The Proceedings of the American Thoracic Society 2:12-19 (2005)
© 2005 The American Thoracic Society
Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease
A Case for Treatment
Tim Higenbottam
AstraZeneca R&D Charnwood, Loughborough, United Kingdom
Correspondence and requests for reprints should be addressed to Tim Higenbottam, M.D., D.Sc., Clinical Science, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK. E-mail: tim.higenbottam{at}astrazeneca.com
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ABSTRACT
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Current pharmacotherapy for chronic obstructive pulmonary disease (COPD) relieves symptoms and reduces exacerbation through improving airflow limitation. Such drugs do not effectively improve exercise tolerance due in part to pulmonary hypertension associated with severe COPD, nor impact on its increased morbidity and mortality. Exercise intolerance is often improved (temporarily) by lung volume reduction surgery and pulmonary rehabilitation. Ambulatory oxygen is the most effective treatment of exercise limitation. Chronic cigarette smoking is the principal cause of COPD. An early change in smokers' lungs is pulmonary artery intimal thickening and vessel narrowing, which, as COPD develops, is correlated with both the severity of emphysema and bronchiolitis. This may be the consequence of combined smoking-induced apoptosis, inflammation, and imperfect repair. End-stage bronchiolitis and emphysema are likely to limit the effectiveness of bronchodilators and corticosteroids. There are effective treatments for idiopathic and scleroderma pulmonary arterial hypertension, which increase exercise tolerance and improve survival. Because idiopathic and COPD pulmonary hypertension share a common vascular intimal thickening, excess endothelin receptor expression, and plasma endothelin-1, an important therapeutic question to address is whether an oral endothelin-1 antagonist can improve exercise tolerance in severe COPD.
Key Words: apoptosis • endothelin-1 • exercise limitation • pulmonary hypertension • tobacco smoke
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THE SUCCESSES AND LIMITATIONS OF EXISTING THERAPY FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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Central to the development of new therapies for chronic obstructive pulmonary disease (COPD) is the recognition that current pharmaceutical medications have only a very limited impact for most patients. This article is designed to encourage an open discussion on the potential of treating the commonly associated pulmonary hypertension (PH) as a means of improving patients' level of activity. To understand their limitations, the treatments in current use for COPD and their effect on exercise make up part of the discussion. The central role of smoking in the pathogenesis is explored with reference to the pulmonary circulation to highlight the difference and/or similarities of COPD-associated PH and idiopathic PH.
Patients with COPD characteristically are older than 60 years. As a result of their cigarette smoking, they have comorbid diseases, including ischemic heart disease and various cancers. Most no longer work, because they have retired or are disabled. Age and infirmity, therefore, limit acceptable therapy for the majority of patients to simple oral or inhaled drugs.
It is estimated that more than 80% of patients with COPD have been cigarette smokers (1). Furthermore, more than 50% of smokers have evidence of COPD (2). There is a relationship between the daily number of cigarettes smoked and the severity of COPD as measured by the annual rate of decline of FEV1 (3). Currently, the most effective treatment for COPD is considered to be quitting cigarette smoking, which not only slows down the rate of loss of FEV1 (Figure 1) but also results in improvement of the symptoms of the disease (4).
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Figure 1. Quitting smoking slows the rate of loss of lung function (FEV1) in patients with chronic obstructive pulmonary disease (COPD). Reprinted by permission from Reference 4.
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Clearly, the responses of the lungs that lead to COPD originate with chronic smoke inhalation. Tobacco smoking causes a widespread injury to the lungs, with extensive epithelial and endothelial cell apoptosis (and necrosis) associated with extensive cellular proliferation in alveoli and airways (Figure 2) (5). Although there is obvious inflammation of the airways and alveoli, chronic smoking actually reduces the expression of several genes that transcribe inflammatory mediators (6). Furthermore, tobacco smoke also causes apoptosis of inflammatory cells, such as alveolar macrophages (7). The mechanisms of cell death are hotly debated but include, for example, overexpression of Bax, which might involve stimulation of the aryl hydrocarbon receptor (5, 8). Furthermore, these pulmonary cellular changes may represent reparative and inflammatory responses to the apoptosis and cell death that are caused by smoking.
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Figure 2. Apoptosis and proliferation is seen in the alveolar wall cells in patients with emphysema. (A) Section stained for terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL). Arrows show staining. (B) Antibody to Bax staining, indicated by arrows. (C) Evidence of proliferation. Arrow shows proliferative cell nuclear antigen (PCNA) staining. (D) PCNA and topoisomerase 11x staining, indicated by arrow. (E) Double staining for TUNEL and epithelial membrane antigen (EMA) antibody staining, shown by arrow. (F) Arrow indicates double staining for Bax and anti–surfactant protein-A (SP-A). (G) Arrow indicates staining for anti-PCNA and SP-A. (H) Arrow indicates staining for PCNA and SP-A. Reprinted by permission from Reference 5.
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It is also likely that smoking itself modifies or impairs these reparative responses. For example, smoking reduces the recruitment of bone marrow progenitor cells necessary for endothelial repair (9). The pulmonary repair mechanisms may also be weakened by the inflammatory responses. Although alveolar macrophages orchestrate the inflammatory responses to epithelial apoptosis, oxidative enzymes, such as myeloperoxidase released from recruited neutrophils recruited to the lungs in smokers (10), may cause further lung injury and altered repair (11).
Instead of resolution and completed repair, the net results of chronic smoking are the development of obliterative bronchiolitis (12) and emphysema (13). Their exact pathobiology remains unknown. The protease and antiprotease hypothesis of direct enzymatic destruction of matrix as a cause of emphysema fails to explain the specific anatomic destruction of the alveolar septa. An alternative explanation proposes apoptosis of alveolar cells (14) followed by the failure of vascular (and potential epithelial) repair as a cause of emphysema. Acute smoke exposure certainly provokes many harmful vascular effects, such as increasing the expression of vasoconstrictor, mitogenic factors, such as endothelin-1 (ET-1) (15). The "earliest" pathology of the lungs of smokers is the development of intimal thickening of pulmonary arteries, the severity of which is correlated with the daily number of cigarettes smoked (16).
In patients with established severe COPD where the FEV1 is 50% predicted or less, emphysema (Figure 3) and obliterating bronchiolitis (Figure 4) serve to "cap" or present a "ceiling" to any improvement in function that can be achieved by therapies that dilate the airways or lessen inflammation. It is against these limitations we should view the success of current therapy for COPD.
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Figure 3. The presence of alveolar septal defects (AAd, shown by arrows) in emphysema was associated with more rapid decline in lung function. Reprinted by permission from Reference 13.
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Figure 4. (A) A single airway from an emphysema patient who had undergone lung volume reduction surgery. The mucosa is folded because the lung was fixed collapsed. (B) A reconstruction of the same airway after the lumen is fully expanded. (C) The frequency distribution of the ratio of the luminal content to the total luminal area for 562 airways from 42 patients with GOLD Stage 4, before and after the luminal area is fully expanded. Although the expansion of the lumen shifts the distribution curve to the left, many airways remain occluded. (D) The relationship between FEV and the median value of luminal occlusion for each of the 159 patients after full expansion. The lower the FEV, the greater the residual occlusion. Reprinted by permission from Reference 13.
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The breathlessness of COPD is lessened by bronchodilators. The inhaled long-acting ß2-agonists and long-acting anticholinergic drugs offer effective bronchodilators. It is possible to reduce the frequency of severe exacerbations of COPD that need hospitalization, oral steroids, or antibiotics with an inhaled combination of corticosteroids and long-acting ß2-agonists, such as budesonide and formoterol, respectively (17). Vaccination against influenza and pneumococcal infection may achieve the same result. For those patients who are hypoxemic (PaO2 
8.5 kPa), long-term oxygen therapy can improve survival (18).
However, the major unmet medical need is the absence of a simple drug therapy that relieves the breathlessness or muscle fatigue that severely limit exercise tolerance in COPD. Through advances in the methods of measurement of exercise tolerance in COPD, we now have greater insight into the relative effectiveness of different pharmacologic and physical therapies in improving exercise limitation. These measurements offer us a simple means of testing and comparing new treatments that may affect different aspects of the pathophysiology of COPD, and potentially could improve activity.
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MEASURING EXERCISE TOLERANCE IN PATIENTS WITH COPD
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The methods of measuring exercise tolerance in COPD first used the self-reports of exercise limitation by the patient. Balke (19) was the first to use a simple test that measured the distance covered in a given time. From this, the 12-minute walk test was developed, and then refined to the "6-minute walking distance" (6MWD). The 6MWD is a self-paced, submaximal level of functional capacity that requires no special equipment. The 6MWD is highly reproducible (8% coefficient of variance) and correlates with both self-report quality of life and survival in patients with COPD (20, 21). Patients acknowledge that an increase in 6MWD of 54 m is associated with improvement of well-being (22).
There are now variants of the so-called "corridor" exercise tests developed from the 6MWD, including the shuttle test and the endurance shuttle (23). These are still being developed. One practical advantage of the 6MWD is that it has been used to assess a number of different therapies in COPD and allows comparisons of their efficacies. Although the bronchodilators and inhaled steroids can improve the FEV1 in COPD, their effects on the 6MWD are relatively unimpressive compared with physical interventions, such as lung volume reduction surgery (LVRS) or exercise rehabilitation.
The main effect of bronchodilators on exercise tolerance is by limiting dynamic lung hyperinflation seen in many patients with COPD. However, dynamic hyperinflation does not occur in all patients with COPD during exercise (24) and correction of its influence on exercise produces a relatively small improvement in comparison to rehabilitation and ambulatory oxygen therapy (Table 1).
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TABLE 1. Effects of various therapies on the 6-MINUTE walking distance in patients with chronic obstructive pulmonary disease
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Cardiopulmonary exercise testing offers a more complete assessment of the constituents of the physiologic adaptations to exercise than the 6MWD. It is, however, less reproducible. A simple derivative test that has emerged from cardiopulmonary exercise testing is the endurance time of a constant-workload submaximal-cycle ergometer test. It has also been used to assess the relative efficacy of bronchodilators (Table 2). Using the symptom-limited constant-workload cycle test, oxygen therapy can increase the endurance time by 115%, which compares with only 32% after treatment with tiotropium and 14 to 15% with short-acting bronchodilators (Table 2). The newer forms of exercise tolerance involving strength building and endurance training achieve even greater improvements in exercise endurance time. These effects, however, are only sustained as long as the training continues. Regardless of the type of exercise test used, there is no simple oral or inhaled drug treatment that greatly improves the exercise limitations of patients with COPD.
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ALTERNATIVE PATHOBIOLOGICAL THERAPEUTIC TARGETS FOR IMPROVED EXERCISE TOLERANCE
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The mechanisms by which current therapies increase exercise tolerance are well known. Because of the reduced lung volume after LVRS, overinflation of the ribcage and distension of the diaphragm are lessened. The resulting increase in chest wall compliance enables the work of breathing to be reduced. Patients achieve the same levels of minute ventilation with exercise but with larger tidal volumes and lower frequency of breathing (Figure 5) (35). Unfortunately, these effects are not sustained. The reasons are not known, however, because the improved total lung capacity is a sustained effect. Perhaps the continued influence of other factors, such as the pulmonary vascular disease and the loss of the earlier rehabilitation effects, are important.
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Figure 5. Influence of lung volume reduction surgery (LVRS) on exercise performance in patients with COPD. The pattern of breathing during constant power exercise test for the control subjects (circles) and the treated with LVRS groups (squares) at 12 months post-randomization. Isopleths represent points of equal ventilation for 15, 20, 25, and 30 L/minute. There are sustained differences at 12 months between the LVRS patients and control subjects. LVRS patients' breathing is with larger tidal volumes and lower frequency of breathing. These differences are significantly less than at 3 months post-randomization. Reprinted by permission from Reference 35.
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Rehabilitation increases the anaerobic threshold by enhancing the aerobic metabolism of the exercising skeletal muscles (31). The lower rate of production of lactic acid enables increased tolerance of exercise, because the ventilation rate is less for a given amount of work. Impressive results have been achieved recently with combined endurance and strength training. Again, however, the duration of these effects is only maintained for as long as the training continues.
Ambulatory oxygen increases the flow of oxygen to exercising muscles within the limits of the disturbance of ventilation and gas exchange experienced by the patient with COPD. As with pulmonary rehabilitation, this also enables a delay in the anaerobic threshold and in the increased production of lactic acid (Figure 6) (36). The addition of helium to the gas mixture with oxygen (heliox gas) may further lessen the work of breathing by reducing airflow limitation (37)
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Figure 6. The impact of breathing 60% oxygen (O2) on exercise, where O2 enables a higher rate of work, as shown by increased duration of exercise, for a given level of ventilation. RA = room air. Reprinted by permission from Reference 30.
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In summary, the pharmaceutical therapy directed to improve airflow limitation, ß2-agonist and anticholinergic bronchodilators, increases exercise endurance by delaying the dynamic hyperinflation that occurs when patients exercise (32–34). This, in turn, limits the work of breathing. However, the results are much less impressive than with physical therapies. Furthermore, not all patients with COPD exhibit dynamic hyperinflation during exercise. Some subjects show an alternative pattern of breathing with reduced volumes and increased expiratory effort (24). In addition, many patients, despite adequate bronchodilatation, do not experience an increase in exercise endurance, complaining not of breathlessness but of leg muscle fatigue (36). At present, the mechanisms underlying the limited exercise tolerance in these patients are unclear.
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PH IN COPD
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The epidemiology of PH in association with COPD is incomplete; the need for right-heart catheterization has limited widespread sampling of "real-life" populations of patients. Age, infirmity, and comorbidities, as described previously, have meant that most modern studies report on selected populations with COPD. If we set our focus on those patients with limited exercise tolerance, most patients will have an FEV1 of 1.0 L or less. Such moderate-to-severe COPD is commonly associated with PH at rest (in 35% of patients) (38) or during exercise (in 58% of patients) (39). There is evidence of right ventricular dysfunction in such patients, particularly when the PH is severe (see article by Naeije [pp. 20–22] in this issue) (40). Although it remains unclear, in the absence of an effective and safe therapy, as to what extent PH limits exercise tolerance in severe COPD, PH and the resulting right ventricular dysfunction could account for both the muscle fatigue and the hypoxia. It is possible that PH contributes to a greater amount of exercise limitation even in the presence of dynamic hyperinflation (see later).
Inhaled nitric oxide (NO), a selective pulmonary vasodilator (41), can reduce the PH and improves gas exchange during exercise (42). Furthermore, when inhaled NO is administered 24 hours daily with oxygen for 3 months, it reduces PH and increases exercise tolerance in patients with COPD (43). To NO we should add now sildenafil, because this drug was submitted to the Food and Drug Administration for approval for the treatment of pulmonary arterial hypertension (PAH) in October 2004. The potential for this agent in COPD is currently being tested in randomized controlled trials.
This contrasts with unselective vasodilators, such as calcium channel blockers, which cause peripheral vasodilatation as well as pulmonary vasodilatation. These drugs, while reducing PH, do so at the expense of worsening gas exchange, and they have not proved effective in clinical practice as a treatment for severe COPD (44). A key question that remains is whether the newer therapies for pulmonary arterial hypertension might also improve PH and therefore exercise tolerance in COPD.
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TREATMENTS FOR PAH
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Over the last 20 years, there have been great strides in the therapy for PAH. For those forms of PAH such as primary (or idiopathic) PH and PAH associated with scleroderma, first intravenous prostacyclin (PGI2) (45) as well as analogs such as inhaled iloprost (46) or subcutaneous treprostinil (47) have been shown to improve exercise tolerance (6MWD) by 15 to 30%. Furthermore, PGI2 increases survival in patients with PAH from around 30% in untreated patients at 3 years to approximately 60% in treated patients (48). To these treatments are now added the oral ET-1 receptor antagonists. For example, bosentan, a mixed ETA and ETB receptor antagonist, improves exercise tolerance and survival in PAH (Figure 7) (49). Newer, more "selective" oral ETA receptor antagonists have also been tested in PAH. These agents include ambrisentan and sitaxsentan, and both have proved to be as effective as bosentan (50, 51), although sitaxsentan may produce a 30% greater improvement in 6MWD than the former drug. The degree of selectivity of these new ETA antagonists is, however, being questioned. Also, they all seem to share with bosentan a degree of dose-limiting liver toxicity (50). There continues a search for improvement of these clinically effective treatments that perhaps will be achieved with enhanced ETA receptor selectivity.
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Figure 7. Prolonged survival in pulmonary arterial hypertension after therapy with bosentan and antagonist of endothelin receptors. The graph shows the effect of the two doses of bosentan on the length of time patients survived or did not require alternative therapy, such as lung transplant surgery or intravenous prostacyclin. Reprinted by permission from Reference 49.
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In all forms of PH, the plasma levels of ET-1 are increased (52), and there is evidence of increased expression of ETA and ETB receptors on pulmonary artery smooth muscle cells (53). Antagonists of ET-1 inhibit and reverse the proliferation of pulmonary arterial intimal fibromuscular cells in experimental PH induced in animals by hypoxia or monocrotaline (54, 55). Intimal fibromuscular cell proliferation is a characteristic of PAH that leads to obliteration and loss of small pulmonary arteries. As we will see later, however, it is also seen in the pulmonary arteries of smokers and in patients with COPD. Thus, although they are being used successfully in the treatment for PAH, it remains to be seen whether the ET-1 antagonists might also provide beneficial clinical effects in PH associated with COPD.
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COULD ET-1 ANTAGONISTS IMPROVE EXERCISE TOLERANCE IN SEVERE COPD?
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Given the patient profile of COPD and the general efficacy and established ease of use of oral ET-1 antagonists in patients with PAH, it is now appropriate to consider whether the use of this class of drug may find a valuable place in the therapy of PH associated with COPD. Moreover, any value would have to be demonstrated for patients with severe COPD in improving exercise tolerance, but without eliciting serious side effects.
It is first important to know how many patients with severe COPD have PH and to know to what degree the PH affects them. Despite many uncertainties, studies indicate that 35% of patients with severe COPD have pulmonary artery pressures (Ppa) of more than 20 mm Hg at rest (38). Of those patients without PH at rest, a further 52% will develop PH during exercise (39). Furthermore, other reports propose that 91% of patients with severe COPD have PH (56). Exercise-induced rises in Ppa predict those patients who will eventually develop PH at rest (39), and are probably associated with exercise-induced hypoxia (57).
There are many similarities in the pathology of PAH and COPD. Pulmonary arteries in patients with COPD show evidence of fibromuscular intimal thickening with a diffuse increase in smooth muscle cells within the intima (Figure 8) (16, 58). Such changes are not solely the result of exposure to hypoxia because they are also seen in smokers without evidence of airflow limitation (16). Furthermore, these changes may represent another aspect of the "direct" toxic effects of tobacco smoke on pulmonary arteries. Smoking is associated with a fall in the bronchoalveolar levels of vascular endothelial growth factor (59). The aryl hydrocarbons of tobacco smoke also cause endothelial cell apoptosis through activation of phospholipase A2 (60). Experimentally, both epithelial and endothelial cell proliferation increases in the region of the alveolar ducts as a result of chronic cigarette smoke exposure (61).
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Figure 8. Pulmonary vascular remodeling in mild COPD. The thickening of the intima of a small pulmonary artery, with staining for actin, emphasizing the diffuse hyperplasia of muscle cells in the intima. Reprinted by permission from Reference 58.
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As we have seen, oxidative injury caused by elevated activity of myeloperoxidase released from recruited neutrophils may hinder the process of tissue repair. For example, in the systemic circulation, myeloperoxidase contributes to advancing myocardial ischemia by consuming endothelial-derived NO and by causing lipid peroxidation. It is important to note that increased lipid peroxidation is a feature of all forms of PH, including that seen in COPD (62), and endothelial NO production is decreased in COPD (63).
A further powerful link between PH and COPD is the effect of pulmonary arterial wall thickness on the levels of PH at rest and after exercise in patients with emphysema after successful LVRS. The surgery improves FEV1 and reduces the dynamic hyperinflation of the lungs with exercise, but both resting and exercise PH in these patients can be predicted from the resected lung specimens' pulmonary arterial wall thickness (Figure 9) (64).
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Figure 9. The relationship between pulmonary artery wall thickness (WT) and the resting and exercise-associated pulmonary artery pressure (Ppa) in patients awaiting LVRS. NS = not significant. Reprinted by permission from Reference 64.
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Plasma levels of ET-1 are increased both in patients with severe COPD (51) and in otherwise healthy individuals at high altitudes (65). There is also evidence that ETA and ETB receptor expression is increased in the pulmonary arteries of patients with COPD (53), contrasting with heart failure where the ET receptor expression is reduced (66) where ET-1 antagonists fail to affect the disease.
Despite these strong pathobiological associations between the pulmonary vascular changes of COPD and ET-1, drugs such as bosentan have not been used to treat patients with COPD. Perhaps this reflects concerns with liver toxicity with bosentan and other ET-1 antagonists. There are, however, unconfirmed reports of another mixed ETA/ETB antagonist undergoing clinical evaluation in COPD and which caused marked reductions in arterial oxygen tensions (PaO2). This finding was assumed to be the result of the drug overcoming hypoxic vasoconstriction, resulting in worsening of ventilation/perfusion mismatching as seen with calcium channel blockers, as noted earlier. Conversely, it is possible that antagonism of ET receptors leads to a reduction of the peripheral carotid body sensitivity to arterial hypoxia, a phenomenon that is mediated by the ETA receptor (67). Thus, ET-1 antagonists may depress the ventilatory response to hypoxia.
Against this background, there are potential risks that might be associated with the use of selective ETA receptor antagonists for the treatment of severe COPD. Resolution of these uncertainties will only come with a proof-of-concept study, perhaps on a small scale, but focused on determining both exercise tolerance as an efficacy measure as well as hypoxia as an adverse effect. We must remember that the goal for developing a simple oral/inhaled therapy to increase exercise tolerance in COPD remains unmet.
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FOOTNOTES
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Conflict of Interest Statement: T.H. is a full-time employee of AstraZeneca.
(Received in original form November 4, 2004; accepted in final form January 24, 2005)
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