Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Georgios Tsaknis MD, PhD
Respiratory Department, Attiko University General Hospital

Download full text pdf here

Cite as: Tsaknis G. Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease. Alveolus 2013 1(2):3-10

Pulmonary arterial hypertension (PAH) is defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest, with a mean pulmonary capillary wedge pressure (PCWP), left atrial pressure or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mmHg validated by right heart catheterization (RHC) [1]. These values are being used by all PAH registries and in all randomized controlled trials (RCTs) [2–7]. Pressure measurements during exercise are no longer recommended or supported by data for pulmonary hypertension (PH) diagnosis. As of 2009, based on the latest Dana Point Classification [1], PH due to underlying parenchymal diseases, such as COPD and interstitial lung disease (ILD), remains in group 3. Other diseases with multisystemic, and more importantly pulmonary, manifestations such as connective tissue diseases (CTDs), or sarcoidosis are categorized separately (groups 1.4.1 and 5.2, resp.). In patients with parenchymal lung disease, PH is reported likely modest (mPAP = 25 to 35 mmHg), although in some subjects PAP can be markedly increased (mPAP = 35 to 50 mmHg) [8, 9]. In such patients, especially in those who have mild-to-moderate impaired lung mechanics, this pressure increase is considered as “out-of-proportion” PH. As an example, in a retrospective study regarding RHC measurements in COPD patients, moderate-to-severe PH.

Recently, the German consensus group attempted to define severe PH in patients with chronic lung disease according to the following criteria (at least two out of three have to meet): (a) mPAP > 35 mmHg, (b) mPAP ≥ 25 mmHg with limited cardiac index (CI < 2.0 L/min/m 2 ), and (c) PVR > 480 dyn/s/cm −5 [10]. This definition describes less than 5% of patients with lung disease and gives a quantitative dimension to the “out-of-proportion” approach. Epidemiological input on the prevalence of “out-of-proportion” PH is not available, except for few scattered data from subgroup analyses out of large studies. In a survey by a cardiac echo laboratory, the prevalence of all-cause PH (determined as systolic PAP > 40 mmHg) was 10.5% [11]. Among those subjects, only 9.7% had underlying lung diseases and hypoxia.

The pathogenesis of “out-of-proportion” PH in COPD (COPD-PH) is quite complex and being continuously elucidated by ongoing research. Pulmonary vascular endothelial dysfunction, as well as the inflammatory effect, is roughly the outline of the disease mechanisms. A major inflammatory factor in COPD is thought to be tobacco smoke inhalation, with established vascular and parenchymal changes in human and experimental animal lungs, and could act additively in COPD-PH as a direct hit to pulmonary vasculature [12, 13]. There is a documented decrease of endothelial NO synthase (eNOS) expression and impaired vasodilation response in asymptomatic smokers, as well as in advanced COPD disease, delineating a potential role of eNOS in the disease [12–18]. Additionally, certain eNOS and ACE polymorphisms have been found to be associated with COPD-PH [19]. Interleukin-6 (IL-6) and the presence of its polymorphism were associated with higher PAP in COPD patients, adumbrating an involvement in COPD-PH pathogenesis [20, 21].

At first, as in other parenchymal lung disease-associated PH subtypes, acute hypoxia-induced vasoconstriction was thought to be the initializing factor in vascular remodeling. In fact, chronic hypoxia induces the neomuscularization of pulmonary arterioles, resulting in intimal thickening by SMC assemblage and extracellular deposition of plenteous collagen and elastin, a phenomenon widely referred as “intimal fibroelastosis.” Of great interest is that these changes have also been described in normoxemic (pO2 within normal range) COPD patients without pulmonary hypertension and also in asymptomatic smokers [17]. In addition, in an experimental animal study, pCO2 as well as pH was found to have an amplifying effect on acute hypoxia-induced vasoconstriction [21]. Recent data proposes an important role for serotonin (5-HT) and its transporter (5-HTT) in intimal fibroelastosis. The 5-HTT LL genotype, which is linked with greater 5-HTT expression, was found to be associated with considerably high PAP in COPD, compared to other polymorphisms [22]. A pathological examination of postpneumonectomy lungs demonstrated mass attraction of mostly CD8+ lymphocytes infiltrating the vascular adventitia [23]. An adaptive response to hypoxemia is polycythemia (increased total erythrocyte number), which is also incriminated for alterations in pulmonary vasculature. It has been shown experimentally that a sole hematocrit increment in dogs can notably increase PVR by 112% (P < 0.01). Moreover, there was a combined augmentation effect of polycythemia and hypoxia, increasing PVR by 308% (P < 0.005) [24]. Recently, it was demonstrated that the presence of excessive erythrocytosis in mice increased the sPAP in vivo [25]. Additive data shows that there is definitely a role of polycythemia in the COPD-PH mechanism, but in humans is yet to be investigated. The true incidence of clinically significant resting “out-of-proportion” PH is difficult to be estimated in COPD patients, as most data comes from reports that include COPD patients with advanced disease, resulting in a notably wide reported range varying from 5% to 70% [26–29]. This is cofounded by several limitations. Firstly, there are no large-scale studies assessing the true prevalence of COPD-PH by means of RHC. Commonly, the test selected for PH documentation in such patients is TTE. As already emphasized elsewhere in this paper, TTE can only estimate sPAP and mPAP values, and only the invasive RHC can establish the presence of elevated PAP. This must be kept in mind by the clinician when evaluating the reported incidence for COPD-PH, because in many settings PH diagnosis relies only on TTE. There is additive data for this statement, showing TTE inaccuracy in PAP and cardiac output (CO) estimation, when compared to RHC, in several PH subtypes [28]. Secondly, most available studies are of retrospective nature and include mostly patients with severe disease (FEV 1 < 30% predicted). As an example, studies on severe COPD patients report an incidence of 91%, with the majority suffering from mild-to-moderate PH (mPAP = 20–35 mmHg) and 1% to 5% suffering from severe disease (mPAP > 35–40 mmHg) [8, 28, 30]. However, in some COPD patients, the hemodynamic impairment might be more severe than expected from the related progress of parenchymal disease. This group of patients is characterized in anecdotal basis as “PH out-of-proportion to degree of respiratory compromise.” This is of significant interest, because such patients have been viewed as potential beneficiaries of PAH-specific therapeutic agents, although, as of now, there is neither consensus on the best candidates for studying such management, nor RCTs running. It seems that there is a strong negative impact on survival from the occurrence of PH in COPD patients, even though the hemodynamic impairment is rather mild in terms of pressure values per se. The 5-year survival regarding severely affected COPD patients with PH (mPAP ≥ 25 mmHg) has been reported as low as 36%, compared to 62% in COPD patients without PH [31]. Although several studies demonstrate high mortality rates in COPD patients with pulmonary hypertension, it is still under discussion if the occurrence of pulmonary hypertension is an independent cause of death or just a sign of disease worsening.

As of today, the European guidelines regarding “out-of-proportion” PH (PH owing to lung disease and/or hypoxia) recommend performance of TTE for screening (Class of recommendation-Level of evidence, I-C) and RHC for a definite diagnosis of PH due to lung disease (I-C). Again, the use of PAH-specific therapeutic agents is not recommended in this group (III-C). Additionally, optimal treatment of the underlying lung disease and the use of supplemental O 2 are the recommended therapeutic measures in such patients. In conclusion, we emphasize again that the use of PAH-specific therapeutic agents is not approved for patients belonging to groups 3 and 5 by the Dana Point classification [1], which is the case of all the diseases analyzed in this review with the exception of CTDs. Clinical studies and RCTs should be performed in such nongroup 1 patients, in an effort to clearly designate subcategories of subjects that might benefit from specific treatments.



[1] N. Galie, M. M. Hoeper, M. Humbert et al., “Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC)and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT),” European Heart Journal, vol. 30, no. 20, pp. 2493–2537, 2009.

[2] M. Humbert, O. Sitbon, A. Chaouat et al., “Pulmonary arterial hypertension in France: results from a national registry,” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 9, pp. 1023–1030, 2006.

[3] A. J. Peacock, N. F. Murphy, J. J. V. McMurrey, L. Caballero, and S. Stewart, “An epidemiological study of pulmonary arterial hypertension,” European Respiratory Journal, vol. 30, no. 1, pp. 104–109, 2007.

[4] G. E. D’Alonzo, R. J. Barst, S. M. Ayres et al., “Survival in patients with primary pulmonary hypertension: results from a national prospective registry,” Annals of Internal Medicine, vol. 115, no. 5, pp. 343–349, 1991.

[5] M. McGoon, D. Gutterman, V. Steen et al., “Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines,” Chest, vol. 126, no. 1, supplement, pp. S14–S34, 2004.

[6] J. Houtchens, D. Martin, and J. R. Klinger, “Diagnosis and management of pulmonary arterial hypertension,” Pulmonary Medicine, vol. 2011, Article ID 845864, 13 pages, 2011.

[7] Y. Ling, M. K. Johnson, D. G. Kiely et al., “Changing demographics, epidemiology and survival of incident pulmonary arterial hypertension,” American Journal of Respiratory and Critical Care Medicine. In press.

[8] G. Thabut, G. Dauriat, J. B. Stern et al., “Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation,” Chest, vol. 127, no. 5, pp. 1531–1536, 2005.

[9] A. Chaouat, A. S. Bugnet, N. Kadaoui et al., “Severe pulmonary hypertension and chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 2, pp. 189–194, 2005.

[10] M. Hoeper, S. Andreas, A. Bastian et al., “Pulmonary hypertension due to chronic lung disease: updated recommendations of the Cologne consensus conference 2011,” International Journal of Cardiology, vol. 154, no. 1, pp. 45–53, 2011.

[11] E. Gabbay, W. Yeow, and D. Playford, “Pulmonary arterial hypertension (PAH) is an uncommon cause of pulmonary hypertension (PH) in an unselected population:

the Armadale echocardiography study,” American Journal of Respiratory and Critical Care Medicine, vol. 175, p. A713, 2007.

[12] H. S. Sekhon, J. L. Wright, and A. Churg, “Cigarette smoke causes rapid cell proliferation in small airways and associated pulmonary arteries,” American Journal of Physiology, vol. 267, no. 5, pp. L557–L563, 1994.

[13] K. A. Hale, S. L. Ewing, B. A. Gosnell, and D. E. Niewoehner, “Lung disease in long-term cigarette smokers with and without chronic air-flow obstruction,” American Review of Respiratory Disease, vol. 130, no. 5, pp. 716–721, 1984.

[14] Z. G. Zhu, H. H. Li, and B. R. Zhang, “Expression of endothelin-1 and constitutional nitric oxide synthase messenger RNA in saphenous vein endothelial cells exposed to arterial flow shear stress,” Annals of Thoracic Surgery, vol. 64,

no. 5, pp. 1333–1338, 1997.

[15] J. S. Stamler, E. Loh, M. A. Roddy, K. E. Currie, and M. A. Creager, “Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans,” Circulation, vol. 89, no. 5, pp. 2035–2040, 1994.

[16] J. A. Barber`a, V. I. Peinado, S. Santos, J. Ramirez, J. Roca, and R. Rodriguez-Roisin, “Reduced expression of endothelial nitric oxide synthase in pulmonary arteries of smokers,” American Journal of Respiratory and Critical Care Medicine,

vol. 164, no. 4, pp. 709–713, 2001.

[17] J. A. Barber`a, V. I. Peinado, and S. Santos, “Pulmonary hypertension in chronic obstructive pulmonary disease,” European Respiratory Journal, vol. 21, no. 5, pp. 892–905, 2003.

[18] A. T. Dinh-Xuan, T. W. Higenbottam, C. A. Clelland et al., “Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease,” The New England Journal of Medicine, vol. 324, no. 22, pp. 1539–1547,


[19] P. Yildiz, H. Oflaz, N. Cine, N. Erginel- ¨Unaltuna, F. Erzengin, and V. Yilmaz, “Gene polymorphisms of endothelial nitric oxide synthase enzyme associated with pulmonary hypertension in patients with COPD,” Respiratory Medicine, vol. 97, no. 12, pp. 1282–1288, 2003.

[20] P. Joppa, D. Petrasova, B. Stancak, and R. Tkacova, “Systemic inflammation in patients with COPD and pulmonary hypertension,” Chest, vol. 130, no. 2, pp. 326–333, 2006.

[21] A. Chaouat, L. Savale, C. Chouaid et al., “Role for interleukin-6 in COPD-related pulmonary hypertension,” Chest, vol. 136, no. 3, pp. 678–687, 2009.

[22] P. A. McFarlane, J. P. Gardaz, and M. K. Sykes, “CO 2 and mechanical factors reduce blood flow in a collapsed lung lobe,” Journal of Applied Physiology Respiratory Environmental and Exercise Physiology, vol. 57, no. 3, pp. 739–743, 1984.

[23] S. Eddahibi, A. Chaouat, N. Morrell et al., “Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease,” Circulation, vol. 108, no. 15, pp. 1839–1844, 2003.

[24] V. I. Peinado, J. A. Barbera, J. Ramirez et al., “Endothelial dysfunction in pulmonary arteries of patients with mild COPD,” American Journal of Physiology, vol. 274, no. 6, pp. 908–913, 1998.

[25] R. L. McGrath and J. V. Weil, “Adverse effects of normovolemic polycythemia and hypoxia on hemodynamics in the dog,” Circulation Research, vol. 43, no. 5, pp. 793–798, 1978.

[26] J. Hasegawa, K. F. Wagner, D. Karp et al., “Altered pulmonary vascular reactivity in mice with excessive erythrocytosis,” American Journal of Respiratory and Critical Care Medicine, vol. 169, no. 7, pp. 829–835, 2004.

[27] S. M. Scharf, M. Iqbal, C. Keller, G. Criner, S. Lee, and H. E. Fessler, “Hemodynamic characterization of patients with severe emphysema,” American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 3, pp. 314–322, 2002.

[28] S. M. Arcasoy, J. D. Christie, V. A. Ferrari et al., “Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 5, pp. 735–740, 2003.

[29] V. Fayngersh, F. Drakopanagiotakis, F. Dennis McCool, and J. R. Klinger, “Pulmonary hypertension in a stable community-based COPD population,” Lung, vol. 189, no. 5, pp. 377–382, 2011.

[30] M. R. Fisher, P. R. Forfia, E. Chamera et al., “Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension,” American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 7, pp. 615–621, 2009.

[31] A. Chaouat, R. Naeije, and E. Weitzenblum, “Pulmonary hypertension in COPD,” European Respiratory Journal, vol. 32, no. 5, pp. 1371–1385, 2008.

[32] M. Oswald-Mammosser, E. Weitzenblum, E. Quoix et al., “Prognostic factors in COPD patients receiving long-term oxygen therapy: importance of pulmonary artery pressure,” Chest, vol. 107, no. 5, pp. 1193–1198, 1995.


Conflicts of Interest: None