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Strasbourg, France
Dr. Weitzenblum is Professor of Medicine and Pulmonology, and Dr. Chaouat is "Practicien Hospitalier," Hôpital de Hautepierre, Service de Pneumologie, Hôpitaux Universitaires de Strasbourg.
Correspondence to: Emmanuel Weitzenblum, MD, FCCP, Professor of Medicine and Pulmonology, Service de Pneumologie, Hôpital de Hautepierre, 67098 Strasbourg. France; e-mail: Emmanuel.weitzenblum{at}chru-strasbourg.fr
Pulmonary hypertension (PH) is frequently observed in patients with advanced COPD as a consequence of chronic alveolar hypoxia.1 In patients with respiratory disease, PH is generally defined by a resting mean pulmonary artery pressure (PAP) measured in the recumbent position of > 20 mm Hg.23 This definition is slightly different from that of idiopathic pulmonary hypertension (resting PAP, > 25 mm Hg4), but the latter has been adopted for all forms of PH following the World Health Organization meetings held in Evian, France, in 1998 and in Venice, Italy, in 2003.5
It is recognized that one of the main characteristics of PH in COPD patients is its mild-to-moderate degree, with a resting PAP in a stable state of the disease usually ranging between 20 and 35 mm Hg,6 which is very different from the levels observed in patients with thromboembolic or idiopathic PH in whom PAP is most often > 40 mm Hg and may exceed 80 mm Hg in some patients. In an earlier study from our group,6 PH (PAP > 20 mm Hg) was present in 62 of 175 patients with moderate-to-severe COPD (mean [± SD] FEV1, 1,230 ± 470 mL), and the mean PAP of these 62 patients was 27 ± 6 mm Hg, which indicates a mild level of PH. In 120 patients who were evaluated for participation in the National Emphysema Treatment Trial, Scharf et al7 observed that only 6 patients (5%) had a PAP > 35 mm Hg. Our group8 has reported that 27 of 998 stable COPD patients who were investigated from 1990 to 2002 had severe PH, which was defined by a PAP of > 40 mm Hg, and only 11 patients (1.1%) had COPD as a unique cause of their PH. Thus, a resting PAP of > 35 to 40 mm Hg is unusual in COPD patients except when they are investigated during an acute exacerbation9 or when there is an associated cardiopulmonary disease, such as left heart disease, collagen vascular disease, or obesity-hypoventilation syndrome.8
In this issue of CHEST (see page 1531), Thabut and colleagues confirm the uncommonness of severe PH in patients with advanced COPD. They investigated 215 COPD patients by right heart catheterization, candidates for lung volume reduction surgery or lung transplantation, and who were observed that the occurrence of moderately severe PH (35 to 45 mm Hg) and severe PH (> 45 mm Hg) was rather infrequent, occurring in 9.8% and 3.7% of the patients, respectively. Of higher interest, they have individualized by statistical analysis ("cluster" analysis) a particular subgroup of 16 "atypical" patients (7.4%) who were characterized by a moderately severe bronchial obstruction (mean FEV1, 48.5 ± 11.8%) contrasting with severe PH (mean PAP, 39.8 ± 10.2 mm Hg) and profound hypoxemia (mean PaO2, 46.2 ± 15.7 mm Hg), but without hypercapnia (mean PaCO2, 39.7 ± 10.9 mm Hg). The atypical patients were less severely obstructed than the remainder, more hypoxemic, and less hypercapnic, and, indeed, their PAP was markedly higher (see Table 3 of the article by Thabut et al). None of these patients had a right-to-left shunt identified on a lung perfusion scan.
Thabut et al propose that this small subgroup represents a subset of COPD patients in whom pulmonary vascular disease is predominant. They emphasize the fact that Scharf et al7 failed to identify such a subgroup, which could be explained by the exclusion criteria of the National Emphysema Treatment Trial study with regard to arterial blood gas levels (patients with PaO2 < 45 mm Hg could not be included). On the other hand, the 11 patients in our own study8 with COPD as a unique cause of severe PH were very similar to the "atypical" subgroup of Thabut et al, with the following mean values: FEV1, 50% predicted; PaO2, 46 mm Hg; PaCO2, 32 mm Hg; PAP, 48 mm Hg; and alveolar-arterial pressure difference, 56 mm Hg (mean [± SD], 54 ± 21 mm Hg in the series of Thabut et al).
Thus, severe PH is observed in a minority of COPD patients who display some physiologic particularities ie, moderate bronchial obstruction contrasting with a marked hypoxemia and normocapnia or hypocapnia. The study by Thabut et al raises the question "How can one explain the presence of severe PH in COPD patients with moderate airflow obstruction (but with pronounced hypoxemia)?" This question is presently unanswered, as the authors state themselves, but at least two interpretations of these results can be proposed.
Some COPD patients could have an increased reactivity in pulmonary arteries and arterioles to stimuli like alveolar hypoxia. In healthy humans, the response of the pulmonary circulation to acute hypoxia (the so-called hypoxic pulmonary vasoconstriction) varies from one subject to another,10 and this interindividual variability is also found in COPD patients.1112 This means that some patients are "high responders" to acute hypoxia, exhibiting a marked increase in PAP and pulmonary vascular resistance during an hypoxic challenge. It can be expected that these patients will develop a marked pulmonary vascular remodeling when exposed to persistent alveolar hypoxia.
The pulmonary vascular response to hypoxia may be inherited, and one study13 has suggested the role of a genetic predisposition to PH in COPD patients since the 5HTT gene polymorphism appears to determine the severity of PH. In 67 hypoxemic COPD patients who had undergone right heart catheterization, those (n = 21) who carried the LL genotype, which is associated with higher levels of 5HTT expression in pulmonary artery smooth muscle cells, had a mean PAP of 34 ± 13 mm Hg compared to 23 ± 5 mm Hg in 34 LS patients (p < 0.002) and 22 ± 4 mm Hg in 12 SS patients (p < 0.005), whereas bronchial obstruction and hypoxemia were similar in the three groups. Thus, the severity of PH may be determined by genetic factors. However, it must be underlined that the LL group in this study differs in some regards from the atypical subgroup in the study by Thabut et al and from our own subgroup of patients with severe PH.8 The LL patients were not hypocapnic but were normocapnic or slightly hypercapnic, and they had moderate hypoxemia (mean PaO2, 58 ± 7 mm Hg), whereas hypoxemia was profound (46 ± 16 mm Hg) in the subgroup in the study by Thabut et al.
The second hypothesis is the fortuitous coexistence of COPD and a pulmonary vascular disease that is somewhat similar to idiopathic pulmonary arterial hypertension and other diseases regrouped in the first chapter of the new classification of pulmonary hypertension.5 Indeed, some characteristics of the atypical COPD subgroup such as normocapnia or hypocapnia and a low cardiac output are closer to those observed in patients with idiopathic PH than in usual COPD patients. However, this hypothesis of an associated pulmonary vascular disease needs to be better documented, particularly by adequate morphologic studies.
Is it necessary to detect these COPD patients with severe PH? In our opinion, the answer is undoubtedly yes, for at least two reasons, as follows: (1) such patients have a poor prognosis; and (2) such patients need an adequate treatment that could include pulmonary vasodilators.
That the level of PH has a prognostic value in COPD patients has been demonstrated by several studies.61415 In one of these studies,14 the 5-year survival rates were 50% in patients with mild PH (20 to 30 mm Hg), 30% in those with moderate-to-severe PH (30 to 50 mm Hg), and 0% in the small group (n = 15) of patients with very severe PH (> 50 mm Hg). Thus, a high degree of PH bears a poor prognosis, and this also has been observed in COPD patients receiving long-term oxygen therapy.16
Which therapy could improve, or at least stabilize, the severe PH observed in some COPD patients? In patients with usual levels of PAP (< 35 mm Hg), it is generally accepted that there is no need for specific therapy. Most of these patients are markedly hypoxemic, and, accordingly, they are given long-term oxygen therapy (LTOT). Long-term oxygen therapy administered for > 15 h per day, in markedly hypoxemic patients (PaO2, < 55 to 60 mm Hg) has been shown to improve1718 or, at least, to stabilize1920 pulmonary hemodynamics, but all of these studies have included a great majority of patients with mild-to-moderate PH (20 to 35 mm Hg). In patients with severe PH, oxygen therapy may prove to be insufficient to stabilize PH or to reduce its progression, particularly in the presence of a true pulmonary vascular disease that is somewhat similar to idiopathic PH. Consequently, other therapies must be proposed, and lung transplantation could be a good choice in some patients, but indeed it cannot be proposed to all patients. Therapy with pulmonary vasodilators and antiproliferative drugs, including prostanoids,21 endothelin receptor antagonists,22 and phosphodiesterase inhibitors,23 have given promising results in the treatment of pulmonary arterial hypertension (mainly idiopathic pulmonary arterial hypertension) with regard to survival, symptoms (dyspnea), quality of life, and pulmonary hemodynamics. They could be tested in COPD patients with severe PH as more as these patients share some characteristics with patients with idiopathic pulmonary arterial hypertension. There are very few of those patients, and the possibility of a multicentric controlled study should be considered.
In summary, severe PH is rather rare in stable patients with COPD but needs to be identified. It is not yet known whether it is a distinct disease, but some studies have convincingly shown that it has similarities with other pulmonary vasculopathies such as idiopathic pulmonary arterial hypertension. Further studies are needed to establish whether patients with severe PH may benefit from therapy with the presently available pulmonary vasodilators and antiproliferative drugs.
References
This article has been cited by other articles:
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  M. K. Han, V. V. McLaughlin, G. J. Criner, and F. J. Martinez Pulmonary Diseases and the Heart Circulation, December 18, 2007; 116(25): 2992 - 3005. [Abstract] [Full Text] [PDF]
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