Легочная гипертензия характеризуется стойким повышением легочного сосудистого сопротивления, приводящим к прогрессивному нарастанию правожелудочковой недостаточности и смерти пациентов. В основе развития легочной гипертензии лежат структурные изменения артерий и артериол малого круга кровообращения вследствие дисфункции эндотелия. Эндотелин-1 – основной патогенетический медиатор легочной артериальной гипертензии и потенциальная мишень для терапевтического воздействия. Эффективность антагонистов рецепторов эндотелина доказана в многочисленных доклинических и клинических исследованиях. Несмотря на различия в активности по отношению к разным рецепторам, эффективность двойных и селективных антагонистов рецепторов эндотелина у больных легочной артериальной гипертензией сравнима. Бозентан – наиболее широко применяющийся легочный вазодилататор, улучшает переносимость физических нагрузок, снижает темпы прогрессирования заболевания. Более современные антагонисты рецепторов эндотелина – амбризентан и мацитентан – обладают преимуществами, связанными не только с их эффективностью, но и значительно лучшим профилем безопасности.
Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.
1. Царева Н.А., Авдеев С.Н., Неклюдова Г.В. Пациент с тяжелым течением идиопатической легочной артериальной гипертензии: есть ли выход? Терапевт. арх. 2017; 9: 100–3. / Tsareva N.A., Avdeev S.N., Neklyudova G.V. Patsient s tyazhelym techeniem idiopaticheskoy legochnoy arterial'noy gipertenzii: est' li vykhod? Terapevt. arkh. 2017; 9: 100–3. [in Russian]
2. Humbert M, Souza R, Galie N et al. Pulmonary arterial hypertension: bridging the present to the future. Eur Respir Rev 2012; 21 (126): 267–70.
3. Galie N, Rubin LJ et al. Pulmonary Arterial Hypertension: epidemiology, pathobiology, assessment, and therapy. J Am Coll Cardiology 2004; 12: 5–12.
4. Barst RJ, McGoon M, Torbicki A et al. Diagnosis and differential assessment of pulmonary artrerial hypertension. J Am Coll Cardiol 2004; 43 (Suppl. 12): 40–7.
5. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006; 114: 1417–31.
6. Galie N, Humbert M, Vachiery JL et al. 2015 ECS/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67–119.
7. Чазова И.Е., Авдеев С.Н., Царева Н.А. и др. Клинические рекомендации по диагностике и лечению легочной гипертонии. Терапевт. арх. 2014; 9: 4–23. / Chazova I.E., Avdeev S.N., Tsareva N.A. i dr. Klinicheskie rekomendatsii po diagnostike i lecheniyu legochnoy gipertonii. Terapevt. arkh. 2014; 9: 4–23. [in Russian]
8. Studer SM, Kingman M, Calo L et al. Considerations for optimal management of patients with pulmonary arterial hypertension: a multi-stakeholder roundtable discussion. Am J Manag Care 2017; 23 (Suppl. 6): S95–S104.
9. Kovacs G, Avian A, Olschewski A, Olschewski H. Zero reference level for right heart catheterization. Eur Respir J 2013; 42: 1586–94.
10. Hoeper MM, Huscher D, Ghofrani HA et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol 2013; 168: 871–80.
11. Humbert M, Sitbon O, Yaici A et al. Survival in incident and prevalent cohort of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36: 549–55.
12. Nickel N, Golpon H, Greer M et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012; 39: 589–96.
13. Callahan WE, Amorosino CS. Endothelial dysfunction in pulmonary hypertension. N Engl J Med 1992; 327: 177–19.
14. Morrell N, Adnot S, Archer S et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (Suppl. 1): 20–31.
15. Benza RL, Miller DP, Gomberg-Maitland M et al. Predicting survivalin pulmonary arterial hypertension: insights from the Registryto Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122: 164–72.
16. Simonneau G, Gatzolis G, Adatia I et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (Suppl. 25): 35–41.
17. Кароли Н.А., Ребров А.П. Легочная гипертония при системных заболеваниях соединительной ткани. Терапевт. арх. 2005; 77 (12): 83–8. / Karoli N.A., Rebrov A.P. Legochnaya gipertoniya pri sistemnykh zabolevaniyakh soedi-nitel'noy tkani. Terapevt. arkh. 2005; 77 (12): 83–8. [in Russian]
18. Кароли Н.А., Ребров А.П. Легочная гипертензия у больных системной склеродермией. Клин. медицина. 2016; 94 (12): 918–23. / Karoli N.A., Rebrov AP. Legochnaya gipertenziya u bol'nykh sistemnoy sklerodermiey. Кlin. meditsina. 2016; 94 (12): 918–23. [in Russian]
19. Моисеева О.М., Рудакова А.В. Фармакоэкономические аспекты применения мацитентана при терапии легочной артериальной гипертонии. Терапевт. арх. 2017; 3: 72–7. / Moiseeva O.M., Rudakova A.V. Farmakoekonomicheskie aspekty primeneniya matsitentana pri terapii legochnoy arterial'noy gipertonii. Terapevt. arkh. 2017; 3: 72–7. [in Russian]
20. Шостак Н.А., Клименко А.А., Демидова Н.А. Роль антагониста рецепторов эндотелина-1 бозентана в лечении легочной гипертензии. Consilium Medicum. 2017; 19 (10): 113–7. / Shostak N.A., Klimenko A.A., Demidova N.A. The role of endothelin-1 receptor antagonist bosentan in the treatment of pulmonary hypertension. Consilium Medicum. 2017; 19 (10): 113–7. [in Russian]
21. Мартынюк Т.В., Наконечников С.Н., Чазова И.Е. Оптимизация специфической терапии легочной артериальной гипертензии: возможности применения антагонистов рецепторов эндотелина. Евразийский кардиол. журн. 2017; 2: 1–8. / Martynyuk T.V., Nakonechnikov S.N., Chazova I.E. Optimizatsiya spetsificheskoy terapii legochnoy arterial'noy gipertenzii: vozmozhnosti primeneniya antagonistov retseptorov endotelina. Evraziyskiy kardiol. zhurn. 2017; 2: 1–8. [in Russian]
22. Ataya A, Cope J, Alnuaimat H. A Review of Targeted Pulmonary Arterial Hypertension-Specific Pharmacotherapy. J Clin Med 2016; 5 (12). pii: E114. Review.
23. Мартынюк Т.В., Архипова О.А., Кобаль Е.А. и др. Применение неселективного антагониста рецепторов эндотелина бозентана у больных идиопатической легочной гипертензией: первый российский опыт и взгляд в будущее. Cистемные гипертензии. 2011; 8 (4): 51–7. / Martynyuk T.V, Arkhipova O.A., Kobal' E.A. et al. Use of the nonselective endothelin receptor antagonist bosentan in patients with idiopathic pulmonary hypertension: the first Russian experience and vision of the future. Systemic Hypertension. 2011; 8 (4): 51–7. [in Russian]
24. Taichman DB, Ornelas J, Chung L et al. Pharmacologic therapy for Pulmonary Arterial Hypertension in Adults CHEST Guideline and Expert Panel Report. CHEST 2014; 146 (2): 449–75.
25. Rivera-Lebron BN, Risbano MG. Ambrisentan: a review of its use in pulmonary arterial hypertension. Ther Adv Respir Dis 2017; 11 (6): 233–44. DOI: 10.1177/1753465817696040
26. Iglarz M, Binkert C, Morrison K et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther 2008; 327: 736–45.
27. Rahaghi FF, Alnuaimat HM, Awdish RLA et al. Recommendations for the clinical management of patients receiving macitentan for pulmonary arterial hypertension (PAH): A Delphi consensus document. Pulm Circ 2017; 7 (3): 702–11. DOI: 10.1177/2045893217721695
28. Galiè N, Jansa P, Pulido T et al. SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension. Eur Heart J 2017; 38 (15): 1147–55. DOI: 10.1093/eurheartj/ehx025
29. Duo-Ji MM, Long ZW. Comparative efficacy and acceptability of endothelin receptor antagonists for pulmonary arterial hypertension: A network meta-analysis. Int J Cardiol 2017; 234: 90–8. DOI: 10.1016/j.ijcard.2016.12.092
30. Jansa P, Pulido T. Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial. Am J Cardiovasc Drugs 2018; 18 (1): 1–11. DOI: 10.1007/s40256-017-0260-1
31. Lajoie AC, Guay CA, Lega JC et al. Trial Duration and Risk Reduction in Combination Therapy Trials for Pulmonary Arterial Hypertension: A Systematic Review. Chest 2017. pii: S0012-3692(17)33125-2. DOI: 10.1016/j.chest.2017.11.014 [Epub ahead of print]
32. Lajoie AC, Bonnet S, Provencher S. Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges. Pulm Circ 2017; 7 (2): 312–25. DOI: 10.1177/2045893217710639
33. Gao XF, Zhang JJ, Jiang XM et al. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials. Patient Prefer Adherence 2017; 11: 871–85. DOI: 10.2147/PPA.S133288
34. Vizza CD, Jansa P, Teal S et al. Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial. BMC Cardiovasc Disord 2017; 17 (1): 239. DOI: 10.1186/s12872-017-0674-3
35. Гайсин И.Р., Рычкова Л.В., Газимзянова А.С. и др. Эффективность мультидисциплинарной системы оказания помощи при легочной гипертензии. Кардиоваск. терапия и профилактика. 2017; 16 (1): 82–90. / Gaysin I.R., Rychkova L.V., Gazimzyanova A.S. i dr. Effektivnost' mul'tidistsiplinarnoy sistemy okazaniya pomoshchi pri legochnoy gipertenzii. Kardiovask. terapiya i profilaktika. 2017; 16 (1): 82–90. [in Russian]
36. Ilja M Blok, Annelieke CMJ, van Riel еt al. From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement? Int J Cardiol 2017; 227: 51–2.
________________________________________________
1. Tsareva N.A., Avdeev S.N., Neklyudova G.V. Patsient s tyazhelym techeniem idiopaticheskoy legochnoy arterial'noy gipertenzii: est' li vykhod? Terapevt. arkh. 2017; 9: 100–3. [in Russian]
2. Humbert M, Souza R, Galie N et al. Pulmonary arterial hypertension: bridging the present to the future. Eur Respir Rev 2012; 21 (126): 267–70.
3. Galie N, Rubin LJ et al. Pulmonary Arterial Hypertension: epidemiology, pathobiology, assessment, and therapy. J Am Coll Cardiology 2004; 12: 5–12.
4. Barst RJ, McGoon M, Torbicki A et al. Diagnosis and differential assessment of pulmonary artrerial hypertension. J Am Coll Cardiol 2004; 43 (Suppl. 12): 40–7.
5. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006; 114: 1417–31.
6. Galie N, Humbert M, Vachiery JL et al. 2015 ECS/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67–119.
7. Chazova I.E., Avdeev S.N., Tsareva N.A. i dr. Klinicheskie rekomendatsii po diagnostike i lecheniyu legochnoy gipertonii. Terapevt. arkh. 2014; 9: 4–23. [in Russian]
8. Studer SM, Kingman M, Calo L et al. Considerations for optimal management of patients with pulmonary arterial hypertension: a multi-stakeholder roundtable discussion. Am J Manag Care 2017; 23 (Suppl. 6): S95–S104.
9. Kovacs G, Avian A, Olschewski A, Olschewski H. Zero reference level for right heart catheterization. Eur Respir J 2013; 42: 1586–94.
10. Hoeper MM, Huscher D, Ghofrani HA et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol 2013; 168: 871–80.
11. Humbert M, Sitbon O, Yaici A et al. Survival in incident and prevalent cohort of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36: 549–55.
12. Nickel N, Golpon H, Greer M et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012; 39: 589–96.
13. Callahan WE, Amorosino CS. Endothelial dysfunction in pulmonary hypertension. N Engl J Med 1992; 327: 177–19.
14. Morrell N, Adnot S, Archer S et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (Suppl. 1): 20–31.
15. Benza RL, Miller DP, Gomberg-Maitland M et al. Predicting survivalin pulmonary arterial hypertension: insights from the Registryto Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122: 164–72.
16. Simonneau G, Gatzolis G, Adatia I et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (Suppl. 25): 35–41.
17. Karoli N.A., Rebrov A.P. Legochnaya gipertoniya pri sistemnykh zabolevaniyakh soedi-nitel'noy tkani. Terapevt. arkh. 2005; 77 (12): 83–8. [in Russian]
18. Karoli N.A., Rebrov AP. Legochnaya gipertenziya u bol'nykh sistemnoy sklerodermiey. Кlin. meditsina. 2016; 94 (12): 918–23. [in Russian]
19. Moiseeva O.M., Rudakova A.V. Farmakoekonomicheskie aspekty primeneniya matsitentana pri terapii legochnoy arterial'noy gipertonii. Terapevt. arkh. 2017; 3: 72–7. [in Russian]
20. Shostak N.A., Klimenko A.A., Demidova N.A. The role of endothelin-1 receptor antagonist bosentan in the treatment of pulmonary hypertension. Consilium Medicum. 2017; 19 (10): 113–7. [in Russian]
21. Martynyuk T.V., Nakonechnikov S.N., Chazova I.E. Optimizatsiya spetsificheskoy terapii legochnoy arterial'noy gipertenzii: vozmozhnosti primeneniya antagonistov retseptorov endotelina. Evraziyskiy kardiol. zhurn. 2017; 2: 1–8. [in Russian]
22. Ataya A, Cope J, Alnuaimat H. A Review of Targeted Pulmonary Arterial Hypertension-Specific Pharmacotherapy. J Clin Med 2016; 5 (12). pii: E114. Review.
23. Martynyuk T.V, Arkhipova O.A., Kobal' E.A. et al. Use of the nonselective endothelin receptor antagonist bosentan in patients with idiopathic pulmonary hypertension: the first Russian experience and vision of the future. Systemic Hypertension. 2011; 8 (4): 51–7. [in Russian]
24. Taichman DB, Ornelas J, Chung L et al. Pharmacologic therapy for Pulmonary Arterial Hypertension in Adults CHEST Guideline and Expert Panel Report. CHEST 2014; 146 (2): 449–75.
25. Rivera-Lebron BN, Risbano MG. Ambrisentan: a review of its use in pulmonary arterial hypertension. Ther Adv Respir Dis 2017; 11 (6): 233–44. DOI: 10.1177/1753465817696040
26. Iglarz M, Binkert C, Morrison K et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther 2008; 327: 736–45.
27. Rahaghi FF, Alnuaimat HM, Awdish RLA et al. Recommendations for the clinical management of patients receiving macitentan for pulmonary arterial hypertension (PAH): A Delphi consensus document. Pulm Circ 2017; 7 (3): 702–11. DOI: 10.1177/2045893217721695
28. Galiè N, Jansa P, Pulido T et al. SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension. Eur Heart J 2017; 38 (15): 1147–55. DOI: 10.1093/eurheartj/ehx025
29. Duo-Ji MM, Long ZW. Comparative efficacy and acceptability of endothelin receptor antagonists for pulmonary arterial hypertension: A network meta-analysis. Int J Cardiol 2017; 234: 90–8. DOI: 10.1016/j.ijcard.2016.12.092
30. Jansa P, Pulido T. Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial. Am J Cardiovasc Drugs 2018; 18 (1): 1–11. DOI: 10.1007/s40256-017-0260-1
31. Lajoie AC, Guay CA, Lega JC et al. Trial Duration and Risk Reduction in Combination Therapy Trials for Pulmonary Arterial Hypertension: A Systematic Review. Chest 2017. pii: S0012-3692(17)33125-2. DOI: 10.1016/j.chest.2017.11.014 [Epub ahead of print]
32. Lajoie AC, Bonnet S, Provencher S. Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges. Pulm Circ 2017; 7 (2): 312–25. DOI: 10.1177/2045893217710639
33. Gao XF, Zhang JJ, Jiang XM et al. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials. Patient Prefer Adherence 2017; 11: 871–85. DOI: 10.2147/PPA.S133288
34. Vizza CD, Jansa P, Teal S et al. Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial. BMC Cardiovasc Disord 2017; 17 (1): 239. DOI: 10.1186/s12872-017-0674-3
35. Gaysin I.R., Rychkova L.V., Gazimzyanova A.S. i dr. Effektivnost' mul'tidistsiplinarnoy sistemy okazaniya pomoshchi pri legochnoy gipertenzii. Kardiovask. terapiya i profilaktika. 2017; 16 (1): 82–90. [in Russian]
36. Ilja M Blok, Annelieke CMJ, van Riel еt al. From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement? Int J Cardiol 2017; 227: 51–2.
Авторы
Н.А.Кароли, С.И.Сажнова, А.П.Ребров*
ФГБОУ ВО «Саратовский государственный медицинский университет им. В.И.Разумовского» Минздрава России. 410012, Россия, Саратов, ул. Большая Казачья, д. 112 *andreyrebrov@yandex.ru
________________________________________________
N.A.Karoli, S.I.Sazhnova, A.P.Rebrov*
V.I.Razumovsky Saratov State Medical University of the Ministry of Health of the Russian Federation. 410012, Russian Federation, Saratov, ul. Bol'shaia Kazach'ia, d. 112 *andreyrebrov@yandex.ru