Pulmonary Hypertension

Increased pulmonary vascular resistance is caused by

• Pathologic vasoconstriction

• Obliteration of the pulmonary vascular bed

Pulmonary hypertension is characterized by variable and sometimes pathologic vasoconstriction and by endothelial and smooth muscle proliferation, hypertrophy, and chronic inflammation, resulting in vascular wall remodeling. Vasoconstriction is thought to be due in part to enhanced activity of thromboxane and endothelin-1 (both vasoconstrictors) and reduced activity of prostacyclin and nitric oxide (both vasodilators).

The increased pulmonary vascular pressure that results from vascular obstruction further injures the endothelium. Injury activates coagulation at the intimal surface, which may worsen the hypertension.

Thrombotic coagulopathy due to platelet dysfunction, increased activity of plasminogen activator inhibitor type 1 and fibrinopeptide A, and decreased tissue plasminogen activator activity may also contribute. Platelets, when stimulated, may also play a key role by secreting substances that increase proliferation of fibroblasts and smooth muscle cells such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β). Focal coagulation at the endothelial surface should not be confused with chronic thromboembolic pulmonary hypertension, in which pulmonary hypertension is caused by organized pulmonary emboli.

Mutations in the BMPR2 gene account for most cases of hereditary PAH and also occurs in idiopathic PAH. Aberrant BMPR2 signaling disturbs the TGF-β/BMP balance, favoring a pro-proliferative and anti-apoptotic response in pulmonary artery smooth muscle and endothelial cells. BMPR2 signaling, therefore, has become an increasingly studied target for pulmonary hypertension treatment (1).

Increased pulmonary venous pressure is typically caused by disorders that affect the left side of the heart and raise left chamber pressures, which ultimately lead to elevated pressure in the pulmonary veins. Elevated pulmonary venous pressures can cause acute damage to the alveolar-capillary wall and subsequent edema. Persistently high pressures may eventually lead to irreversible thickening of the walls of the alveolar-capillary membrane, decreasing lung diffusion capacity.

Most commonly, pulmonary venous hypertension occurs in left heart failure with preserved ejection fraction (HFpEF), typically in older females who have hypertension and metabolic syndrome. In patients with pulmonary hypertension related to left-sided heart disease, elevated pulmonary vascular resistance ([PVR] defined as the transpulmonary gradient divided by cardiac output) are associated with worse outcomes.

In most patients, pulmonary hypertension eventually leads to right ventricular hypertrophy followed by dilation and right ventricular failure. Right ventricular failure limits cardiac output during exertion.

Increased pulmonary venous blood flow due to congenital heart disease can cause pulmonary hypertension. This can occur in conditions such as atrial septal defects, ventricular septal defects, and patent ductus arteriosus, presumably through the development of characteristic pulmonary vascular lesions. However, the true effect of increased pulmonary blood flow is poorly defined, and increased flow may lead to vascular obstruction only with concomitant pulmonary vascular resistance or a second stimulus.

1. 1. Cuthbertson I, Morrell NW, Caruso P. BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension. Circ Res 2023;132(1):109-126. doi:10.1161/CIRCRESAHA.122.321554

1. 1. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023;61(1):2200879. Published 2023 Jan 6. doi:10.1183/13993003.00879-2022

2. 2. Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J 2019;53(1):1801899. doi:10.1183/13993003.01899-2018

Treatment of pulmonary arterial hypertension (PAH) is rapidly evolving. Medications target 5 aberrant pathways implicated in the development of PAH:

• Endothelin pathway

• Nitric oxide pathway

• Prostacyclin pathway

• Activin receptor signaling pathway

• Inflammatory pathway

The endothelin pathway is targeted by bosentan, ambrisentan, and macitentan, which are oral endothelin-receptor antagonists (ERAs). is targeted by bosentan, ambrisentan, and macitentan, which are oral endothelin-receptor antagonists (ERAs).

The nitric oxide pathway is targeted by sildenafil, tadalafil, and vardenafil, which are oral phosphodiesterase 5 (PDE5) inhibitors. Riociguat, a soluble guanylate cyclase stimulator, also acts via the nitric oxide pathway. is targeted by sildenafil, tadalafil, and vardenafil, which are oral phosphodiesterase 5 (PDE5) inhibitors. Riociguat, a soluble guanylate cyclase stimulator, also acts via the nitric oxide pathway.

The prostacyclin pathway is targeted by IV epoprostenol, a prostacyclin analog, which improves function and lengthens survival even in patients who are unresponsive to a vasodilator during catheterization (is targeted by IV epoprostenol, a prostacyclin analog, which improves function and lengthens survival even in patients who are unresponsive to a vasodilator during catheterization (1). Disadvantages are the need for continuous central catheter infusion and frequent, troubling adverse effects, including flushing, diarrhea, and bacteremia due to the indwelling central catheter. Prostacyclin analogs that are inhaled, taken orally, or given subcutaneously or IV (iloprost and treprostinil) are available. Selexipag is an orally bioavailable small molecule that activates the prostacyclin I2 receptor and lowers mortality and morbidity rates (). Disadvantages are the need for continuous central catheter infusion and frequent, troubling adverse effects, including flushing, diarrhea, and bacteremia due to the indwelling central catheter. Prostacyclin analogs that are inhaled, taken orally, or given subcutaneously or IV (iloprost and treprostinil) are available. Selexipag is an orally bioavailable small molecule that activates the prostacyclin I2 receptor and lowers mortality and morbidity rates (2).

The activin receptor signaling pathway has recently been implicated in pulmonary hypertension and is targeted by sotatercept, an activin signaling inhibitor. Dysregulation of this pathway is characterized by elevated levels of serum and pulmonary activin A, activin B, follistatin, follistatin-like 3 and reduced levels of inhibin-alpha in pulmonary arterial hypertension (has recently been implicated in pulmonary hypertension and is targeted by sotatercept, an activin signaling inhibitor. Dysregulation of this pathway is characterized by elevated levels of serum and pulmonary activin A, activin B, follistatin, follistatin-like 3 and reduced levels of inhibin-alpha in pulmonary arterial hypertension (3). These proteins, which are members of the transforming growth factor beta (TGF-beta) superfamily, have been implicated in pulmonary vascular remodeling and are helpful in predicting mortality in PAH.

BMPR2 is the most common gene mutation in patients with heritable PAH and in idiopathic PAH. The BMPR2 gene encodes for the BMP protein, which is also a member of the TGF-beta superfamily. Sotatercept helps restore the balance between anti-proliferation (BMP) and pro-proliferation (activin) signaling pathways that is dysregulated in patients with PAH related to BMP signaling. When added to background therapy for pulmonary hypertension, gene encodes for the BMP protein, which is also a member of the TGF-beta superfamily. Sotatercept helps restore the balance between anti-proliferation (BMP) and pro-proliferation (activin) signaling pathways that is dysregulated in patients with PAH related to BMP signaling. When added to background therapy for pulmonary hypertension,sotatercept reduced pulmonary vascular resistance in a dose-dependent manner. This change was driven by a reduction in mean pulmonary artery pressures rather than pulmonary artery wedge pressure or cardiac output. This finding was consistent among all background therapy (including prostacyclin infusion therapy) subgroups (4). In a phase 3 trial of sotatercept or placebo added to standard of care background therapy, patients who received sotatercept demonstrated significant improvement in the 6-minute walk test at 24 weeks. Patients randomized to sotatercept also demonstrated significant improvement in pulmonary vascular resistance, NT-proBNP levels, quality of life, risk of death, and World Health Organization (WHO) functional class (5).

The inflammatory pathway is targeted by seralutinib, a small-molecule kinase inhibitor that treats the pulmonary artery smooth muscle cell hypertrophy and proliferation as well as perivascular inflammation that occurs in PAH. Seralutinib is a potent inhibitor of derived growth factor receptor alpha and beta, colony stimulating factor 1 receptor, and mast/stem cell growth factor receptor kit (6). In a phase 2 trial, when seralutinib was administered to patients with PAH functional class II or III (see table Functional Status of Patients With Pulmonary Hypertension), there was a significant reduction in the pulmonary vascular resistance (7).

Guidelines for the initial approach to therapy recommend vasoactive testing in the catheterization laboratory. If patients are vasoreactive, they should be treated with a calcium channel blocker. Patients who are not vasoreactive should be treated based on their functional class (see table Functional Status of Patients With Pulmonary Hypertension). Patients who are WHO functional class IV with high-risk findings such as chest pain or syncope should be started on combination therapy with an intravenous or subcutaneous prostacyclin plus ambrisentan (ERA) and tadalafil (PDE5) (). Patients who are WHO functional class IV with high-risk findings such as chest pain or syncope should be started on combination therapy with an intravenous or subcutaneous prostacyclin plus ambrisentan (ERA) and tadalafil (PDE5) (8). Patients with WHO functional class IV without high-risk features should be started on combination therapy with ambrisentan and tadalafil or macitentan (ERA) and tadalafil. (). Patients with WHO functional class IV without high-risk features should be started on combination therapy with ambrisentan and tadalafil or macitentan (ERA) and tadalafil. (9, 10).

With rare exception, combination therapy is generally preferred in patients with Group 1 and Group 4 pulmonary hypertension and is supported by a growing body of evidence. For example, in a randomized trial comparing the efficacy of monotherapy with oral ambrisentan 10 mg and oral tadalafil 40 mg to combination therapy of these same 2 medications all taken once daily, combination therapy significantly reduced NT-proBNP levels and increased 6-minute walk distances and the percentage of satisfactory clinical responses (is generally preferred in patients with Group 1 and Group 4 pulmonary hypertension and is supported by a growing body of evidence. For example, in a randomized trial comparing the efficacy of monotherapy with oral ambrisentan 10 mg and oral tadalafil 40 mg to combination therapy of these same 2 medications all taken once daily, combination therapy significantly reduced NT-proBNP levels and increased 6-minute walk distances and the percentage of satisfactory clinical responses (11). Also, adverse clinical outcomes (death, hospitalization, disease progression, or poor long-term outcome) were fewer with combination therapy than with monotherapy. This example supports targeting multiple pathways by beginning treatment of PAH with combination therapy. However, phosphodiesterase 5 inhibitors cannot be combined with riociguat (a soluble guanylate cyclase stimulant) because both medication classes increase cyclic guanosine monophosphate (cGMP) levels, and the combination can lead to dangerous hypotension. Patients with severe right heart failure who are at high risk of sudden death may benefit from early therapy with an intravenous or subcutaneous prostacyclin analog-containing combination regimen (typically in combination with a PDE5 inhibitor and an ERA).). Also, adverse clinical outcomes (death, hospitalization, disease progression, or poor long-term outcome) were fewer with combination therapy than with monotherapy. This example supports targeting multiple pathways by beginning treatment of PAH with combination therapy. However, phosphodiesterase 5 inhibitors cannot be combined with riociguat (a soluble guanylate cyclase stimulant) because both medication classes increase cyclic guanosine monophosphate (cGMP) levels, and the combination can lead to dangerous hypotension. Patients with severe right heart failure who are at high risk of sudden death may benefit from early therapy with an intravenous or subcutaneous prostacyclin analog-containing combination regimen (typically in combination with a PDE5 inhibitor and an ERA).

The SERAPHIN study demonstrated a significant reduction in morbidity and mortality with the use of macitentan, which could be delivered alone or as background therapy for PAH (primarily phosphodiesterase 5 inhibitors) (The SERAPHIN study demonstrated a significant reduction in morbidity and mortality with the use of macitentan, which could be delivered alone or as background therapy for PAH (primarily phosphodiesterase 5 inhibitors) (12). In the PATENT-1 trial, riociguat increased 6-minute walk distance, decreased pulmonary vascular resistance, and improved functional class when used as sequential combination therapy in patients receiving an endothelin-receptor antagonist or prostacyclin analog (as well as when used as monotherapy) (). In the PATENT-1 trial, riociguat increased 6-minute walk distance, decreased pulmonary vascular resistance, and improved functional class when used as sequential combination therapy in patients receiving an endothelin-receptor antagonist or prostacyclin analog (as well as when used as monotherapy) (13). The FREEDOM-EV study found that adding oral treprostinil to baseline monotherapy with an ERA or PDE5 inhibitor was more effective than placebo in reducing clinical worsening, reducing NT-proBNP, improving functional class, and improving 6-minute walk distance (). The FREEDOM-EV study found that adding oral treprostinil to baseline monotherapy with an ERA or PDE5 inhibitor was more effective than placebo in reducing clinical worsening, reducing NT-proBNP, improving functional class, and improving 6-minute walk distance (14).

Morbidity and mortality are lower with selexipag (a prostacyclin pathway agonist) than with placebo when Morbidity and mortality are lower with selexipag (a prostacyclin pathway agonist) than with placebo whenselexipag is combined with a PDE 5 inhibitor, an ERA, or both (15, 16). However, studies suggest that initial triple-therapy combining macitentan, tadalafil, and selexipag does not improve pulmonary vascular resistance or hemodynamics more than initial double therapy with ). However, studies suggest that initial triple-therapy combining macitentan, tadalafil, and selexipag does not improve pulmonary vascular resistance or hemodynamics more than initial double therapy withmacitentan and tadalafil alone (9). In certain clinical scenarios in patients with idiopathic, heritable, drug- or toxin-induced, or systemic rheumatic disease associated PAH, adding selexipag is recommended for patients receiving dual oral ERA/PDE5 inhibitor therapy (17).

Selected subgroups are sometimes treated differently. Prostacyclin analogs, endothelin-receptor antagonists, and guanylate cyclase stimulators have been studied primarily in idiopathic PAH; however, these medications can be used cautiously (attending to drug metabolism and drug-drug interactions) in patients with PAH due to systemic rheumatic disease, HIV, or portopulmonary hypertension. Vasodilators should be avoided in patients with PAH due to pulmonary veno-occlusive disease due to the risk of catastrophic pulmonary edema (18).

Lung transplantation offers the only hope of cure but has high morbidity because of rejection (bronchiolitis obliterans syndrome) and infection. The 5-year survival rate is 50% (19). Lung transplantation is reserved for patients with class IV disease (defined as dyspnea associated with minimal activity, leading to bed-to-chair limitations) or complex congenital heart disease in whom all therapies have failed and who meet other health criteria to be a transplant candidate.

Adjunctive therapies to treat heart failure, including diuretics, are necessary for many patients. Most patients should receive warfarin unless contraindicated.to treat heart failure, including diuretics, are necessary for many patients. Most patients should receive warfarin unless contraindicated.

Primary treatment involves management of the underlying disorder. Patients with left-sided heart disease may need surgery for valvular disease. No multicenter trials have demonstrated benefit from using PAH-specific therapies for pulmonary hypertension secondary to left-heart disease. Therefore, the use of these medications is not recommended for group 2 patients. However, the inhaled prostacyclin analog treprostinil has been shown to improve exercise capacity.may need surgery for valvular disease. No multicenter trials have demonstrated benefit from using PAH-specific therapies for pulmonary hypertension secondary to left-heart disease. Therefore, the use of these medications is not recommended for group 2 patients. However, the inhaled prostacyclin analog treprostinil has been shown to improve exercise capacity.

Patients with lung disorders and hypoxia benefit from supplemental oxygen as well as treatment of the primary disorder. There is no conclusive evidence to support the use of pulmonary vasodilators in COPD (chronic obstructive pulmonary disease). Inhaled treprostinil has been shown to improve exercise capacity in patients with pulmonary hypertension secondary to and hypoxia benefit from supplemental oxygen as well as treatment of the primary disorder. There is no conclusive evidence to support the use of pulmonary vasodilators in COPD (chronic obstructive pulmonary disease). Inhaled treprostinil has been shown to improve exercise capacity in patients with pulmonary hypertension secondary tointerstitial lung disease (20). The use of riociguat and the ERAs are generally contraindicated in pulmonary hypertension secondary to interstitial lung disease due to an increase in adverse events in clinical trials (). The use of riociguat and the ERAs are generally contraindicated in pulmonary hypertension secondary to interstitial lung disease due to an increase in adverse events in clinical trials (21, 22).

The first-line treatment for patients with severe pulmonary hypertension secondary to chronic thromboembolic disease includes surgical intervention with pulmonary thromboendarterectomy. During cardiopulmonary bypass, an organized endothelialized thrombus is dissected along the pulmonary vasculature in a procedure more complex than acute surgical embolectomy. This procedure cures pulmonary hypertension in a substantial percentage of patients and restores cardiopulmonary function; operative mortality in high volume centers is < 5% (23). Balloon pulmonary angioplasty is another interventional option. This procedure should be done only at expert centers for symptomatic patients who are not eligible for pulmonary endarterectomy. Riociguat has improved exercise capacity and pulmonary vascular resistance in patients who are not surgical candidates or for whom the risk to benefit ratio is too high (). Balloon pulmonary angioplasty is another interventional option. This procedure should be done only at expert centers for symptomatic patients who are not eligible for pulmonary endarterectomy. Riociguat has improved exercise capacity and pulmonary vascular resistance in patients who are not surgical candidates or for whom the risk to benefit ratio is too high (13). Macitentan has also demonstrated improvements in pulmonary vascular resistance, 6-minute walk test, and NT-proBNP levels in inoperable patients with chronic thromboembolic pulmonary hypertension (). Macitentan has also demonstrated improvements in pulmonary vascular resistance, 6-minute walk test, and NT-proBNP levels in inoperable patients with chronic thromboembolic pulmonary hypertension (24). Macitentan has also demonstrated safety when used combination with other PAH therapies, including riociguat (25).

Patients with sickle cell disease who have pulmonary hypertension are aggressively treated using hydroxyurea, iron chelation, and supplemental oxygen as indicated. In symptomatic patients with elevated pulmonary vascular resistance with normal pulmonary artery wedge pressure confirmed by right heart catheterization (similar to PAH pathophysiology), selective pulmonary vasodilator therapy (with epoprostenol or an endothelin-receptor antagonist) can be considered. Sildenafil increases incidence of painful crises in patients with sickle cell disease and so should be used only if patients have limited vaso-occlusive crises and are being treated with hydroxyurea or transfusion therapy. who have pulmonary hypertension are aggressively treated using hydroxyurea, iron chelation, and supplemental oxygen as indicated. In symptomatic patients with elevated pulmonary vascular resistance with normal pulmonary artery wedge pressure confirmed by right heart catheterization (similar to PAH pathophysiology), selective pulmonary vasodilator therapy (with epoprostenol or an endothelin-receptor antagonist) can be considered. Sildenafil increases incidence of painful crises in patients with sickle cell disease and so should be used only if patients have limited vaso-occlusive crises and are being treated with hydroxyurea or transfusion therapy.

1. 1. Barst RJ, Rubin LJ, Long WA, et al: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334(5):296–301, 1996. doi: 10.1056/NEJM199602013340504

2. 2. Sitbon O, Channick R, Chin KM, et al: Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 373: 2522-33, 2015. doi: 10.1056/NEJMoa1503184

3. 3. Guignabert C, Savale L, Boucly A, et al: Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension. Circulation 147(24):1809–1822, 2023. doi:10.1161/CIRCULATIONAHA.122.061501

4. 4. Humbert M, McLaughlin V, Gibbs JSR, et al: Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med 384(13):1204–1215, 2021. doi: 10.1056/NEJMoa2024277

5. 5. Hoeper MM, Badesch DB, Ghofrani HA, et al: Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med 388(16):1478–1490, 2023. doi:10.1056/NEJMoa2213558

6. 6. Pullamsetti SS, Sitapara R, Osterhout R, et al: Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension. Int J Mol Sci 24(16):12653, 2023. doi:10.3390/ijms241612653

7. 7. Frantz RP, McLaughlin VV, Sahay S, et al: Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med 12(7):523–534, 2024. doi:10.1016/S2213-2600(24)00072-9

8. 8. Humbert M, Kovacs G, Hoeper MM, et al: 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension [published correction appears in Eur Heart J. 2023 Apr 17;44(15):1312. doi: 10.1093/eurheartj/ehad005]. Eur Heart J 2022;43(38):3618-3731. doi:10.1093/eurheartj/ehac237

9. 9. Chin KM, Sitbon O, Doelberg M, et al: Three- versus two-drug therapy for patients with newly diagnosed pulmonary arterial hypertension. J Am Coll Cardiol 78(14):1393–1403, 2021. doi: 10.1016/j.jacc.2021.07.057

10. 10. Maron BA: Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer. J Am Heart Assoc 12(8):e029024, 2023. doi:10.1161/JAHA.122.029024

11. 11. Galie N, Barbera JA, Frost AE, et al: Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 373: 834-44, 2015. doi: 10.1056/NEJMoa1413687

12. 12. Pulido T, Adzerikho I, Channick RN, et al: Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 369(9):809–818, 2013. doi:10.1056/NEJMoa1213917

13. 13. Ghofrani HA, Galiè N, Grimminger F, et al: Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369(4): 330-340, 2013. doi: 10.1056/NEJMoa1209655

14. 14. White RJ, Jerjes-Sanchez C, Bohns Meyer GM, et al: Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial. Am J Respir Crit Care Med 201(6):707–717, 2020. doi: 10.1164/rccm.201908-1640OC

15. 15. Tamura Y, Channick RN: New paradigm for pulmonary arterial hypertension treatment. Curr Opin Pulm Med 22(5): 429-33, 2016. doi: 10.1097/MCP.0000000000000308

16. 16. McLaughlin VV, Channick R, Chin K, et al: Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: Results of the GRIPHON study. J Am Coll Cardiol 65 (suppl): A1538, 2015.

17. 17. McLaughlin VV, Channick R, De Marco T, et al: Results of an expert consensus survey on the treatment of pulmonary arterial hypertension with oral prostacyclin pathway agents. Chest 157(4):955–965, 2020. doi: 10.1016/j.chest.2019.10.043

18. 18. Condon DF, Nickel NP, Anderson R, et al: The 6th World Symposium on Pulmonary Hypertension: what's old is new. F1000Research 8:F1000 Faculty Rev-888, 2019. doi: 10.12688/f1000research.18811.1

19. 19. Hendriks PM, Staal DP, van de Groep LD, et al: The evolution of survival of pulmonary arterial hypertension over 15 years. Pulm Circ 12(4):e12137, 2022. doi:10.1002/pul2.12137

20. 20. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al: Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 384(4):325–334, 2021. doi: 10.1056/NEJMoa2008470

21. 21. Nathan SD, Behr J, Collard HR, et al: Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study. Lancet Respir Med 7(9):780–790, 2019. doi: 10.1016/S2213-2600(19)30250-4

22. 22. Sahay S, Channick R, Chin K, et al: Macitentan in pulmonary hypertension (PH) due to chronic lung disease: Real-world evidence from OPUS/OrPHeUS. J Heart Lung Trans 40 (4) [Suppl]: S105-S106, 2021.

23. 23. Hoeper MM, Madani MM, Nakanishi N, Meyer B, Cebotari S, Rubin LJ: Chronic thromboembolic pulmonary hypertension. Lancet Respir Med 2(7):573–582, 2014. doi:10.1016/S2213-2600(14)70089-X

24. 24. Ghofrani HA, Simonneau G, D'Armini AM, et al: Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med 5(10):785–794, 2017. doi:10.1016/S2213-2600(17)30305-3

25. 25. Channick R, McLaughlin V, Chin K, et al: Treatment of chronic thromboembolic pulmonary hypertension (CTEPH): Real-world experience with macitentan. J Heart Lung Trans 38(4) [suppl]: S483, 2019. doi: https://www.jhltonline.org/article/S1053-2498(19)31231-8/fulltext

1. 1. Hendriks PM, Staal DP, van de Groep LD, et al: The evolution of survival of pulmonary arterial hypertension over 15 years. Pulm Circ 12(4):e12137, 2022. doi:10.1002/pul2.12137

2. 2. McGoon MD, Miller DP: REVEAL: a contemporary US pulmonary arterial hypertension registry. Eur Respir Rev 21(123):8–18, 2012. doi:10.1183/09059180.00008211