change in inspiratory capacity (IC), inspiratory reserve volume (IRV), tidal volume (V T ) and breathing frequency (f ), all as a function of increasing WR (orV E ); quantitative flow-volume loop analysis (mentioned only briefly in the current review) and (4) metabolic and cardiocirculatory responses:VO 2 -WR,VCO 2 -VO 2 ("V-slope" method to estimate the lactate threshold), heart rate (HR) and O 2 pulse as a function ofVO 2 (Weisman and Zeballos, 1994;Johnson et al., 1999;Ofir et al., 2008a;Chin et al., 2013;Guenette et al., 2014;Elbehairy et al., 2015a,b;Faisal et al., 2015Faisal et al., , 2016. We begin by briefly reviewing the natural changes in respiratory physiology that negatively impact exercise capacity with advancing age, since the healthy elderly are the appropriate reference population for most patients with chronic respiratory conditions. We then describe the abnormal responses to exercise in three separate lung disease categories (obstructive, restrictive and pulmonary vascular diseases). In so doing, we uncover common mechanisms of dyspnea and exercise intolerance across these diverse diseases. Finally, we hope to demonstrate that a simple systematic approach that emphasizes both perceptual and physiological responses (ventilatory control and mechanics) allows the clinician to develop a cogent physiological rationale for effective treatment of dyspnea and exercise tolerance in these common chronic respiratory diseases.

Respiratory Responses to Exercise in Older Healthy Individuals
The healthy respiratory system admirably fulfills its primary task of ensuring that alveolar ventilation (V A ) is commensurate with the increasing muscular metabolic demands of incremental exercise, even at high intensities (West, 2004). Moreover, it accomplishes this feat while maintaining arterial blood gas and acid-base homeostasis and ensuring minimal perceived breathing difficulty. Young, untrained adults can accomplish high peak V E (e.g., 120 L/min) with little respiratory discomfort while requiring only 5-7% of their total bodyVO 2 (Aaron et al., 1992).
The work and O 2 cost of breathing during exercise, and attendant perceived breathing difficulty, are minimized in young adults through several acute physiological adjustments. First,V E is maintained close toV A during exercise because of enhanced ventilation/perfusion (V A /Q) relationships, while increased V T reduces the "wasted" fraction of the breath [physiological dead space (V D )] (Johnson et al., 1994). Second, the behavior of the operating lung volumes is carefully controlled to minimize increases in elastic loading of the inspiratory muscles (Henke et al., 1988). Thus, in young adults, end-expiratory lung volume (EELV) reduction by expiratory muscle recruitment during exercise allows V T expansion to about 50-60% of the vital capacity (VC) by encroachment on both the expiratory and the inspiratory reserve volumes (Henke et al., 1988). This helps mitigate the increased elastic work associated with breathing closer to total lung capacity (TLC). Finally, resistive work is minimized despite high flow rates during exercise by intraand extra-thoracic airway dilatation (England and Bartlett, 1982;Warren et al., 1984).
These adaptations in pulmonary gas exchange and dynamic respiratory mechanics are variably attenuated with increasing age. These aging effects include progressive reductions in alveolar-capillary surface area for gas exchange, worsening oḟ V A /Q relationships, and smaller increases in V T during exercise due to decreased chest wall compliance preventing normal declines in physiological dead space (Ofir et al., 2008b;Faisal et al., 2015). SubmaximalV E is, therefore, increased at any giveṅ VCO 2 ,VO 2 or WR, reflecting the higher physiological dead space (Figure 1) (Faisal et al., 2015). The reduced efficiency in FIGURE 1 | Comparison of ventilation (A), ventilatory equivalent for carbon dioxide (V E /VCO 2 ) (B), end-tidal CO 2 (C), and arterial oxygen saturation (D), all plotted against oxygen uptake, during incremental cycle exercise in healthy young and older adults. Values are mean ± SEM. *P < 0.05 healthy young versus older adults. P ET CO 2 , partial pressure of end-tidal carbon dioxide; SpO2, oxygen saturation by pulse oximetry. Reproduced with permission from the publisher (Faisal et al., 2015).
Age-related changes in the pulmonary connective tissue matrix are associated with reduced static elastic recoil pressure and driving pressure for expiratory flow (Frank et al., 1957;Olafsson and Hyatt, 1969;D'Errico et al., 1989;Johnson et al., 1994;Pride, 2005). Increased lung compliance and reduced airway tethering, together with changes in the autonomic balance of airway smooth muscle tone (possibly increased cholinergic influences), predisposes the elderly to expiratory flow limitation (EFL) (Turner et al., 1968;D'Errico et al., 1989;Johnson et al., 1991Johnson et al., , 1994Verbeken et al., 1992;Wilkie et al., 2012). During resting breathing, closing volume and the ratio of residual volume (RV) to TLC are both increased (Mittman et al., 1965;Anthonisen et al., 1969;Bode et al., 1976;McClaran et al., 1995). Resting IC is also diminished compared with younger individuals due to reduction in diaphragmatic strength with age, likely as a result of muscle atrophy and the age-related decrease in fast twitch fibers (Anthonisen et al., 1969;Tolep et al., 1995;Polkey et al., 1997). These changes are amplified by the higher ventilatory requirements of exercise, such that dynamic hyperinflation (DH); the transient increase of EELV above the resting value, can occur particularly at highV E in fit elderly individuals (DeLorey and Babb, 1999;Ofir et al., 2008b;Faisal et al., 2015).
Inability to reduce EELV in the elderly means that elastic work of breathing is increased and work sharing between expiratory and inspiratory muscles is compromised (Ofir et al., 2008b;Faisal et al., 2015). Moreover, the more rapid decline in dynamic IRV and earlier attainment of a plateau in the V T /V E relation have negative sensory consequences (DeLorey and Babb, 1999;Ofir et al., 2008b;Faisal et al., 2015). The combination of higher ventilatory demand and increased resistive and elastic loading of the respiratory muscles means that the O 2 cost of breathing may represent as much as 13% of the totalVO 2 in healthy older individuals (Harms et al., 1997). Generally, older more sedentary individuals avoid dyspnea provocation simply by avoiding high intensity exercise; however, critical respiratory mechanical constraints and attendant respiratory discomfort are well documented in older elite athletes who are determined to meet the challenge of exercising at high power outputs (Dempsey et al., 1984;Johnson et al., 1991). The agerelated physiological derangements of pulmonary gas exchange and respiratory mechanics outlined above are exaggerated in patients in the early stages of various chronic lung diseases. This underlines the importance of using age-matched controls in studies of exercise pathophysiology in disease states.

Cardiovascular Responses to Exercise in Healthy Elderly
Age-related declines in peakVO 2 are influenced by changes in the cardio-circulatory system, which undergoes significant structural changes during healthy aging (Arbab-Zadeh et al., 2004;Fujimoto et al., 2012;Strait and Lakatta, 2012). While global left ventricular (LV) systolic function and peak stroke volume (SV) are largely unchanged (Forman et al., 1992;Lakatta, 2003;Strait and Lakatta, 2012;Bhella et al., 2014), peak cardiac output falls by ∼25% between 20 and 80 years of age (Fleg et al., 2005). Additionally, peak HR declines by 0.7 beats.min −1 .year −1 (Tanaka et al., 2001) as a result of reduced beta(β)-adrenergic responsiveness with advancing age, which is partially offset by exercise-induced ventricular dilation (Filburn and Lakatta, 1984;Fleg et al., 1994;Brubaker and Kitzman, 2011). Thus, reduced HR and maldistributed cardiac output are responsible for the cardiac contribution to age-related decline in peakVO 2 . Simply speaking, the cardiac response of the aging individual during exercise has been likened to that of a young person on β-blockers (Cheitlin, 2003).
Age attenuates the normal increases in HR, LV ejection fraction, and cardiac output observed during supine and upright incremental exercise (Geokas et al., 1990;Stratton et al., 1994). Aging hearts may utilize different mechanisms to increase SV during exercise compared to younger ones. Exercising elderly subjects try to maintain their SV via increases in enddiastolic volume, i.e., through the Frank-Starling mechanism; cardiac output may not be increased efficiently in subjects not exhibiting this cardiac dilatation. In younger subjects, SV is increased by a progressive decrease in end-systolic volume and little change in end-diastolic volume, in other words by an increase in the LV ejection fraction (Geokas et al., 1990;Stratton et al., 1994). It is worth noting that age does not alter the cardiac output-VO 2 relationship; however, for a given cardiac output, older subjects have decreased blood flow to the exercising leg muscles (Betik and Hepple, 2008).
The lactate threshold declines with age (Neder et al., 1999a;Pollock et al., 2015), though it increases with aging when expressed as % peakVO 2 (Iredale and Nimmo, 1997). Decreases in the lactate threshold occur less rapidly during aging than the observed decreases inVO 2 (Posner et al., 1987). These phenomena have been attributed to age-related decrease in maximalVO 2 (Reinhard et al., 1979;Cunningham et al., 1985;Posner et al., 1987). The occurrence of the lactate threshold at a higher percentage of maximumVO 2 in older individuals (Iredale and Nimmo, 1997) may also be attributed to decreased lactate production, improved clearance, or both. Moreover, the β-adrenergic receptor system has a significant effect on blood lactate concentration during exercise, with β-adrenergic stimulation increasing lactate production (Stainsby and Brooks, 1990). Thus, reduced β-adrenergic receptor sensitivity in advanced age may decrease lactate production, altering the balance between production and removal. Alteration in muscle fiber composition and recruitment may also play a role in circulating blood lactate levels (Spirduso, 1995).

CHRONIC OBSTRUCTIVE PULMONARY DISEASE
It is generally believed that smokers with unremarkable spirometric abnormalities, who are free of troublesome respiratory symptoms, need no treatment beyond the imperative of a smoking cessation intervention. However, this view is rapidly changing. Recent epidemiological studies have confirmed that activity-related dyspnea, activity restriction, poor quality of life, and increased risk of mortality are present in many symptomatic smokers with only minor spirometric abnormalities (Furlanetto et al., 2014;Regan et al., 2015;Woodruff et al., 2016). In this context, we now have a much better understanding of the heterogeneous nature of the physiological impairment in smokers with minor airway obstruction (Ofir et al., 2008a;Deesomchok et al., 2010;Chin et al., 2013;Guenette et al., 2014;Elbehairy et al., 2015aElbehairy et al., ,b, 2016. Established abnormalities in mild COPD include: increased alveolar-to-arterial O 2 tension gradient (A-aPO 2 ) during resting breathing (Barbera et al., 1991;Rodriguez-Roisin et al., 2009;Elbehairy et al., 2015a); reduced diffusing capacity of the lungs for carbon monoxide (D L CO) and reduced transfer factor (Kirby et al., 2013;Harvey et al., 2015); increased peripheral airways resistance (Hogg et al., 2004;McDonough et al., 2011); maldistribution of alveolar ventilation (Buist, 1973); EFL, pulmonary gas trapping (increased ratio of RV to TLC) and reduced IC (Ofir et al., 2008a;Chin et al., 2013;Guenette et al., 2014;Elbehairy et al., 2015a,b).
Similar derangements of pulmonary gas exchange, dynamic respiratory mechanics and muscle function are seen in more advanced COPD. They differ from those changes observed in mild COPD in that they are more pronounced and occur at significantly lowerV E and WR Neder et al., 2015;Faisal et al., 2016).

Increased Inspiratory Neural Drive during Exercise in COPD: Increased Chemostimulation
The physiological adjustments that optimize pulmonary gas exchange and mechanics in youth and are attenuated by natural aging are further eroded by tobacco-related lung injury. Normally, the ventilatory response to exercise is coupled to metabolic demand (increasingVCO 2 ) throughout incremental exercise (i.e.,V E /VCO 2 = 1/[PaCO 2 ×(1 − V D /V T )]). In other words, the higher theV E /VCO 2 (i.e., less "efficient" ventilation), the lower the level at which PaCO 2 is regulated (i.e., CO 2 setpoint) and the greater the fraction of the breath that is wasted as V D (Wasserman et al., 1999). Poor ventilatory efficiency is a key physiological abnormality in symptomatic smokers with largely preserved forced expiratory volume in one second (FEV 1 ) (Ofir et al., 2008a;Chin et al., 2013;Guenette et al., 2014;O'Donnell et al., 2014a;Neder et al., 2015;Elbehairy et al., 2015a,b). The physiological basis for this seems to stem from an enlarged V D per se, rather than a small V T or a low PaCO 2 set point (Elbehairy et al., 2015a). In fact, added external V D predictably increasesV E /VCO 2 in these patients . Additionally, reduced pulmonary perfusion and resultant areas of highV A /Q mean that less CO 2 is presented to the alveoli for removal with net dilution of PetCO 2 from the expired V T (Hansen et al., 2007;Elbehairy et al., 2015a). Regardless of the mechanism(s), the excessive ventilatory response erodes mechanical reserves, thereby contributing to exertional dyspnea and exercise intolerance (Ofir et al., 2008a;Chin et al., 2013;Guenette et al., 2014;Elbehairy et al., 2015a,b).
During the challenge of incremental exercise, the dominant abnormalities in mild COPD include (Figure 2): (1) increased chemostimulation of respiratory centers secondary to the effects of high physiological dead space compared with healthy controls, which is indirectly reflected by higherV E /VCO 2 nadir and steeperV E -VCO 2 slope; and (2) increased airways resistance and DH due to the combined effects of peripheral airway disease (EFL), increased ventilatory demand and central motor command output (Ofir et al., 2008a;Chin et al., 2013;Guenette et al., 2014;Elbehairy et al., 2015a,b). These combinations of increased mechanical loading of the muscles, dynamic functional muscle weakness (due to geometric muscle fiber shortening), and increased velocity of contraction means that efferent motor output to the respiratory muscles from cortical centers in the brain must increase to maintain adequate force generation (Pride and Macklem, 1986). Reduced IC during exercise (due to increased EELV) coupled with higher inspiratory neural drive (due to inefficient pulmonary gas exchange and increased mechanical loading) result in critical mechanical constraints and higher exertional dyspnea ratings earlier in exercise in mild COPD than in age-matched healthy controls (see also next section) (Ofir et al., 2008a;Chin et al., 2013;Guenette et al., 2014;Elbehairy et al., 2015a,b).
In moderate-to-severe COPD, the progressively increasing intrinsic mechanical loading of the functionally weakened respiratory muscles requires augmented increases in efferent motor drive (from the motor cortex) to achieve a given force generation (Figure 3) (Gandevia et al., 1981;Gandevia, 1982;Turner, 1991;Faisal et al., 2016). Additionally, reflex stimulation of the central and peripheral chemoreceptors occurs as a result of: (1)V A /Q abnormalities (decreased ventilatory efficiency, highV A /Q lung units, and increased physiological dead space) (Caviedes et al., 2012;Neder et al., 2015); (2)  Values are mean ± SEM. *p < 0.05 mild COPD vs. healthy controls at rest, at standardized work rates or at peak exercise. V E /VCO 2 , ventilatory equivalent for carbon dioxide; IC, inspiratory capacity; IRV, inspiratory reserve volume; Fb, breathing frequency; PETCO 2 , partial pressure of end-tidal carbon dioxide; SpO 2 , oxygen saturation by pulse oximetry. Reproduced with permission from the publisher .
Frontiers in Physiology | www.frontiersin.org FIGURE 3 | Dyspnea intensity (Borg units) (A), diaphragm electromyography (EMGdi) (B) and selected ventilatory and indirect gas exchange responses (C-I) to incremental cycle exercise test in patients with moderate COPD and age-matched healthy controls. Values are mean ± SEM. Square symbols represent tidal volume-ventilation inflection points. *p < 0.05 for COPD vs. control subjects at rest, at standardized work rates, at peak exercise, or at the tidal volume-ventilation inflection points. EMGdi/EMGdi,max, an index of inspiratory neural drive to the crural diaphragm;VE, minute ventilation; V E /VCO 2 , ventilatory equivalent for carbon dioxide; PETCO 2 , partial pressure of end-tidal carbon dioxide; SpO 2 , oxygen saturation by pulse oximetry; VT, tidal volume; Fb, breathing frequency; IRV, inspiratory reserve volume; TLC, total lung capacity. Reproduced with permission from the publisher .
(e.g., early metabolic acidosis) due to deconditioning or impaired cardiac function (Patessio et al., 1993;Pleguezuelos et al., 2016). In advanced COPD, alveolar hypoventilation with CO 2 retention can occur, reflecting critical mechanical limitation and respiratory muscle dysfunction, particularly in the setting of high V D and restricted V T expansion (see below) (O'Donnell et al., 2002(O'Donnell et al., , 2014a. Finally, the negative haemodynamic consequences of combined resting and dynamic hyperinflation may reduce cardiac output, and thus O 2 delivery to the contracting peripheral muscles, amplifying metabolic acidosis and ventilatory stimulation (Chiappa et al., 2008;Laveneziana et al., 2009Laveneziana et al., , 2011Vasilopoulou et al., 2012).
As previously reported, V D /V T was found to be higher in mild COPD patients compared with healthy controls due to higher V D rather than smaller V T (Elbehairy et al., 2015a). Similar to heart failure (Woods et al., 2010), V D /V T worsens in tandem with COPD severity (O'Donnell et al., 2014b). Interestingly, while the most commonly-used parameter of ventilatory efficiency (V E -VCO 2 slope) increases from mild to severe heart failure (Sue, 2011); it decreases from mild to (very) severe COPD . This seemingly paradoxical finding is explained by the worsening mechanical constraints on increasing ventilation in COPD (Figure 4) (O'Donnell et al., , 2014b, which in endstage disease can lead to hypercapnia at end-exercise (O'Donnell et al., 2002;Poon et al., 2015). Thus, caution is necessary when using theV E -VCO 2 relationship to interpret the trajectory of increases in physiological dead space in patients with limiting mechanical constraints.

Abnormal Dynamic Respiratory Mechanics during Exercise in COPD
Increased respiratory motor drive and respiratory muscle effort occur in COPD due to increased elastic loading [including increased inspiratory threshold loading due to the effect of intrinsic positive end-expiratory pressure (PEEP)], decreased dynamic lung compliance, and increased resistive loading of the respiratory muscles (Potter et al., 1971;Dodd et al., 1984;Jolley et al., 2015;Faisal et al., 2016). IC is a useful non-invasive marker of dynamic respiratory mechanics in pulmonary diseases, as it indicates how close the patient is breathing to TLC. In both mild and advanced COPD, critical dynamic mechanical constraints are indicated by DH and by premature encroachment of endinspiratory lung volume (EILV) on TLC, i.e., the attainment of a critically reduced IRV (Figures 2, 3) (Ofir et al., 2008a;O'Donnell et al., 2011O'Donnell et al., , 2012Chin et al., 2013;Guenette et al., 2013Guenette et al., , 2014Elbehairy et al., 2015a,b;Faisal et al., 2016). Thus, V T becomes positioned close to TLC and the upper reaches of the S-shaped pressure-volume relation of the relaxed respiratory system, where compliance is decreased and the inspiratory muscles are functionally weakened. This explains the blunted V T response and relative tachypnea in COPD compared with healthy controls (Figures 2, 3) Faisal et al., 2016). This increased breathing frequency and velocity of shortening of the inspiratory muscles causes further functional weakness of those muscles (Leblanc et al., 1988).
Expiratory muscle activity is relatively increased in COPD, but fails to prevent DH (Ciavaglia et al., 2014;Laveneziana et al., 2014). In fact, excessive expiratory muscle recruitment may have deleterious hemodynamic effects, which further compromise exercise performance (Potter et al., 1971;Kyroussis et al., 2000). Evidence that respiratory muscle fatigue is present at the limits of tolerance in advanced COPD is inconclusive, but some degree of dynamic functional weakness of the overloaded inspiratory muscles is measurable in such patients (Mador et al., 2000); however, overt "static" (resting) inspiratory muscle weakness is reported in a subset of advanced COPD patients and is multifactorial (Gosselink et al., 1996;Charususin et al., 2016). In this group, it is anticipated that further dynamic respiratory muscle weakness will occur at higher ventilation during progressive exercise (Rodrigues et al., in press).

Cardiovascular Responses to Exercise in COPD
Despite the fact that cardio-circulatory abnormalities are well documented in patients in the early stages of COPD, as tobacco smoking is a common risk factor (Sin et al., 2005;Malerba et al., 2011), crude non-invasive assessment of cardiac function during exercise may not be different from control subjects. For example, there is relatively greater variability in HR responses to incremental exercise in mild COPD patients compared with age-matched controls. HR at submaximal WR andVO 2 is often higher in patients with mild COPD compared with age-matched controls Elbehairy et al., 2015a,b). However, this finding alone is not diagnostic for cardiac abnormality. On the other hand, O 2 pulse (a surrogate for SV during exercise) and HR reserve (predicted maximal HR minus peak HR) were not different during exercise in a group of patients with mildmoderate COPD (FEV 1 62% predicted) and patients with more preserved FEV 1 (94% predicted) compared with control subjects (Wang et al., 2011;Elbehairy et al., 2015a). Use of these crude exercise measures might not, therefore, be conclusive when assessing early cardiovascular changes in patients with mild COPD.
Patients with mild COPD are unlikely to develop pulmonary arterial hypertension (PAH) at rest, though one report suggests that it presented in up to 17% of their sample (Gupta et al., 2011). These patients would also have an increased likelihood of developing PAH during exercise, as supported by Portillo et al. who showed an abnormal increase of pulmonary artery pressure (PAP) during exercise in 70% of patients with GOLD grade 2 COPD (Portillo et al., 2015). Patients with exercise-induced PAH are also more prone to develop resting PAH in subsequent years (Kessler et al., 2001). To the best of our knowledge, there are no studies of exercise-induced PAH in GOLD grade 1 COPD patients.
The effect of more severe COPD on cardiac performance during exercise is complex, multifactorial, difficult to assess using HR responses during CPET and generally needs additional testing. Severe lung hyperinflation and excessive expiratory muscle recruitment can impair venous return and reduce right ventricular preload (Aliverti and Macklem, 2001). The large intrathoracic pressure swings generated during exercise to overcome increased elastic and resistive loads may result in LV dysfunction (increased LV afterload), especially in patients with cardiac comorbidity. Additionally, several studies have demonstrated increased pulmonary vascular resistance (PVR) during exercise in moderate-severe COPD (Light et al., 1984;Mahler et al., 1984;Magee et al., 1988;Oswald-Mammosser et al., 1991), which results from emphysematous vascular destruction in conjunction with reduced volume or compliance of the pulmonary vascular bed and, in some cases, from vasoconstriction due to regional alveolar hypoxemia (Light et al., 1984;Mahler et al., 1984;Magee et al., 1988;Agusti et al., 1990;Oswald-Mammosser et al., 1991). In some cases, mechanical compression of intra-alveolar vessels may also occur as a result of regional DH. Finally, severe lung hyperinflation can mechanically impede cardiac output (e.g., tamponade) in very advanced COPD (Stone et al., 2016;Watz, 2016).
PAP and right ventricular afterload are generally much higher in moderate-severe COPD than in health at a given cardiac output (Matthay et al., 1980;Agusti et al., 1990). Right ventricular afterload during exercise is increased in COPD because of the increased PVR associated with breathing at lung volumes close to TLC, and earlier studies showed failure to increase right ventricular ejection fraction despite a rise in right ventricular end-diastolic pressure (Matthay et al., 1980;Magee et al., 1988;Agusti et al., 1990;Vizza et al., 1998). LV ejection fraction is generally preserved in COPD in the absence of concomitant ischemic heart disease or hypertension (Morrison et al., 1987;Vizza et al., 1998); however, LV diastolic function may be impaired because of ventricular interdependence, i.e., increased tension or displacement of the right ventricle as a result of increased PVR, which may impede LV diastolic filling (Morrison et al., 1987;Vizza et al., 1998). Cardiac output has been found to increase normally withVO 2 during submaximal exercise in COPD, despite the increased PVR, but peak cardiac output (anḋ VO 2 ) reaches lower values than in health (Mahler et al., 1984;Montes de Oca et al., 1996). This maintained cardiac output profile is attributable to decreased SV, and correspondingly increased HR, at a givenVO 2 in COPD patients compared with healthy individuals (Mahler et al., 1984).

Exertional Dyspnea in COPD
Exercise performance in COPD is primarily limited by ventilatory factors and accompanying intolerable respiratory discomfort in the majority of patients with more advanced COPD. Progressive reduction of resting IC (as resting lung hyperinflation increases) with disease progression helps explain the diminishing operating limits for V T expansion and progressively earlier attainment of a minimal IRV during exercise ( Figure 5) . The point at which V T reaches a critical minimal IRV is important during exercise. This is where the disparity between increasing inspiratory neural drive and the muscular/mechanical response of the respiratory system abruptly widens [i.e., where neuromechanical dissociation (NMD) begins] and marks the threshold beyond which dyspnea intensity rises sharply to intolerable levels (O'Donnell et al., 2004(O'Donnell et al., , 2006. The hypothesis that activity-related dyspnea and exercise intolerance are closely related to increased inspiratory neural drive and NMD in COPD is supported by studies showing that bronchodilator therapy, which improves dynamic mechanics (increases resting IC), delays mechanical limitation and partially restores neuromechanical coupling, delays the dyspnea threshold and prolongs exercise endurance time (O'Donnell et al., 2004(O'Donnell et al., , 2006. Additionally, interventions that directly or indirectly reduce inspiratory neural drive [e.g., supplemental oxygen (O'Donnell et al., 1997(O'Donnell et al., , 2001Somfay et al., 2001), opiates (Mahler et al., 2009;Jensen et al., 2012;Johnson et al., 2013;Rocker et al., 2013;Ekström et al., 2015), and exercise training (Carrieri-Kohlman et al., 1996;Wadell et al., 2013)] can further improve dyspnea and exercise tolerance.

BRONCHIAL ASTHMA
We focused in our review on chronic respiratory diseases in which functional consequences are largely non-reversible; we provide only a brief outline of the main pathophysiological mechanisms of exercise intolerance in patients with bronchial asthma. Asthma is a heterogeneous airway inflammatory disease characterized by EFL which is largely or fully reversed either spontaneously or after treatment (GINA, 2016). Patients with asthma respond variably to the stress of exercise depending on the degree of obstruction and bronchodilator reversibility. Furthermore, some atypical causes of exertional dyspnea are more common in asthma than other chronic respiratory diseases, including psychogenic hyperventilation (Ritz et al., 2008), dysfunctional breathing (Agache et al., 2012) and paradoxical vocal cord motion (Low et al., 2017). Thus, exercise responses in asthma characteristically vary among patients and in a given patient on different days (Del Giacco et al., 2015).

Increased Inspiratory Neural Drive during Exercise in Asthma: Increased Chemostimulation
The presence of recurrent bronchoconstriction (or persistent airflow obstruction) in some patients with bronchial asthma is associated with resting and exertional dyspnea which contributes to a sedentary lifestyle (Ford, 2003;Verlaet et al., 2013;Damera and Panettieri, 2014). Excessive exercise ventilation due to an increased chemostimulation (early metabolic acidosis) (Neder et al., 1999b) and increased wasted ventilation (Anderson et al., 1972) have been reported and might accelerate the rate of airway dehydration, a potent trigger for mediator release and exerciseinduced bronchoconstriction in some patients (Parsons et al., 2013). Bronchoconstriction may cause an uneven distribution of ventilation relative to perfusion with consequent widening of the A-aPO 2 (Wagner et al., 1987). However, most studies reported that, on average, asthmatic patients did not present with substantial hypoxemia or hypercapnia (Feisal and Fuleihan, 1979;Graff-Lonnevig et al., 1980;Wagner et al., 1987). Yet, an influential study (Haverkamp et al., 2005) reported that a sizeable fraction of habitually active asthmatic subjects (∼35%) developed gas exchange abnormalities during exercise, which was associated with more extensive EFL, DH and increased airway resistance. Of note, post-exercise sputum histamine was correlated with measures of gas exchange inefficiency (Haverkamp et al., 2005). These data suggest that release of airway-related mediators worsened ventilation distribution during exercise (Haverkamp et al., 2005). In fact, a more proactive treatment of airway inflammation with higher doses of inhaled steroids was associated with improved exertional A-aPO 2 in mild to moderate asthma (Haverkamp et al., 2007). Thus, some patients with apparently well-controlled asthma may present with subtle physiological abnormalities which are amplified by the stress of exercise (Feisal and Fuleihan, 1979;Wagner et al., 1996;Rossman et al., 2014;Del Giacco et al., 2015). In patients with difficult to control asthma, CPET has been found useful to ascertain whether or not there is a "respiratory" cause of exercise limitation, a finding that impacts on disease management (McNicholl et al., 2011).

Abnormal Dynamic Respiratory Mechanics during Exercise in Asthma
Gas trapping and lung hyperinflation might occur in patients with bronchial asthma depending on the prevailing level of airway narrowing (Vermeulen et al., 2016). In this context, the sub-group of patients with "fixed, " poorly-reversible airflow obstruction may present with mechanical-ventilatory constraints and exertional dyspnea akin to COPD (O'Donnell and . At the other end of the functional spectrum, asthmatic adults (Rossman et al., 2014) and children (Santuz et al., 1997) with largely preserved FEV 1 may present with mechanical and pulmonary gas exchange responses indistinguishable to sedentary controls. Interestingly, however, there is some evidence that patients with apparently-preserved lung function may develop significant inspiratory constraints secondary to higher operating lung volumes. As expected, these abnormalities were associated with lower exercise endurance and higher exertional dyspnea (Laveneziana et al., 2013b). These patients may present with tidal EFL leading to DH and a critically-low IRV (Kosmas et al., 2004). Similar to COPD, a V T inflection point marked a change in dyspnea quality from "my breathing requires more effort" to "I cannot take a deep breath in, " thereby indicating that the inspiratory constraints are centrally perceived as an abnormal response (Kosmas et al., 2004;Laveneziana et al., 2013b;Vermeulen et al., 2016).
The reported variability in the presence and extent of mechanical and gas exchange abnormalities in asthma might be partially related to the complexities involved in the control of bronchomotor tone during exercise (Pellegrino et al., 1998;Crimi et al., 2002;Rossman et al., 2014). Thus, increases in operating lung volumes, if associated with increases in V T , are expected to dilate the airways due to the augmented radial traction (Pellegrino et al., 1998). In fact, airway caliber has been found to fluctuate inversely with decreased and increased work load in asthmatics (Crimi et al., 2002). These findings raised the hypothesis that stretching of airway smooth muscle (ASM) might convey an important influence on airway function during exercise in these patients (Rossman et al., 2014). Recent evidence, however, demonstrates that the influence of lung stretching on ASM contractile activity is dynamically modulated by other potent physiological mechanisms, including vagally-mediated neuromuscular reflexes, parasympathetic tone, sympathetic excitation/circulating catecholamines and release of airway-derived mediators (Klansky et al., 2016). Increases in EELV might also have some beneficial effects in increasing airway diameter and/or reducing airway closure, due to airwayslung parenchyma interdependence (Brown et al., 2001). These sources of variability would add to the large circadian fluctuations in airway inflammation (Durrington et al., 2014) and further increase the heterogeneity of exercise responses in individual patients over time (Del Giacco et al., 2015).

RESTRICTIVE LUNG DISEASES
Restrictive lung disorders (e.g., lung parenchymal diseases, neuromuscular disorders, chest wall restriction, and pulmonary resection) are characterized by an inability to expand V T appropriately during the increased metabolic demand of exercise. Here, we focus solely on the interstitial lung diseases (ILD). Exercise intolerance is multifactorial in ILD, but intolerable exertional symptoms, increased central inspiratory neural drive (relative to maximum), and abnormal cardiac function, in varying combinations, are important contributors (Krishnan and Marciniuk, 2002).
The pathophysiological hallmark of ILD is reduced static lung compliance (i.e., increased lung elastic recoil), which simultaneously restricts lung volume expansion and increases the driving pressure for expiratory airflow; thus, TLC, VC, and IC are reduced while the ratio of FEV 1 /FVC is usually increased (Parker et al., 2011). At rest, arterial blood gases may appear normal or reveal mild hypoxemia and a compensated respiratory alkalosis (American Thoracic Society, 2000). Disruption of the pulmonary microvasculature and the alveolar-capillary interface in ILD causes impaired gas exchange (i.e., decreased arterial O 2 saturation, widened A-aPO 2 , and decreased D L CO) (American Thoracic Society, 2000; Egan et al., 2005;Holland et al., 2008;Parker et al., 2011;Cortes-Telles et al., 2014). At rest, the increased ventilatory demand secondary to increasedV A /Q abnormalities, coupled with increased elastic loading of the inspiratory muscles, can result in an increased work and O 2 cost of breathing (American Thoracic Society, 2000;Faisal et al., 2016).

Increased Inspiratory Neural Drive during Exercise in ILD: Increased Chemostimulation
Similar to COPD, central inspiratory neural drive to breathe is higher when metabolic and ventilatory demand acutely increase during exercise in patients with ILD compared with healthy controls at any given work rate   (Figure 6). This reflects (in highly variable combinations) the increased chemostimulation of central bulbo-pontine respiratory control centers and the increased efferent (cortical) motor output as a result of increased elastic loading of the respiratory muscles (Nishimura et al., 1989).
As discussed in COPD, increased chemostimulation in ILD similarly results from the effects of highV E /VCO 2 : reduced efficiency of CO 2 elimination occurs as a result of increased wasted ventilation and/or relative alveolar hyperventilation due to changes in the CO 2 set-point (Figure 6) Faisal et al., 2016). A key finding in fibrosing ILD is arterial hypoxemia with widened A-aPO 2 during exercise (Hamer, 1964;Weitzenblum et al., 1983;Agusti et al., 1991;Hughes et al., 1991), which can occur in early stages of the disease, even before resting pulmonary function tests show overt impairment in D L CO and lung mechanics (Johnson et al., 1960;Keogh et al., 1984).
The mechanisms of arterial O 2 desaturation with exercise include: inter-and intra-regionalV A /Q inequalities in the lungs, increased perfusion of units with lowV A /Q with poorly oxygenated mixed venous blood, diffusion disequilibrium with decreased pulmonary capillary transit time, and, in some individuals, increased intra-cardiac and intra-pulmonary rightto-left shunting (Hamer, 1964;Weitzenblum et al., 1983;Agusti et al., 1991;Hughes et al., 1991). Alveolar hyperventilation in response to hypoxemia is associated with low PaCO 2 with a concomitant increase in PAO 2 , which further contributes to widen exertional A-aPO 2 (Risk et al., 1984). Alveolar hypoventilation is not commonly reported during exercise, even in advanced ILD, but severe V T restriction in the setting of a fixed high V D can potentially cause CO 2 retention in endstage disease (Javaheri and Sicilian, 1992). Correlations have been found between the low resting D L CO and arterial hypoxemia during exercise (Agusti et al., 1991), but there is considerable overlap in this relationship, particularly in patients with mild to moderate disease.
Additional sources of ventilatory stimulation in ILD may include: altered reflex afferent activation of vagal receptors in the lung parenchyma and airways (Paintal, 1969), early metabolic acidosis due to deconditioning, and increased peripheral muscle ergo-receptor activation (Hansen and Wasserman, 1996). As in FIGURE 6 | Dyspnea intensity (Borg units) (A), diaphragm electromyography (EMGdi) (B), and selected ventilatory and indirect gas exchange responses (C-I) to incremental cycle exercise test in patients with interstitial lung disease (ILD) and age-matched healthy controls. Values are mean ± SEM. Square symbols represent tidal volume-ventilation inflection points. *p < 0.05 for ILD vs. control subjects at rest, at standardized work rates, at peak exercise, or at the tidal volume-ventilation inflection points. EMGdi/EMGdi,max, an index of inspiratory neural drive to the crural diaphragm;VE, minute ventilation;VE/VCO 2 , ventilator equivalent for carbon dioxide; PETCO 2 , partial pressure of end-tidal carbon dioxide; SpO 2 , oxygen saturation by pulse oximetry; VT, tidal volume; Fb, breathing frequency; IRV, inspiratory reserve volume; TLC, total lung capacity. Reproduced with permission from the publisher .

Abnormal Dynamic Respiratory Mechanics during Exercise in ILD
During exercise, patients with ILD experience dynamic restrictive mechanical constraints, which, as already seen in COPD, are reflected in high V T /IC ratios and an early plateau of the V T response as it reaches the critical minimal IRV earlier in exercise compared with healthy individuals (Figure 6) . As in COPD, low V T precludes a normal decrement in V D /V T ratio, worsening ventilatory inefficiency and increasing inspiratory neural drive. This leaves tachypnea as the only available option to respond to the higher drive (Javaheri and Sicilian, 1992). This rapid and shallow pattern of breathing helps attenuate the effects of increased elastic work of breathing and the attendant respiratory discomfort; however, as ventilation increases during exercise, the work of breathing increases dramatically in order to overcome the high elastic loads of the stiff lungs and chest wall while breathing close to the reduced TLC (O'Donnell et al., 2000). Moreover, the increased velocity of shortening of the inspiratory muscles results in dynamic functional inspiratory muscle weakness. Consequently, in most instances, exercise intolerance in ILD is explained by true ventilatory limitation and associated severe dyspnea (Kabitz et al., 2006;Holland, 2010;Walterspacher et al., 2013;Panagiotou et al., 2016).
In ILD, the pressure-volume relationship of the entire respiratory system is contracted along its volume axis, but retains its S-shape. The resting IC and IRV are usually diminished. With exercise, EILV encroaches further on the upper non-linear extreme of the pressure-volume relationship "beyond the Sbend, " where there is significant elastic loading (Parker et al., 2011). V T reaches a plateau at 50-60% of the reduced VC (or ∼ 70% of IC) early in exercise: minimal dynamic IRV and the V T plateau are reached together with a step increase in breathing frequency . A few studies report that IC remains largely unaltered throughout exercise, reflecting a diminished expiratory reserve volume (ERV) and a reduced ability to decrease EELV (Marciniuk et al., 1994;O'Donnell et al., 1998). However, EFL has been described in some patients with ILD and may reflect co-existent airway obstruction as a result of smoking or actual airway involvement as part of the interstitial disease process (e.g., hypersensitivity pneumonitis) (Jones and Rebuck, 1979;Marciniuk et al., 1994). Interestingly, the presence of EFL in ILD was associated with worsening dyspnea compared with those with ILD who had normal airway function (Marciniuk et al., 1994).
Inspiratory muscle function is often relatively preserved in patients with ILD, reflecting the training effects of intrinsic mechanical loading and the mechanical advantage of the inspiratory muscles at the lower than normal operating lung volumes (DeTroyer and Yernault, 1980;O'Donnell et al., 1998). However, in some individuals, involvement of these muscles in the underlying systemic inflammatory disease process, the effects of cachexia, high dose oral steroids, malnutrition, electrolytic disturbances, and/or global skeletal muscle deconditioning may have a deleterious impact on function (Baydur et al., 2001;Kabitz et al., 2006;Panagiotou et al., 2016).

Cardiovascular Responses to Exercise in ILD
The characteristic cardiac abnormality in ILD is increased PVR with consequent right ventricular hypertrophy ultimately leading to corpulmonale during the terminal phase of the illness (Weitzenblum et al., 1983;Sturani et al., 1986). LV ejection fraction and systolic pressures are usually preserved, as are pulmonary artery occlusion pressures (Lupi-Herrera et al., 1985;Bush and Busst, 1988). Cardiac output is usually normal at rest and during low levels of exercise in ILD, but the rate of rise of cardiac output is diminished at higher work rates, due in part to increased PVR (Lupi-Herrera et al., 1985;Bush and Busst, 1988). PAP is high at rest and further increases during exercise in the majority of patients with ILD (Hawrylkiewicz et al., 1982;Weitzenblum et al., 1983;Jezek et al., 1985). Values for PAP of ∼ 40 mmHg are not unusual, even in moderate ILD during minimal activity. High levels of PAP are required during exercise to maintain cardiac output when PVR is increased; PAP is often double the normal value or higher (Weitzenblum et al., 1983;Sturani et al., 1986). Obliteration of the vascular bed by progressive parenchymal fibrosis is the main explanation for the reduced vascular bed and the increased PVR in ILD (Enson et al., 1975). Other factors contributing to the increased PVR are hypoxic vasoconstriction and reduced lung volume.
HR responses to incremental exercise in ILD are variable. HR at submaximal work rates is often higher than normal (Widimsky et al., 1977;Baughman et al., 1984), reflecting the relatively reduced SV and greater sympathetic stimulation secondary to hypoxemia. Maximal HR, however, is generally diminished, and there is adequate cardiac reserve at exercise termination . Diminished cardiac reserve may become evident in patients with cardiac involvement in the disease process (i.e., sarcoidosis, Eklund et al., 1989) or in patients with additional extensive pulmonary vascular disease (i.e., scleroderma, Guttadauria et al., 1979). As mentioned in the COPD section, traditional assessments of cardiac function during exercise based mainly on HR measurement are often relatively insensitive.

Exertional Dyspnea in ILD
Increasing dyspnea intensity during CPET correlates well with increasing amplitude of the inspiratory neural drive to the diaphragm, the increasing esophageal pressure relative to maximum, and the increasing V T /IC ratio (a measure of prevailing mechanical constraints) in ILD (Figure 7) (O'Donnell et al., 1998;Faisal et al., 2016). Thus, as in COPD, dyspnea rises as a function of the increasing fractional inspiratory neural drive to the inspiratory muscles, increased contractile respiratory muscle effort, and intrinsic restriction of appropriate V T expansion . Similarly, interventions that attenuate chemostimulation, for example by delaying the rise in metabolicVCO 2 (e.g., exercise training, Ferreira et al., 2009;Dowman et al., 2013Dowman et al., , 2014 or by reducing efferent output from respiratory centers (e.g., O 2 supplementation, opiates), alleviate exertional dyspnea in patients with ILD (Visca et al., 2011;Bajwah et al., 2013;O'Donnell et al., 2016).

PULMONARY ARTERIAL HYPERTENSION (PAH)
Pulmonary hypertension is defined as a mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest as measured through right heart catheterization (Hoeper et al., 2013). Although still controversial, values >30 mmHg during exercise are also deemed indicative of pulmonary hypertension (Hoeper, 2009). Pulmonary hypertension is consistently associated with reduced exercise capacity (Miyamoto et al., 2000;Riley et al., 2000a;Sun et al., 2001;Ferrazza et al., 2009). It has long been known that peakVO 2 and poor ventilatory efficiency correlate significantly with morbidity and mortality in patients with pulmonary hypertension (Schwaiblmair et al., 2012). FIGURE 7 | Relation between dyspnea intensity (Borg units) and diaphragm electromyography (EMGdi) (A) and V T /IC (B) during incremental cycle exercise test in patients with moderate COPD, ILD and age-matched healthy controls. (C) Shows the relation between V T /VC and EMGdi/EMGdi,max (an index of inspiratory neural drive to the crural diaphragm); note the similar blunted V T /VC response to the increased neural drive in both ILD and COPD patients compared with healthy subjects. Values are mean ± SEM. Square symbols represent tidal volume-ventilation inflection points. Selection frequency of descriptors of exertional dyspnea at end-exercise in the three groups is shown in (D). *p < 0.05 for ILD vs. control subjects and † p < 0.05 for COPD vs. control subjects. COPD, chronic obstructive pulmonary disease; IC, inspiratory capacity; V T , tidal volume; VC, vital capacity; ILD, interstitial lung disease. Reproduced from with permission from the publisher .
In this review, we will focus primarily on cardiopulmonary response patterns in patients with increased PVR and PAP in whom dynamic ventilatory mechanics are largely preserved during exercise [e.g., idiopathic PAH (class 1) and chronic thromboembolic pulmonary hypertension (class 4)]. We will therefore exclude consideration of patients with pulmonary hypertension secondary to primary cardiac diseases (class 2) or COPD or restrictive lung diseases (class 3). Typical CPET findings in patients with PAH include (Figure 8): (1) inefficient intra-pulmonary gas exchange; (2) variable degrees of O 2 desaturation; (3) hyperdynamic circulatory and ventilatory responses; (4) reduced peakVO 2 and/or impaired rate of submaximalVO 2 ; and (5) variable combinations of leg effort and dyspnea as the limiting symptoms. Thus, PAH is usually suspected when ventilatory responses to exercise and the inspiratory neural drive to breathe are abnormally elevated despite a relatively preserved maximal flow-volume loop (Figure 9) (Theodore et al., 1986;Reybrouck et al., 1998;Miyamoto et al., 2000;Riley et al., 2000a;Sun et al., 2001;Wensel et al., 2002).

Increased Inspiratory Neural Drive during Exercise in PAH: Increased Chemostimulation
In patients with PAH,V E at any given submaximal exercise intensity is increased, reflecting poor pulmonary perfusion relative to ventilation (larger wasted ventilation) and, in some patients, alveolar hyperventilation (low CO 2 set-point) (Theodore et al., 1986;Reybrouck et al., 1998;Sun et al., 2001;Wensel et al., 2002). As in COPD and ILD, in PAH, high V D /V T is related not only to increased areas of highV A /Q but also to a low V T (see below). Thus, patients with PAH present with poor ventilatory efficiency expressed either as a highV E /VCO 2 nadir or a steepV E -VCO 2 slope (Figure 8) (Reybrouck et al., 1998;Mitani et al., 2002;Schwaiblmair et al., 2012). In most FIGURE 8 | Proposed panel displays for interpretation of key perceptual (A), ventilatory, and dynamic respiratory mechanical (B-I) responses to incremental exercise test in patients with chronic respiratory diseases. Data showing these responses in a patient with pulmonary arterial hypertension (PAH) and an age and gender matched healthy control.VE/VCO 2 , ventilatory equivalent for carbon dioxide; PETCO 2 , partial pressure of end-tidal carbon dioxide; SpO 2 , oxygen saturation by pulse oximetry; Fb, breathing frequency; IRV, inspiratory reserve volume; TLC, total lung capacity.
patients, increased dyspnea scores at relatively low levels of exercise are commensurate with the exaggerated increases in ventilation. Thus, increased neural drive secondary to increased chemostimulation is likely a key mechanism of increased dyspnea intensity in PAH relative to healthy controls.
TheV E -VCO 2 slope andV E /VCO 2 nadir may further increase if another source of ventilatory stimulus adds to the alreadyincreased inspiratory neural drive. As discussed below, the ventilatory threshold is often lower in PAH than in health, reflecting reduced O 2 delivery (due to cardiac impairment) to the active peripheral muscles and a greater reliance on anaerobic glycolysis (Riley et al., 2000b). Significant skeletal muscle deconditioning can arise as a result of dyspnea-related inactivity in patients with PAH, which again may be associated with an earlier metabolic acidosis and increased ventilatory stimulation (de Jesus Perez, 2014).
Arterial O 2 desaturations with widening of the A-aPO 2 typically occur to a variable extent in patients with established PAH (Riley et al., 2000a;Sun et al., 2001;Wensel et al., 2002). The widened A-aPO 2 reflects criticalV A /Q inequalities and a diffusion defect as a result of reduced red cell transit times through the abnormal pulmonary vasculature (Riley et al., 2000a;Sun et al., 2001;Wensel et al., 2002). Cardiac impairment in PAH results in a lower mixed venous O 2 saturation, which in the setting of alveolar units with lowV A /Q ratios negatively impacts arterial oxygenation (Hoeper et al., 2007). Any concomitant hypoxemia secondary to areas of lowV A /Q or right-to-left shunt (e.g., patent foramen ovale) may further increase ventilation and compromise O 2 delivery (Steenhuis et al., 2000;Hoeper et al., 2007). PetCO 2 levels are often diminished at higher levels of exercise compared with health, reflecting relative alveolar hyperventilation and dilution of expired CO 2 (see the COPD section) (Riley et al., 2000b;Yasunobu et al., 2005;Hansen et al., 2007). In fact, it has been suggested that PAH should be suspected in patients who present with unexplained dyspnea and exercise limitation whose PetCO 2 at the ventilatory threshold is <30 mmHg (Yasunobu et al., 2005).

Abnormal Dynamic Respiratory Mechanics during Exercise in PAH
One would anticipate that dynamic ventilatory mechanics during exercise should not be abnormal in patients with PAH in the absence of concomitant COPD or restrictive thoracic diseases. However, it is conceivable that in some PAH patients with high ventilatory demand and rapid breathing frequency, DH may occur, particularly toward the end of exercise in the setting of EFL. Indeed, recent studies have provided evidence that EFL, DH, and restrictive mechanical constraints on V T expansion can occur in a proportion of non-smokers with PAH with no evidence of EFL at rest (Laveneziana et al., 2013a;Richter et al., 2013;Laveneziana et al., 2015). As expected, these patients might present with increased dyspnea intensity at any given ventilation.
In general, and perhaps surprisingly, breathing pattern responses to exercise are usually more rapid and shallow in PAH than in health (Laveneziana et al., 2013a). In many patients, reduced V T expansion is not easily explained by restrictive mechanics, as IRV is generally preserved or increased at peak exercise compared with healthy controls. Relative tachypnea may be related to activation of unmyelinated pulmonary C fibers and/or altered mechanoreceptor inputs from the right heart and pulmonary vasculature in a manner that remains incompletely understood (Aguggini et al., 1987). Additionally, studies have indicated that some patients with primary pulmonary hypertension may show a mild restrictive spirometric pattern as indicated by a modest reduction in TLC with preservation of the FEV 1 /FVC ratio (Horn et al., 1983). The underlying mechanism(s) remain unclear, but reduced lung compliance and dynamic inspiratory respiratory muscle weakness have been suggested as potential contributors (Phipps et al., 1983;Rich et al., 1987;Polkey et al., 1995;Sun et al., 2003;Deboeck et al., 2004;Escribano et al., 2005;Meyer et al., 2005). Regardless of the mechanism(s), a shallow breathing pattern will amplify the effect of a high V D on the V D /V T ratio and augment the increase in the ventilatory drive.

Cardiovascular Responses to Exercise in PAH
A healthy pulmonary vasculature is a prerequisite for accommodating increased cardiac output during exercise while minimizing increases in PVR. In PAH, high PAP (secondary to the failure to recruit additional pulmonary vessels) and right ventricular pressure overload (with potential leftward shift of the interventricular septum) combine to impair the increase in SV during exercise (Janicki, 1990;Holverda et al., 2006). Thus, despite a compensatory increase in HR due to sympathetic over-excitation, cardiac output may fail to adequately meet the higher muscular demands for O 2 (Janicki, 1990;Holverda et al., 2006). Impairments in peripheral O 2 delivery to skeletal muscles usually worsen as the demand for O 2 increases, i.e., as exercise becomes more intense. Consequently, patients with PAH may present with a reduced slope of the relationship betweenVO 2 and WR ( V O 2 / WR <8-9 ml.min −1 .watts −1 ) (Deboeck et al., 2004;Yasunobu et al., 2005). In patients with advanced PAH, V O 2 / WR plateaus or even decreases near the end of exercise. The final consequence is a very low peakVO 2 due to the combination of low peak WR and decreased change inVO 2 for a given change in WR. Impairment in O 2 delivery may also increase the contribution of anaerobic metabolism in the earlier stages of exercise leading to greater increases in CO 2 production (from lactate buffering) for a given change inVO 2 , i.e., an early lactate threshold (Deboeck et al., 2004;Yasunobu et al., 2005).
The impact of the tachycardic response on the HR/ V O 2 relationship (O 2 pulse, i.e., the amount of O 2 taken in for a given heart beat) depends on the ability of active skeletal muscle to extract O 2 from arterial blood and widened arterial-venous O 2 difference (Wasserman et al., 1999). As most of the increase in the arterial-venous O 2 difference occurs during early exercise, the HR/VO 2 ratio during late exercise is chiefly influenced by SV. Consequently, patients with PAH and impaired SV show a flattened, downward-displaced O 2 pulse profile (Janicki, 1990;Wasserman et al., 1999;Deboeck et al., 2004;Yasunobu et al., 2005;Holverda et al., 2006). In advanced disease, a flat O 2 pulse indicates a severely-impaired SV. The relative tachycardia that remains during the recovery period, observed as a slowed postexercise HR decrease, has been found to be an ominous sign in PAH (Riley et al., 2000b;Deboeck et al., 2004;Ramos et al., 2012).

Exertional Dyspnea in PAH
The mechanisms of exertional dyspnea in PAH are less well studied than in the other chronic respiratory diseases. As in COPD and ILD, existing data support an important role of increased inspiratory neural drive, at least as indirectly assessed by measures of ventilatory output. The increased drive mainly reflects increased chemostimulation as a result ofV/Q abnormalities. In PAH, operating lung volumes are close to normal but DH has also been described in some individuals at higher exercise intensities (Laveneziana et al., 2013a;Richter et al., 2013;Laveneziana et al., 2015). Regardless of the mechanism of restriction, the inability to expand V T in response to the increasing inspiratory neural drive (or inspired effort) during exercise contributes importantly to low peak ventilatory capacity and perceived respiratory discomfort. Traditionally, it has also been assumed that direct afferent from the right ventricle and pulmonary arterial afferents also play a contributory role, but the data to support this are inconclusive (Aguggini et al., 1987). It remains to be determined if neuro-mechanical dissociation occurs in PAH at the limits of tolerance, and whether qualitative descriptor choices are different from those of COPD and ILD.

COMPARISON OF EXERCISE RESPONSES IN COPD, ILD AND PAH
At first glance, the four lung diseases under consideration are remarkably different in their underlying pathology, static respiratory mechanics, nature and extent of the mechanical load, respiratory muscle characteristics and recruitment patterns, and pulmonary gas exchange. A comparison of the tidal and maximal flow-volume loops during exercise allows easy diagnostic differentiation (Figure 9). However, differences in respiratory mechanics, inspiratory neural drive to the diaphragm, ventilation, breathing pattern and the behavior of dynamic IRV during conventional CPET are remarkably similar in obstructive and restrictive diseases when compared to the healthy condition. In COPD, V T is restricted by the effects of resting and dynamic lung hyperinflation, whereas in ILD, the restriction is reflecting the reduced TLC and IRV   (Figures 3, 6).
Patients with ILD often have better preservation of inspiratory muscle force-generating capacity, reflecting the mechanical advantage of lower operating lung volumes . Furthermore, patients with ILD, unlike COPD patients, do not usually have to contend with inspiratory threshold and resistive loading. However, clinically stable ILD patients generally have relatively greater tachypnea and often more severe gas exchange abnormalities during exercise (O'Donnell et al., 2016). These latter abnormalities generally occur earlier in ILD than COPD and may precede the development of other resting pulmonary function tests abnormalities.

Common Mechanisms of Dyspnea
In COPD and ILD, dyspnea during exercise fundamentally reflects an imbalance between the increased demand to breathe and the ability to meet that demand (Scano et al., 2010). The rise in dyspnea intensity correlates closely with the following physiological ratios:V E /MVC (maximum ventilatory capacity); oesophageal pressure (Pes)/Pes max ; V T /IC or EILV/TLC; and inspiratory neural drive to the diaphragm relative to maximum (EMGdi/EMGdi max ) (Figure 7) (Gandevia and Hugh-Jones, 1957;Leblanc et al., 1988;Laveneziana et al., 2013a;Guenette et al., 2014;Elbehairy et al., 2016;Faisal et al., 2016). This indicates that respiratory discomfort is provoked when there is critical encroachment on reserves of ventilatory output, muscle force generation, V T expansion or inspiratory neural drive to the diaphragm (Gandevia and Hugh-Jones, 1957;Leblanc et al., 1988;Laveneziana et al., 2013a;Guenette et al., 2014;Faisal et al., 2016;Elbehairy et al., 2016).
Current neurophysiological constructs propose that the intensity of dyspnea rises with increasing tidal inspiratory efferent neural activity relative to the maximum possible neural activation (from bulbo-pontine and cortical motor centers in the brain) as indirectly represented by the above physiological ratios Elbehairy et al., 2016;Faisal et al., 2016). Afferent neural inputs from multiple sensory receptors throughout the respiratory system relay precise information concerning the dynamic status of the respiratory system (Caruana-Montaldo et al., 2000;Sant'Ambrogio and Widdicombe, 2001;Widdicombe, 2009). An increase in motor command to ventilatory muscles is perceived as a sensation of respiratory work/effort, or dyspnea (Killian and Jones, 1984), and the increase in ventilation (relative to maximal possible ventilation) required to perform moderate or intense exercise is accompanied by an increasing awareness of increased work or effort of breathing, even in healthy subjects (Killian, 1998). It is further postulated that concomitant increased central corollary discharge from cortical and bulbo-pontine control centers to the somato-sensory cortex, where unpleasant respiratory sensations are consciously perceived, is a final common pathway Chen et al., 1992;Banzett et al., 2008).
At exercise termination in both COPD and ILD, central respiratory efferent drive reaches almost maximal values, but the respiratory muscle pump, which is overloaded or functionally weakened, responds inadequately to the increased electrical activation. Thus, despite near maximal drive and effort, very little In the patient with COPD, there is a leftward shift of the curve with noticeable expiratory flow limitation during exercise (i.e., tidal loops at peak exercise exceed maximal expiratory envelope). In the patient with ILD, there is a rightward shift of the curve with no expiratory flow limitation and adequate reserves of inspiratory and expiratory flow at end exercise. Note the markedly reduced inspiratory reserve volume (IRV) in both ILD and COPD patients compared with healthy subject (IRV, TLC-end-inspiratory lung volume). In PAH; the flow-volume curve is close to the healthy subject due to absence of respiratory mechanical problem in most classical cases. Solid lines, maximal and tidal loops at rest; dashed lines, tidal loops at peak exercise; dotted lines, predicted normal maximal expiratory loop. COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; TLC, total lung capacity; RV, residual volume; IC, inspiratory capacity; PAH, pulmonary arterial hypertension. Reproduced with permission from the publisher (O'Donnell et al., 1997(O'Donnell et al., , 1998 air enters the lungs with each breath (Figure 7) . This disparity is perceived as unpleasant and is the result of central integration of efferent central outputs and multiple afferent peripheral inputs from the respiratory muscles, chest wall and lungs (Carrieri-Kohlman et al., 2001;Widdicombe, 2009). In line with this theory, it has been repeatedly shown that external imposition of mechanical loads to impede respiration in healthy volunteers in the face of increasing chemostimulation reliably provokes respiratory sensations akin to "unsatisfied inspiration" (Figure 7) (O'Donnell et al., 1997(O'Donnell et al., , 1998Faisal et al., 2016). In contrast to obstructive and restrictive lung diseases, dyspnea during activity in PAH appears to be more closely related to the increased inspiratory neural drive reflecting pulmonary gas exchange and cardio-circulatory abnormalities than to deranged mechanics, per se (Aguggini et al., 1987).
Although definitive experimental verification is lacking, it is believed that vagal afferent input from the lungs and pulmonary vasculature directly to the somato-sensory cortex, or spinal input from mechanoreceptors in the respiratory muscles and chest wall, can directly induce unpleasant respiratory sensations that shape the clinical expression of dyspnea in all three conditions (Adrian, 1933;Chen et al., 1992;Chen and Kou, 2000;Banzett et al., 2008;Lee, 2009). Indeed, activation of the pulmonary C fibers and the high-threshold A Delta fibers may alter breathing pattern and contribute to dyspnea (Yu, 2009;Lee and Yu, 2014). Activation of those pulmonary afferents may cause further DH by inducing tachypnea (Yu et al., 1998;Soukhova et al., 1999;Yu, 2000) or by suppression of expiratory muscle activity, thus adding more burdens on the inspiratory muscles (Yu et al., 2001). Notwithstanding, a recent study provides strong evidence that the relationship between increased dyspnea intensity and increased inspiratory neural drive to the diaphragm during exercise is not affected by major disease-specific differences in afferent inputs from the airways, lung parenchyma, chest wall, and respiratory muscles (Figure 7) . Additionally, respiratory discomfort beyond a certain threshold evokes emotive responses, such as anxiety, fear, panic or distress. The threshold of the affective distress likely varies between individuals and is thought to be linked to increased activation of limbic and paralimbic centers in the brain and associated over-activation of the sympathetic nervous system (Banzett et al., 2000;von Leupoldt et al., 2008).

SUMMARY AND CLINICAL IMPLICATIONS
Based on solid physiological principles established by foundational researchers in the field, such as Wasserman and Whipp (Wasserman et al., 1999), CPET interpretation has traditionally focused on measuring peakVO 2 and has incorporated quantitative assessments of cardiac and ventilatory reserves as well as aerobic capacity. The simple format proposed here extends this approach to include evaluation of perceived intensity of exertional dyspnea and its physiological origins in an individual presenting with respiratory symptoms. This approach is focused on uncovering integrated pathophysiological abnormalities that help explain the origins of dyspnea and exercise intolerance in the individual and is less concerned with diagnostic differentiation. Specifically, analysis of ventilatory efficiency, breathing pattern and operating lung volumes throughout exercise permits a useful non-invasive assessment of pulmonary gas exchange and the prevailing respiratory mechanical constraints which are known to contribute to dyspnea perception. In this context, measurement of operating lung volumes throughout exercise is arguably more sensitive than traditional assessments of breathing reserve (V E /MVC), at least in patients with earlier or milder COPD and ILD (Dempsey, 2013;Faisal et al., 2016).
The physiological perturbations of early COPD and ILD are generally akin to the effects of accelerated aging: age-related pulmonary gas exchange and mechanical derangements are exaggerated, and inspiratory neural drive and attendant exertional dyspnea become amplified at any given work rate. Indeed, we believe that an exercise challenge test that incorporates the above-outlined measurements allows a comprehensive physiological characterization of pathophysiology in symptomatic patients in the early phases of COPD, ILD, and PAH, whose resting pulmonary function tests are close to the normal range. Using this approach, it is possible to uncover unanticipated abnormalities such as dynamic lung hyperinflation and attendant mechanical constraints, which require further diagnostic evaluation and targeted treatment. For example, the finding of DH in a symptomatic patient with ILD or PAH might lead to a therapeutic trial of a bronchodilator.
Knowledge of the common mechanisms of exertional dyspnea in COPD, ILD, and PAH enables the development of a cogent physiological rationale for personalized management. Thus, interventions that reduce the heightened inspiratory neural drive (exercise training, supplemental O 2 , or opioid medication) can successfully ameliorate dyspnea during physical activity in selected patients. Similarly, interventions that improve respiratory mechanics and dynamic respiratory muscle function (e.g., bronchodilators in COPD, specific inspiratory muscle training in selected patients with measurable weakness) can enhance neuro-mechanical coupling of the respiratory system and improve dyspnea and exercise intolerance. Finally, identification of heterogeneous physiological derangements of pulmonary gas exchange and mechanics during exercise earlier in the course of these common chronic respiratory diseases sets the stage for more precise clinical phenotyping of patients and raises the prospect of developing targeted therapeutic interventions and evaluating their clinical efficacy.

AUTHOR CONTRIBUTIONS
All authors played a role in the content and writing of all sections of the review. In addition: DO and JN provided the original idea for the review.

FUNDING
AE has received financial support through the John Alexander Stewart scholar award from Queen's University. The funders had no role in writing this review. DO, AE, DB, ND, and JN have no conflicts of interest that are directly relevant to the content of this article. Outside the submitted work, DO has received research funding via Queen's University from AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline; and has served on speakers bureaus, consultation panels and advisory boards for AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline.