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Epidemiology and treatment of pulmonary arterial hypertension

Key Points

  • In the Western world, idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH) are the most common subtypes of PAH; PAH is increasingly diagnosed in an ageing population with comorbidities

  • The aetiology of PAH is distinct in the developing world; congenital heart disease-associated PAH is the most common form in China, whereas infectious causes such as schistosomiasis is common in countries such as Brazil

  • PAH registries worldwide continue to report improvement in survival with the use of current PAH therapy

  • Five classes of drugs are now approved for the treatment of PAH, including endothelin 1 receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues, and prostacyclin IP receptor agonist

  • Combination therapy is currently considered standard of care in PAH, and evidence supports the early and aggressive use of combination therapy at the time of diagnosis

Abstract

In the past 2 decades, major changes have occurred in the epidemiological and treatment landscape of pulmonary arterial hypertension (PAH). Previously regarded as a disease of the young and middle-aged, contemporary registries from the Western world have demonstrated an increase in the age of patients with PAH, many of whom are elderly with multiple comorbidities. Another important observation is the improvement in survival of patients with PAH in the modern treatment era compared with historical cohorts, before the availability of advanced therapy. The management of PAH has also become more complex, and numerous drugs are now approved that target the endothelin 1, nitric oxide, and prostacyclin pathways. Combining drugs from different classes is now considered the standard of care and has been demonstrated to improve outcomes. Furthermore, the current treatment paradigm is the early use of combination therapy, often at the time of diagnosis, particularly in patients with severe disease. This Review provides a comprehensive update on the epidemiology and pharmacotherapy of PAH.

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Figure 1: Molecular targets of approved PAH drug therapies.

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References

  1. Humbert, M. et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43, 13S–24S (2004).

    CAS  PubMed  Google Scholar 

  2. Humbert, M. et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 130, 2189–2208 (2014).

    PubMed  Google Scholar 

  3. Tonelli, A. R. et al. Causes and circumstances of death in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 188, 365–369 (2013).

    PubMed  PubMed Central  Google Scholar 

  4. Vonk-Noordegraaf, A. et al. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J. Am. Coll. Cardiol. 62, D22–D33 (2013).

    PubMed  Google Scholar 

  5. Simonneau, G. et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 62, D34–D41 (2013).

    PubMed  Google Scholar 

  6. Galie, N. et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur. Respir. J. 46, 903–975 (2015).

    CAS  PubMed  Google Scholar 

  7. Hoeper, M. M. et al. Definitions and diagnosis of pulmonary hypertension. J. Am. Coll. Cardiol. 62, D42–50 (2013).

    PubMed  Google Scholar 

  8. Peacock, A. J. et al. An epidemiological study of pulmonary arterial hypertension. Eur. Respir. J. 30, 104–109 (2007).

    CAS  PubMed  Google Scholar 

  9. Humbert, M. et al. Pulmonary arterial hypertension in France: results from a national registry. Am. J. Respir. Crit. Care Med. 173, 1023–1030 (2006).

    PubMed  Google Scholar 

  10. Ling, Y. et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am. J. Respir. Crit. Care Med. 186, 790–796 (2012).

    PubMed  Google Scholar 

  11. Strange, G. et al. Pulmonary hypertension: prevalence and mortality in the Armadale echocardiography cohort. Heart 98, 1805–1811 (2012).

    PubMed  Google Scholar 

  12. D'Alonzo, G. E. et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med. 115, 343–349 (1991).

    CAS  PubMed  Google Scholar 

  13. Rich, S. et al. Primary pulmonary hypertension. A national prospective study. Ann. Intern. Med. 107, 216–223 (1987).

    CAS  PubMed  Google Scholar 

  14. Humbert, M. et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122, 156–163 (2010).

    PubMed  Google Scholar 

  15. Thenappan, T. et al. A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur. Respir. J. 30, 1103–1110 (2007).

    CAS  PubMed  Google Scholar 

  16. Thenappan, T. et al. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur. Respir. J. 35, 1079–1087 (2010).

    CAS  PubMed  Google Scholar 

  17. Badesch, D. B. et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 137, 376–387 (2010).

    PubMed  Google Scholar 

  18. Benza, R. L. et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 142, 448–456 (2012).

    PubMed  Google Scholar 

  19. Escribano-Subias, P. et al. Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur. Respir. J. 40, 596–603 (2012).

    PubMed  Google Scholar 

  20. Jiang, X., Humbert, M. & Jing, Z. C. in Pulmonary Vascular Disorders Vol. 41 (eds Humbert, M., Souza, R. & Simonneau, G.) 85–93 (Karger, 2012).

    Google Scholar 

  21. Jing, Z. C. et al. Registry and survival study in chinese patients with idiopathic and familial pulmonary arterial hypertension. Chest 132, 373–379 (2007).

    PubMed  Google Scholar 

  22. Hoeper, M. M. et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int. J. Cardiol. 168, 871–880 (2013).

    PubMed  Google Scholar 

  23. Ogawa, A. et al. Survival of Japanese patients with idiopathic/heritable pulmonary arterial hypertension. Am. J. Cardiol. 119, 1479–1484 (2017).

    PubMed  Google Scholar 

  24. Chung, W. J. et al. Baseline characteristics of the Korean Registry of Pulmonary Arterial Hypertension. J. Korean Med. Sci. 30, 1429–1438 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. Jansa, P. et al. Epidemiology and long-term survival of pulmonary arterial hypertension in the Czech Republic: a retrospective analysis of a nationwide registry. BMC Pulm. Med. 14, 45 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. Alves, J. L. Jr et al. Pulmonary arterial hypertension in the southern hemisphere: results from a registry of incident Brazilian cases. Chest 147, 495–501 (2015).

    PubMed  Google Scholar 

  27. Mueller-Mottet, S. et al. Long-term data from the Swiss pulmonary hypertension registry. Respiration 89, 127–140 (2015).

    PubMed  Google Scholar 

  28. Zhang, R. et al. Survival of Chinese patients with pulmonary arterial hypertension in the modern treatment era. Chest 140, 301–309 (2011).

    PubMed  Google Scholar 

  29. Lee, W. T. et al. Predicting survival in pulmonary arterial hypertension in the UK. Eur. Respir. J. 40, 604–611 (2012).

    PubMed  Google Scholar 

  30. McGoon, M. D. et al. Pulmonary arterial hypertension: epidemiology and registries. J. Am. Coll. Cardiol. 62, D51–D59 (2013).

    PubMed  Google Scholar 

  31. Hoeper, M. M. & Simon, R. G. J. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur. Respir. Rev. 23, 450–457 (2014).

    PubMed  Google Scholar 

  32. Poms, A. D. et al. Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis. Chest 144, 169–176 (2013).

    PubMed  Google Scholar 

  33. Halpern, S. D. & Taichman, D. B. Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest 136, 37–43 (2009).

    PubMed  Google Scholar 

  34. Larkin, E. K. et al. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 186, 892–896 (2012).

    PubMed  PubMed Central  Google Scholar 

  35. Benza, R. L. et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest 141, 354–362 (2012).

    PubMed  Google Scholar 

  36. Kawut, S. M. et al. Sex and race differences in right ventricular structure and function: the multi-ethnic study of atherosclerosis-right ventricle study. Circulation 123, 2542–2551 (2011).

    PubMed  PubMed Central  Google Scholar 

  37. Jacobs, W. et al. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest 145, 1230–1236 (2014).

    PubMed  Google Scholar 

  38. Sitbon, O. et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur. Respir. J. 47, 1727–1736 (2016).

    CAS  PubMed  Google Scholar 

  39. Gall, H. et al. The Giessen Pulmonary Hypertension Registry: survival in pulmonary hypertension subgroups. J. Heart Lung Transplant. http://dx.doi.org/10.1016/j.healun.2017.02.016 (2017).

  40. Benza, R. L. et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 122, 164–172 (2010).

    PubMed  Google Scholar 

  41. Evans, J. D. et al. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir. Med. 4, 129–137 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Montani, D. et al. Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study. Lancet Respir. Med. 5, 125–134 (2017).

    CAS  PubMed  Google Scholar 

  43. Tamby, M. C. et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 60, 765–772 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Humbert, M. et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur. Respir. J. 36, 549–555 (2010).

    CAS  PubMed  Google Scholar 

  45. Sitbon, O. et al. Validation of two predictive models for survival in pulmonary arterial hypertension. Eur. Respir. J. 46, 152–164 (2015).

    PubMed  Google Scholar 

  46. Giaid, A. et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 328, 1732–1739 (1993).

    CAS  PubMed  Google Scholar 

  47. Giaid, A. & Saleh, D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 333, 214–221 (1995).

    CAS  PubMed  Google Scholar 

  48. Humbert, M., Sitbon, O. & Simonneau, G. Treatment of pulmonary arterial hypertension. N. Engl. J. Med. 351, 1425–1436 (2004).

    CAS  PubMed  Google Scholar 

  49. Guignabert, C. et al. New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest 147, 529–537 (2015).

    PubMed  Google Scholar 

  50. Morrell, N. W. et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β1 and bone morphogenetic proteins. Circulation 104, 790–795 (2001).

    CAS  PubMed  Google Scholar 

  51. Humbert, M. et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 151, 1628–1631 (1995).

    CAS  PubMed  Google Scholar 

  52. Price, L. C. et al. Inflammation in pulmonary arterial hypertension. Chest 141, 210–221 (2012).

    CAS  PubMed  Google Scholar 

  53. Perros, F. et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 185, 311–321 (2012).

    PubMed  Google Scholar 

  54. McMurtry, M. S. et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 95, 830–840 (2004).

    CAS  PubMed  Google Scholar 

  55. Zhao, L. et al. Heterogeneity in lung 18FDG uptake in pulmonary arterial hypertension: potential of dynamic 18FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments. Circulation 128, 1214–1224 (2013).

    CAS  PubMed  Google Scholar 

  56. Perros, F. et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 178, 81–88 (2008).

    CAS  PubMed  Google Scholar 

  57. Tu, L. et al. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am. J. Respir. Cell Mol. Biol. 45, 311–322 (2011).

    CAS  PubMed  Google Scholar 

  58. Guignabert, C. et al. Pathogenesis of pulmonary arterial hypertension: lessons from cancer. Eur. Respir. Rev. 22, 543–551 (2013).

    PubMed  Google Scholar 

  59. Yuan, J. X. et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98, 1400–1406 (1998).

    CAS  PubMed  Google Scholar 

  60. Antigny, F. et al. Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation 133, 1371–1385 (2016).

    CAS  PubMed  Google Scholar 

  61. Machado, R. D. et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am. J. Hum. Genet. 68, 92–102 (2001).

    CAS  PubMed  Google Scholar 

  62. Ma, L. et al. A novel channelopathy in pulmonary arterial hypertension. N. Engl. J. Med. 369, 351–361 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Soubrier, F. et al. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 62, D13–D21 (2013).

    CAS  PubMed  Google Scholar 

  64. Humbert, M. & Ghofrani, H. A. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax 71, 73–83 (2016).

    PubMed  Google Scholar 

  65. Galie, N. et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N. Engl. J. Med. 373, 834–844 (2015).

    CAS  PubMed  Google Scholar 

  66. Davie, N. et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am. J. Respir. Crit. Care Med. 165, 398–405 (2002).

    PubMed  Google Scholar 

  67. Hirata, Y. et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J. Clin. Invest. 91, 1367–1373 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Rubin, L. J. et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346, 896–903 (2002).

    CAS  PubMed  Google Scholar 

  69. Humbert, M. et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur. Respir. J. 30, 338–344 (2007).

    CAS  PubMed  Google Scholar 

  70. Galie, N. et al. Ambrisentan therapy for pulmonary arterial hypertension. J. Am. Coll. Cardiol. 46, 529–535 (2005).

    CAS  PubMed  Google Scholar 

  71. Galie, N. et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 117, 3010–3019 (2008).

    CAS  PubMed  Google Scholar 

  72. Iglarz, M. et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J. Pharmacol. Exp. Ther. 327, 736–745 (2008).

    CAS  PubMed  Google Scholar 

  73. Pulido, T. et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N. Engl. J. Med. 369, 809–818 (2013).

    CAS  PubMed  Google Scholar 

  74. Rybalkin, S. D. et al. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ. Res. 93, 280–291 (2003).

    CAS  PubMed  Google Scholar 

  75. Galie, N. et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med. 353, 2148–2157 (2005).

    CAS  PubMed  Google Scholar 

  76. Rubin, L. J. et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 140, 1274–1283 (2011).

    CAS  PubMed  Google Scholar 

  77. Galie, N. et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 119, 2894–2903 (2009).

    CAS  PubMed  Google Scholar 

  78. Stasch, J. P. et al. NO-independent regulatory site on soluble guanylate cyclase. Nature 410, 212–215 (2001).

    CAS  PubMed  Google Scholar 

  79. Stasch, J. P., Pacher, P. & Evgenov, O. V. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123, 2263–2273 (2011).

    PubMed  PubMed Central  Google Scholar 

  80. Ghofrani, H. A. et al. Riociguat for the treatment of pulmonary arterial hypertension. N. Engl. J. Med. 369, 330–340 (2013).

    CAS  PubMed  Google Scholar 

  81. Humbert, M. et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann. Rheum. Dis. 76, 422–426 (2017).

    CAS  PubMed  Google Scholar 

  82. Ghofrani, H. A. et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N. Engl. J. Med. 369, 319–329 (2013).

    CAS  PubMed  Google Scholar 

  83. Olschewski, H. et al. Cellular pathophysiology and therapy of pulmonary hypertension. J. Lab. Clin. Med. 138, 367–377 (2001).

    CAS  PubMed  Google Scholar 

  84. Coleman, R. A., Smith, W. L. & Narumiya, S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol. Rev. 46, 205–229 (1994).

    CAS  PubMed  Google Scholar 

  85. Barst, R. J. et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N. Engl. J. Med. 334, 296–301 (1996).

    CAS  PubMed  Google Scholar 

  86. Sitbon, O. et al. EPITOME-2: an open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension. Am. Heart J. 167, 210–217 (2014).

    CAS  PubMed  Google Scholar 

  87. Jing, Z. C. et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 127, 624–633 (2013).

    CAS  PubMed  Google Scholar 

  88. McLaughlin, V. V. et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J. Am. Coll. Cardiol. 55, 1915–1922 (2010).

    CAS  PubMed  Google Scholar 

  89. Asaki, T. et al. Selexipag: an oral and selective IP prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. J. Med. Chem. 58, 7128–7137 (2015).

    CAS  PubMed  Google Scholar 

  90. Sitbon, O. et al. Selexipag for the treatment of pulmonary arterial hypertension. N. Engl. J. Med. 373, 2522–2533 (2015).

    CAS  PubMed  Google Scholar 

  91. European Medicines Agency. EMA concludes safety review of Uptravi. EMA http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/04/news_detail_002726.jsp&mid=WC0b01ac058004d5c1 (2017).

  92. Barst, R. J. et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S78–S84 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. McLaughlin, V. V. et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 174, 1257–1263 (2006).

    CAS  PubMed  Google Scholar 

  94. Hoeper, M. M. et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur. Respir. J. 28, 691–694 (2006).

    CAS  PubMed  Google Scholar 

  95. Simonneau, G. et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann. Intern. Med. 149, 521–530 (2008).

    PubMed  Google Scholar 

  96. Tapson, V. F. et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest 142, 1383–1390 (2012).

    CAS  PubMed  Google Scholar 

  97. Tapson, V. F. et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest 144, 952–958 (2013).

    CAS  PubMed  Google Scholar 

  98. McLaughlin, V. et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur. Respir. J. 46, 405–413 (2015).

    PubMed  Google Scholar 

  99. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00323297 (2014).

  100. Lajoie, A. C. et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis. Lancet Respir. Med. 4, 291–305 (2016).

    CAS  PubMed  Google Scholar 

  101. Galie, N. et al. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur. Respir. J. 45, 1314–1322 (2015).

    CAS  PubMed  Google Scholar 

  102. Humbert, M. et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur. Respir. J. 24, 353–359 (2004).

    CAS  PubMed  Google Scholar 

  103. Coghlan, J. G. et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2016-210236 (2016).

  104. Galie, N. et al. AMBITION: a randomised, multicentre study of first line ambrisentan and tadalafil combination therapy in subjects with pulmonary arterial hypertension (PAH). Eur. Respir. J. 44, A2916 (2014).

    Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02558231 (2016).

  106. Hassoun, P. M. et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 192, 1102–1110 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Sitbon, O. et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur. Respir. J. 43, 1691–1697 (2014).

    PubMed  Google Scholar 

  108. Rosenkranz, S. et al. Left ventricular heart failure and pulmonary hypertension. Eur. Heart J. 37, 942–954 (2016).

    PubMed  Google Scholar 

  109. Opitz, C. F. et al. Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. J. Am. Coll. Cardiol. 68, 368–378 (2016).

    PubMed  Google Scholar 

  110. Charalampopoulos, A. et al. Response to pulmonary arterial hypertension drug therapies in patients with pulmonary arterial hypertension and cardiovascular risk factors. Pulm. Circ. 4, 669–678 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. van Campen, J. S. et al. Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study. Eur. Respir. J. 48, 787–796 (2016).

    PubMed  Google Scholar 

  112. Gomez-Arroyo, J. et al. Treatment for pulmonary arterial hypertension-associated right ventricular dysfunction. Ann. Am. Thorac Soc. 11, 1101–1115 (2014).

    PubMed  Google Scholar 

  113. Mathai, S. C. et al. Tricuspid annular plane systolic excursion is a robust outcome measure in systemic sclerosis-associated pulmonary arterial hypertension. J. Rheumatol. 38, 2410–2418 (2011).

    PubMed  Google Scholar 

  114. Forfia, P. R. et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am. J. Respir. Crit. Care Med. 174, 1034–1041 (2006).

    PubMed  Google Scholar 

  115. van Wolferen, S. A. et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur. Heart J. 28, 1250–1257 (2007).

    PubMed  Google Scholar 

  116. van de Veerdonk, M. C. et al. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J. Am. Coll. Cardiol. 58, 2511–2519 (2011).

    PubMed  Google Scholar 

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E.M.T.L. and M.H. researched the data for the article, and E.M.T.L. wrote the manuscript. All the authors made substantial contributions to discussion of content, and edited/reviewed the manuscript before submission.

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Correspondence to Marc Humbert.

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E.M.T.L. has relationships with Actelion, AstraZeneca, GSK, and Menarini. Relationships include serving on speaker bureaus, consultancy on advisory boards, and research funding support. D.S.C. received support from Actelion, including serving on the speaker bureau and funding for research. M.H. has relationships with drug companies including Actelion, Bayer, GSK, Merck, Novartis, Pfizer, and United Therapeutics. In addition to being an investigator in trials involving these companies, relationships include consultancy service and membership of scientific advisory boards. E.G. declares no competing interests.

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Lau, E., Giannoulatou, E., Celermajer, D. et al. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol 14, 603–614 (2017). https://doi.org/10.1038/nrcardio.2017.84

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