ABSTRACT: Mild-to-moderate pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD); such a complication is associated with increased risks of exacerbation and decreased survival. Pulmonary hypertension usually worsens during exercise, sleep and exacerbation. Pulmonary vascular remodelling in COPD is the main cause of increase in pulmonary artery pressure and is thought to result from the combined effects of hypoxia, inflammation and loss of capillaries in severe emphysema.
A small proportion of COPD patients may present with ‘‘out-of-proportion’’ pulmonary hypertension, defined by a mean pulmonary artery pressure .35–40 mmHg (normal is no more than 20 mmHg) and a relatively preserved lung function (with low to normal arterial carbon dioxide tension) that cannot explain prominent dyspnoea and fatigue. The prevalence of out-ofproportion pulmonary hypertension in COPD is estimated to be very close to the prevalence of idiopathic pulmonary arterial hypertension.
Cor pulmonale, defined as right ventricular hypertrophy and dilatation secondary to pulmonary hypertension caused by respiratory disorders, is common. More studies are needed to define the contribution of cor pulmonale to decreased exercise capacity in COPD. These studies should include improved imaging techniques and biomarkers, such as the B-type natriuretic peptide and exercise testing protocols with gas exchange measurements.
The effects of drugs used in pulmonary arterial hypertension should be tested in chronic obstructive pulmonary disease patients with severe pulmonary hypertension. In the meantime, the treatment of cor pulmonale in chronic obstructive pulmonary disease continues to rest on supplemental oxygen and a variety of measures aimed at the relief of airway obstruction.
KEYWORDS: Chronic obstructive pulmonary disease, hypoxaemia, inflammation, oxygen therapy, pulmonary hypertension, vasodilator agents
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide with an increasing prevalence during the past decades . One established complication of COPD is the development of pulmonary hypertension (PH). Typically, PH appears when airflow limitation is severe and is associated with chronic hypoxaemia, the main pathophysiological cause being chronic alveolar hypoxia, although new mechanisms have emerged recently. In older studies, mean pulmonary artery pressure (P¯ pa) was significantly linked to the severity of COPD and was considered to be an important prognostic factor and part of the justification for long-term oxygen therapy (LTOT). Nowadays, in a time of LTOT, PH is a significant risk factor for hospitalisation  and is still associated with a shorter life expectancy . In most cases, PH is mild to moderate [4–6] but it may be severe and could be observed without major airflow limitation. This latter condition has been termed ‘‘out-of-proportion’’ PH. In a recent study , it has been reported that, unlike ‘‘usual’’ PH in COPD patients undergoing LTOT (the most common situation), out-of-proportion PH often leads rapidly to right heart failure and death. Given the increasing number of patients, the recognition of susceptibility factors for PH in this disease has important implications for a clear understanding of the natural history of COPD. A better diagnosis strategy for PH in COPD is also mandatory, as is new treatment, particularly in out-of-proportion PH. It must be emphasised that out-of-proportion PH does not match with any group of the last published classification of PH  and, thus, there is a need for a consensual definition of this condition.
PH is defined as P¯ pa .20 mmHg and is placed in the heterogeneous group of PH associated with disorders of the respiratory system and/or hypoxaemia . The reason for setting such a threshold is that in healthy subjectsP¯ pa is always ,20 mmHg at rest and, as stated above, a P¯ pa .20 mmHg is associated with increased morbidity and mortality. However, in some recent studies PH was defined by P¯ pa .25 mmHg [8, 9]. These various definitions should be kept in mind when comparing studies, particularly in terms of prevalence of PH in populations of COPD. Although severe PH in COPD could be defined by P¯ pa .35 mmHg in patients undergoing optimal treatment (including LTOT), it must be emphasised that this is not a consensual definition. Cor pulmonale is defined as right ventricular hypertrophy and dilatation or both, secondary to PH caused by respiratory disorders . This article is part of a review series on pulmonary hypertension [11–16].
EPIDEMIOLOGY OF PH IN COPD
Prevalence of PH in COPD
Determination of prevalence of PH in COPD has been hampered by difficulties in obtaining valid data from an adequate population-based sample of COPD. The main reason is that right heart catheterisation (RHC) cannot be performed on a large scale for ethical reasons and it is well known that echocardiography alone is subject to some error . Only studies of hospitalised subjects are available. BURROWS et al.  reported 36 yrs ago that 50 patients with COPD and severe airflow limitation (forced expiratory volume in one second (FEV1)/vital capacity (VC) ratio of 37%) had an average P¯ pa value of 26 mmHg. In a larger sample of 175 patients with a mean FEV1/VC ratio of 40%, WEITZENBLUM et al.  observed a prevalence of PH (defined as P¯ pa .20 mmHg) of 35%.
The 120 patients with severe emphysema evaluated for participation in the National Emphysema Treatment Trial  had a mean¡SD P¯ pa of 26.3¡5.2 mmHg. The 95% confidence interval (CI) of the true mean in such a population was 25.4–27.2 mmHg. These results obtained when LTOT was readily available confirmed that PH when present in patients with severe COPD is mild to moderate, but also extremely prevalent, since in this series of patients 91% had P¯ pa .20 mmHg. VIZZA et al. , in a cohort of 168 patients with COPD listed for lung transplantation, observed similar results in terms ofP¯ pa, with a 95% CI of 24.1–25.9 mmHg. THABUT et al. , investigating the two types of population, i.e. candidates for lung volume reduction surgery (LVRS) and candidates for lung transplantation, had comparable results. Mild (P¯ pa 26– 35 mmHg), moderate (36–45 mmHg) and severe (.45 mmHg) PH was present in 36.7, 9.8 and 3.7% of the 215 patients, respectively. In a large series of 998 patients with COPD  with less airway limitation and hypoxaemia than the two studies quoted above, the P¯ pa was 20.3¡8.1 mmHg. This latter study demonstrated that the prevalence of P¯ pa .20 mmHg in hospitalised COPD patients is ,50%. When considering patients listed for LVRS or lung transplantation the prevalence of PH would lie between 70–90%.
In the large population of patients with COPD, it is worthwhile to estimate the proportion of those with severe PH. In the study reported by SCHARF et al.  considering pulmonary haemodynamics of patients with severe emphysema, only 5% of the population as a whole had P¯ pa .35 mmHg. It should be made clear that this latter figure is underestimated since severe PH was a criterion of exclusion in the National Emphysema Treatment Trial . In the studies conducted in France by THABUT et al.  and by CHAOUAT et al. , 13.5% and 5.8% of the population had severe PH (P¯ pa o35 mmHg), respectively. Interestingly, in these two studies P¯ pa was positively skewed, indicating that a significant number of patients with COPD had severe PH (fig. 1). Importantly, all the patients in both studies, even those with a high elevation of P¯ pa, were in a stable state of the disease and had optimal treatment including LTOT.The othermethod by which the prevalence of PHin COPD can be estimated is to look at recent epidemiological studies devoted to COPD. The prevalence of COPD among adults in eight European cities has been estimated to be as high as 6.2% . Knowing that COPD is usually progressive, many patients will be at risk of PH in the near future . Furthermore, it must be considered that this population of COPD has lot of comorbidities that could raise the level of PH. Indeed, ischaemic heart disease, hypertensive cardiomyopathy, chronic heart failure and worsening of chronic respiratory failure due to obesity are frequently encountered . According to a prevalence of COPD of ,5% in the adult population in most European countries, and that 6% of patients have severe or very severe disease, the number of patients in Europe with severe PH (1% of the severe and very severe COPD patients are likely to have P¯ pa .40 mmHg ) may be ,7,500. When related to the adult French population, the figurewould be 650, which is very close to a prevalence of 15 cases per million patients with pulmonary arterial hypertension (PAH) in the same country . In light of all these studies, it is highly probable that the number of COPD patients with PH is high, with a mild-tomoderate increase inP¯ pa in most cases, but undoubtedly there are also a significant number of patients with severe PH.