Pathogenetic therapy of pulmonary hypertension

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Pulmonary hypertension (PH) is a hemodynamic and pathophysiological condition characterized by an increase in mean pulmonary artery pressure of ≥20 mmHg. at rest, measured during right heart compartment catheterization. All over the world, 5 main groups of PH are fundamentally distinguished. The most studied in terms of selecting the optimal pathogenetic therapy is idiopathic pulmonary arterial hypertension (IPAH), which belongs to the 1st group according to the 2018 PH classification. The key point in the pathogenesis of PH is the imbalance of the main vasodilating (for example, nitric oxide, prostacyclin) and vasoconstrictor substances (endothelin-1, thromboxane A2, serotonin) with predominance of the latter. Taking into account the complexity of pathogenesis, patients with pulmonary arterial hypertension require a multifaceted, holistic, and interdisciplinary approach. Current article is devoted to the review of medicamentous remedies for the treatment of PH, as well as the strategy for their prescription.

Full Text

Restricted Access

About the authors

Natalya A. Tsareva

I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of Russia (Sechenov university)

Author for correspondence.
Email: n_tsareva@mail.ru
ORCID iD: 0000-0001-9357-4924

phd in medical sciences, associate professor of the department of pulmonology 

Russian Federation, 119991, Moscow, 8/2 Trubetskaya Str.

Mikhail V. Khachaturov

I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of Russia (Sechenov university)

Email: khachaturov.michael@gmail.com
ORCID iD: 0000-0001-7606-6565

5th year student 

Russian Federation, 119991, Moscow, 8/2 Trubetskaya Str.

Sergey N. Avdeev

I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of Russia (Sechenov university)

Email: serg_avdeev@list.ru
ORCID iD: 0000-0002-5999-2150

md, professor, academician of RAS, vice-rector for research work, head of the department of pulmonology 

Russian Federation, 119991, Moscow, 8/2 Trubetskaya Str.

References

  1. Humbert M., Kovacs G., Hoeper M.M. et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022; 43(38): 3618–731. https://dx.doi.org/10.1093/eurheartj/ehac237.
  2. Galie N., McLaughlin V.V., Rubin L.J. et al. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J. 2019; 53(1): 1802148. https://dx.doi.org/10.1183/13993003.02148-2018.
  3. Humbert M., Kovacs G., Hoeper M.M. et al.; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022; 43(38): 3618–31. https://dx.doi.org/10.1093/eurheartj/ehac237.
  4. Lau E.M.T., Giannoulatou E., Celermajer D.S. et al. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017; 14(10): 603–14. https://dx.doi.org/10.1038/nrcardio.2017.84.
  5. Leber L., Beaudet A., Muller A. Epidemiology of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Identification of the most accurate estimates from a systematic literature review. Pulm Circ. 2021; 11(1): 2045894020977300. https://dx.doi.org/10.1177/2045894020977300.
  6. O’Callaghan D.S., Savale L., Montani D. et al. Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol. 2011; 8(9): 526–38. https://dx.doi.org/10.1038/nrcardio.2011.104.
  7. Barst R.J., Chung L., Zamanian R.T. et al. Functional class improvement and 3-year survival outcomes in patients with pulmonary arterial hypertension in the REVEAL Registry. Chest. 2013; 144(1): 160–68. https://dx.doi.org/10.1378/chest.12-2417.
  8. Galie N., Humbert M., Vachiery J.L. et al.; ESC Scientific Document Group. 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): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016; 37(1): 67–119. https://dx.doi.org/10.1093/eurheartj/ehv317.
  9. Hoeper M.M., Kramer T., Pan Z. et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017; 50(2): 1700740. https://dx.doi.org/10.1183/13993003.00740-2017.
  10. Badagliacca R., Papa S., Manzi G. et al. Usefulness of adding echocardiography of the right heart to risk-assessment scores in prostanoid-treated pulmonary arterial hypertension. JACC Cardiovasc Imaging. 2020; 13(9): 2054–56.
  11. https://dx.doi.org/10.1016/j.jcmg.2020.04.005.
  12. Lewis R.A., Johns C.S., Cogliano M. et al. Identification of cardiac magnetic resonance imaging thresholds for risk stratification in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2020; 201(4): 458–68. https://dx.doi.org/10.1164/rccm.201909-1771OC.
  13. Weatherald J., Boucly A., Chemla D. et al. Prognostic value of follow-up hemodynamic variables after initial management in pulmonary arterial hypertension. Circulation. 2018; 137(7): 693–704. https://dx.doi.org/10.1161/CIRCULATIONAHA.117.029254.
  14. Savarese G., Paolillo S., Costanzo P. et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol. 2012; 60(13): 1192–201.
  15. https://dx.doi.org/10.1016/j.jacc.2012.01.083
  16. Warwick G., Thomas P.S., Yates D.H. Biomarkers in pulmonary hypertension. Eur Respir J. 2008; 32(2): 503–12.
  17. https://dx.doi.org/10.1183/09031936.00160307.
  18. Hoeper M.M., Kramer T., Pan Z. et al. Mortality in pulmonary arterial hypertension: Prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017; 50(2): 1700740.
  19. https://dx.doi.org/10.1183/13993003.00740-2017.
  20. Hoeper M.M., Pausch C., Olsson K.M. et al. COMPERA 2.0: A refined four-stratum risk assessment model for pulmonary arterial hypertension. Eur Respir J. 2022; 60(1): 2102311. https://dx.doi.org/10.1183/13993003.02311-2021.
  21. Rich S., Kaufmann E., Levy P.S. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992; 327(2): 76–81. https://dx.doi.org/10.1056/NEJM199207093270203.
  22. McKeever R.G., Hamilton R.J. Calcium channel blockers. [Updated 2022 Jul 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.
  23. Sitbon O., Humbert M., Jais X. et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005; 111(23): 3105–11. https://dx.doi.org/10.1161/CIRCULATIONAHA.104.488486.
  24. Galie N., Ussia G., Passarelli P. et al. Role of pharmacologic tests in the treatment of primary pulmonary hypertension. Am J Cardiol. 1995; 75(3): 55A–62A. https://dx.doi.org/10.1016/s0002-9149(99)80384-1.
  25. Correale M., Ferraretti A., Monaco I. et al. Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: Where do we stand? Vasc Health Risk Manag. 2018; 14: 253–64. https://dx.doi.org/10.2147/VHRM.S133921.
  26. Denton C.P., Humbert M., Rubin L. et al. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis. 2006; 65(10): 1336–40.
  27. https://dx.doi.org/10.1136/ard.2005.048967.
  28. Humbert M., Barst R.J., Robbins I.M. et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004; 24(3): 353–59. https://dx.doi.org/10.1183/09031936.04.00028404.
  29. Gatzoulis M.A., Beghetti M., Galie N. et al.; BREATHE-5 Investigators. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: Results of the BREATHE-5 open-label extension study. Int J Cardiol. 2008; 127(1): 27–32.
  30. https://dx.doi.org/10.1016/j.ijcard.2007.04.078.
  31. Simonneau G., Galie N., Jansa P. et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol. 2014; 172(2): 332–39. https://dx.doi.org/10.1016/j.ijcard.2013.12.179.
  32. McLaughlin V., Channick R.N., Ghofrani H.A. et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015; 46(2): 405–13. https://dx.doi.org/10.1183/13993003.02044-2014.
  33. Rubin L.J., Badesch D.B., Barst R.J. et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002; 346(12): 896–903. https://dx.doi.org/10.1056/NEJMoa012212. Erratum in: N Engl J Med. 2002; 346(16): 1258.
  34. Galie N., Olschewski H., Oudiz R.J. et al; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. 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. 2008; 117(23): 3010–19. https://dx.doi.org/10.1161/CIRCULATIONAHA.107.742510.
  35. Simonneau G., Channick R.N., Delcroix M. et al. Incident and prevalent cohorts with pulmonary arterial hypertension: Insight from SERAPHIN. Eur Respir J. 2015; 46(6): 1711–20. https://dx.doi.org/10.1183/13993003.00364-2015.
  36. McLaughlin V., Hoeper M., Tamura Y. et al. UNISUS study design: a phase 3 superiority study comparing the efficacy, safety, and tolerability of macitentan 75 mg vs macitentan 10 mg in patients with pulmonary arterial hypertension (PAH). Eur Heart J. 2022; 43(2): ehac544.1929. https://dx.doi.org/10.1093/eurheartj/ehac544.1929.
  37. Humbert M., Segal E.S., Kiely D.G. et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J. 2007; 30(2): 338–44. https://dx.doi.org/10.1183/09031936.00138706.
  38. Clozel M., Maresta A., Humbert M. Endothelin receptor antagonists. Handb Exp Pharmacol. 2013; 218: 199–227.
  39. https://dx.doi.org/10.1007/978-3-642-38664-0_9.
  40. Vachiery J.L., Galie N., Barbera J.A. et al.; AMBITION Study Group. Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension-related hospitalization in the AMBITION trial. J Heart Lung Transplant. 2019; 38(2): 194–202.
  41. https://dx.doi.org/10.1016/j.healun.2018.11.006.
  42. Galie N., Brundage B.H., Ghofrani H.A. et al.; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009; 119(22): 2894–903.
  43. https://dx.doi.org/10.1161/CIRCULATIONAHA.108.839274. Erratum in: Circulation. 2011; 124(10): e279.
  44. Padda I.S., Tripp J. Phosphodiesterase Inhibitors. [Updated 2022 Nov 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.
  45. Galie N., Ghofrani H.A., Torbicki A. et al.; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005; 353(20): 2148–57.
  46. https://dx.doi.org/10.1056/NEJMoa050010. Erratum in: N Engl J Med. 2006; 354(22): 2400–1.
  47. Rubin L.J., Badesch D.B., Fleming T.R. et al.; SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: The SUPER-2 study. Chest. 2011; 140(5): 1274–83. https://dx.doi.org/10.1378/chest.10-0969.
  48. Ghofrani H.A., Galie N., Grimminger F. et al.; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369(4): 330–40. https://dx.doi.org/10.1056/NEJMoa1209655.
  49. Rubin L.J., Galie N., Grimminger F. et al. Riociguat for the treatment of pulmonary arterial hypertension: A long-term extension study (PATENT-2). Eur Respir J. 2015; 45(5): 1303–13. https://dx.doi.org/10.1183/09031936.00090614.
  50. Hoeper M.M., Simonneau G., Corris P.A. et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017; 50(3): 1602425. https://dx.doi.org/10.1183/13993003.02425-2016.
  51. Hoeper M.M., Al-Hiti H., Benza R.L. et al.; REPLACE investigators. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): A multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2021; 9(6): 573–84. https://dx.doi.org/10.1016/S2213-2600(20)30532-4.
  52. Galie N., Manes A., Branzi A. Prostanoids for pulmonary arterial hypertension. Am J Respir Med. 2003; 2(2): 123–37.
  53. https://dx.doi.org/10.1007/BF03256644.
  54. Clapp L.H., Abu-Hanna J.H.J., Patel J.A. Diverse pharmacology of prostacyclin mimetics: Implications for pulmonary hypertension. In: Nakanishi, T., Baldwin, H., Fineman, J., Yamagishi, H. (eds) Molecular mechanism of congenital heart disease and pulmonary hypertension. Springer, Singapore. https://doi.org/10.1007/978-981-15-1185-1_5.
  55. Olschewski H. Inhaled iloprost for the treatment of pulmonary hypertension. Eur Respir Rev. 2009; 18(111): 29–34.
  56. https://dx.doi.org/10.1183/09059180.00011111.
  57. Hoeper M.M., Leuchte H., Halank M. et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006; 28(4): 691–94. https://dx.doi.org/10.1183/09031936.06.00057906.
  58. McLaughlin V.V., Oudiz R.J., Frost A. et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006; 174(11): 1257–63. https://dx.doi.org/10.1164/rccm.200603-358OC.
  59. Kuwano K., Hashino A., Noda K. et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary artery. J Pharmacol Exp Ther. 2008; 326(3): 691–99. https://dx.doi.org/10.1124/jpet.108.138305.
  60. Sitbon O., Channick R., Chin K.M. et al.; GRIPHON Investigators. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015; 373(26): 2522–33. https://dx.doi.org/10.1056/NEJMoa1503184.
  61. Chin K., Sitbon O., Doelberg M. et al. Three- versus two-drug therapy for patients with newly diagnosed pulmonary arterial hypertension. J Am Coll Cardiol. 2021; 78(14): 1393–403. https://dx.doi.org/10.1016/j.jacc.2021.07.057.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies