Идиопатическая легочная артериальная гипертензия: современный подход к диагностике и лекарственной терапии

Рассматриваются современные аспекты диагностики, классификации и лечения легочной гипертензии (ЛГ). Представлена новая классификация, включающая все известные на сегодняшний день формы ЛГ. Приводится функциональная классификация данной патологии. Подробно изложена диагностическая программа, включающая как рутинные методы обследования больных, так и высокочувствительные и инновационные исследования (компьютерно-томографическая ангиография сосудов легких, перфузионная сцинтиграфия легких, катетеризация правых отделов сердца и т. д.) Отражены факторы прогноза 1-годичной выживаемости пациентов с ЛГ. Приводятся характеристики основных звеньев патогенеза. Рассматриваются эндотелиновый и простациклиновый пути патофизиологии ЛГ, а также роль оксида азота и стимуляторов растворимой гуанилатциклазы. Изложены традиционные подходы, используемые при терапии ЛГ, включающие применение антагонистов кальция, кислорода, антикоагулянтов и диуретиков. Приводится характеристика критериев проведения «острого» теста на вазореактивность. Представлены основные классы лекарственных препаратов (антагонисты рецепторов к эндотелину, простациклины, стимуляторы растворимой гуанилатциклазы, ингибиторы фосфодиэстеразы 5-го типа, селективные агонисты рецепторов простациклина). Подробно рассматриваются современные пути патогенетической терапии ЛГ, а также основные направления поиска новых эффективных и безопасных лекарственных средств, способных улучшить прогноз, замедлить прогрессирование заболевания, а также повлиять на качество жизни пациентов.

1. Galie N., Hoeper M.M., Humbert M. et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Respir. J. 2009; 34 (6): 1219–1263. DOI: 10.1183/09031936.00139009.

2. Чазова И.Е., Мартынюк Т.В., ред. Легочная гипертензия. М.: Практика; 2015.

3. Vachiery J.-L., Gaine S. Challenges in the diagnosis and treatment of pulmonary arterial hypertension. Eur. Respir. Rev. 2012; 21 (126): 313–320. DOI: 10.1183/09059180.00005412.

4. Chemla D., Castelain V., Herve P. et al. Haemodynamic evaluation of pulmonary hypertension. Eur. Respir. J. 2002; 20 (5): 1314–1331. DOI: 10.1183/09031936.02.00068002.

5. Benza R.L., Miller D.P., Gomberg-Maitland M. 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. 2010; 122 (2): 164–172. DOI: 10.1161/CIRCULATIONAHA.109.898122.

6. Badesch B.D., Champion H.C., Gomez-Sanchez M.A. et al. Diagnosis and assessment of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2009; 54 (30): S55–S56. DOI: 10.1016/j.jacc.2009.04.011.

7. Berger R.M., Beghetti M., Humpl T. et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. 2012; 379 (9815): 537–546. DOI: 10.1016/S0140-6736(11)61621-8.

8. Trulock E., Edwards L., Taylor D. et al. Registry of the International Society for Heart and Lung Transplantation twenty fourth official adult lung and heart lung transplantation report 2007. J. Heart Lung Transplant. 2007; 26 (8): 782–795. DOI: 10.1016/j.healun.2007.06.003.

9. Stehlik J., Edwards L.B., Kucheryavaya A.Y. et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report–2010. J. Heart Lung Transplant. 2010; 29 (10): 1089– 1103. DOI: 10.1016/j.healun.2010.08.007.

10. Sitbon O., Morrell N.W. Pathways in pulmonary arterial hypertension: the future is here. Eur. Respir. Rev. 2012; 21 (126): 321–327. DOI: 10.1183/09059180.00004812.

11. Solomon J.J., Olson A.L., Fischer A. et al. Scleroderma lung disease. Eur. Respir. Rev. 2013; 22 (127): 6–19. DOI: 10.1183/09059180.00005512.

12. Guazzi M., Galie N. Pulmonary hypertension in left heart disease. Eur. Respir. Rev. 2012; 21 (126): 338–346. DOI: 10.1183/09059180.00004612.

13. Diller G.P., Dimopoulos K., Okonko D. et al. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation. 2005; 112 (8): 828–835. DOI: 10.1161/CIRCULATIONAHA.104.529800.

14. Peacock A.J., Murphy N.F., McMurray J.J.V. et al. An epidemiological study of pulmonary arterial hypertension. Eur. Respir. J. 2007; 30 (1): 104–109. DOI: 10.1183/09031936.00092306.

15. Galie N., Palazzini M., Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur. Heart J. 2010; 31 (1): 2080–2086. DOI: 10.1093/eurheartj/ehq152.

16. Michelakis E.D. The role of the NO axis and its therapeutic implications in pulmonary arterial hypertension. Heart Fail. Rev. 2003; 8 (1): 5–21. DOI: 10.1023/A:1022150819223.

17. Rubin L.J., Simonneau G., Badesch D. et al. The study of risk in pulmonary arterial hypertension. Eur. Respir. Rev. 2012; 21 (125): 234–238. DOI: 10.1183/09059180.00003712.

18. Humbert M., Souza R., Galie N. et al. Pulmonary arterial hypertension: bridging the present to the future. Eur. Respir. Rev. 2012; 21 (126): 267–270. DOI: 10.1183/09059180.00005312.

19. Simonneau G., Gatzolis G., Adatia I. et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 2013; 62 (25, Suppl.): D35–D41. DOI: 10.1016/j.jacc.2013.10.029.

20. 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 (3): 549–555. DOI: 10.1183/09031936.00057010.

21. Galie N., Hoeper M., Torbicki A. 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). Eur. Heart J. 2009; 30 (20): 2493– 2537. DOI: 10.1093/eurheartj/ehr046.

22. 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 (3): 589–596. DOI: 10.1183/09031936.00092311.

23. Soubrier F., Chung W.K., Machado R. et al. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2013; 62 (25, Suppl.): D13–D21. DOI: 10.1016/j.jacc.2013.10.035.

24. Eyries M., Montani D., Girerd B. et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat. Genet. 2014; 46 (1): 65–69. DOI: 10.1038/ng.2844.

25. D’Alto M., Mahadevan V.S. Pulmonary arterial hypertension associated with congenital heart disease. Eur. Respir. Rev. 2012; 21(126): 328–337. DOI: 10.1183/09059180.00004712.

26. Huang J.B., Liang J., Zhou L.Y. Eisenmenger Syndrome: Not Always Inoperable. Respir. Care. 2012; 57 (9): 1488–1495. DOI: 10.4187/respcare.01418.

27. Rubin L.J. Primary pulmonary hypertension. Chest. 1993; 104 (1): 236–250.

28. Rubin L.J., Badesch D.B. Evaluation and management of the patient with pulmonary arterial hypertension. Ann. Intern. Med. 2005; 143 (4): 282–292. DOI: 10.7326/0003-4819-143-4200508160-00009.

29. Galie N., Rubin L.J. Introduction: new insights into a challenging disease: A review of the third world symposium on pulmonary arterial hypertension. Am. Coll. Cardiol. J. 2004; 43 (12): S1. DOI: 10.1016/j.jacc.2004.03.003.

30. Galie N., Torbicki A., Barst R. et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur. Heart. J. 2004; 25 (24): 2243–2278. DOI: 10.1016/j.ehj.2004.09.014.

31. Hambly N., Alawfi F., Mehta S. Pulmonary hypertension: diagnostic approach and optimal management. CMAJ. 2016; 188 (11): 804–812. DOI: 10.1503/cmaj.151075.

32. McLaughlin V.V., Archer S.L., Badesch D.B. et al. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009; 119 (16): 2250–2294. DOI: 10.1161/CIRCULATIONAHA.109.192230.

33. Чазова И.Е., Жданов В.С., Веселова С.П., Мареев В.Ю. Патология первичной легочной гипертензии. Архив патологии. 1993; (3): 52–55.0

34. Lowe B.S., Therrien J., Ionescu-Ittu R. et al. Diagnosis of pulmonary hypertension in the congenital heart disease adult population impact on outcomes. J. Am. Coll. Cardiol. 2011; 58 (5): 538–546. DOI: 10.1016/j.jacc.2011.03.033.

35. Raymond R.J., Hinderliter A.L., Willis P.W. et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J. Am. Coll. Cardiol. 2002; 39 (7): 1214–1219.

36. Humbert M., Sitbon O., Chaouat A. et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010; 122 (2): 156–163. DOI: 10.1161/CIRCULATIONAHA.109.911818.

37. 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 (3): 549–555. DOI: 10.1183/09031936.00057010.

38. Stenmark K.R., Davie N., Frid M. et al. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda). 2006; 21 (2): 134–145. DOI: 10.1152/physiol.00053.2005.

39. Tuber R.M., Cool C.D., Yeager M. et al. The pathobiology of pulmonary hypertension. Endothelium. Clin. Chest Med. 2001; 22 (3): 405–418.

40. Gossage J.R., Christman B.W. Mediators of acute and chronic pulmonary hypertension. Semin. Respir. Crit. Care Med. 1994; 15 (4): 453–462.

41. Galie N., Manes A., Branzi A. New insights on pulmonary arterial hypertension. Rev. Esp. Cardiol. 2004; 57 (7): 603– 607. DOI: 10.1016/S1885-5857(06)60282-X.

42. Duong-Quy S. Physiopathology of pulmonary hypertension: from bio-molecular mechanism to target treatment. J. Vasc. Med. Surg. 2016; 22 (4): 294–299. DOI: 10.4172/2329-6925.1000294.

43. Duplain H., Burcelin R., Sartori C. et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation. 2001; 104 (3): 342–345. DOI: 10.1161/01.CIR.104.3.342.

44. Barst R.J., McGoon M., Torbicki A. et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2004; 43 (12, Suppl.): S40–S47. DOI: 10.1016/j.jacc.2004.02.032.

45. McGoon M.D. The assessment of pulmonary hypertension. Clin. Chest Med. 2001; 22 (3): 493–508.

46. McLaughlin V.V., McGoon M.D. Pulmonary arterial hypertension. Circulation. 2006; 114 (13): 1417–1431. DOI: 10.1161/CIRCULATIONAHA.104.503540.

47. Trip P., Nossent E.J., de Man F.S. et al. Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur. Respir. J. 2013; 42 (6): 1575–1585. DOI: 10.1183/09031936.00184412.

48. Sun X.G., Hansen J.E., Oudiz R.J., Wasserman K. Pulmonary function in primary pulmonary hypertension. J. Am. Coll. Cardiol. 2003; 41 (6): 1028–1035. DOI: 10.1016/S0735-1097(02)02964-9.

49. Чазова И.Е., Мартынюк Т.В., Авдеев С.Н. и др. Клинические рекомендации по диагностике и лечению легочной гипертензии. Терапевтический архив. 2014; 86 (9): 4–23. DOI: terapevticheskij-arkhiv/2014/9/030040-3660201491.

50. Rudski L.G., Lai W.W., Afilalo J. et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J. Am. Soc. Echo- cardiogr. 2010; 23 (7): 685–713. DOI: 10.1016/j.echo.2010.05.010.

51. Lang R.M., Badano L.P., Mor-Avi V. et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur. Heart J. Cardiovasc. Imaging. 2015; 28 (1): 1–39. DOI: 10.1016/j.echo.2014.10.003.

52. Lang I., Madani M. Update on Chronic Thromboembolic Pulmonary Hypertension. Circulation. 2014; 130 (6): 508– 518. DOI: 10.1161/CIRCULATIONAHA.114.009309.

53. Rajaram S., Swift A.J., Telfer A. et al. 3D contrast-enhanced lung perfusion MRI is an effective screening tool for chronic thromboembolic pulmonary hypertension: results from the ASPIRE Registry. Thorax. 2013; 68 (7): 677–678. DOI: org/10.1136/thoraxjnl-2012-203020.

54. Sitbon O., Badesch D., Channick R. Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. 2003; 124 (1): 247–254. DOI: 10.1378/chest.124.1-suppl.247S.

55. Channick R.N., Simonneau G., Sitbon O. et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet. 2001; 358 (9288): 1119–1123. DOI: 10.1016/S0140-6736(01)06250-X.

56. Galie N., Rubin L., Hoeper M. et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomized controlled trial. Lancet. 2008; 371 (2930): 2093–2100. DOI: 10.1016/S0140-6736(08)60919-8.

57. 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. JACC. 2012; 60 (13): 1192–1201. DOI: 10.1016/j.jacc.2012.01.083.

58. Barst R.J., Maislin G., Fishman A.P. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999; 99 (9): 1197–1208. DOI: 10.1161/01.CIR.99.9.1197.

59. Langleben D. Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Clin. Chest Med. 2007; 28 (1): 117–125.

60. 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. Системные гипертензии. 2011; 8 (4): 51–56.

61. Provencher S., Sitbon O., Humbert M. et al. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur. Heart J. 2006; 27 (5): 589–595. DOI: 10.1093/eurheartj/ehi728.

62. Авдеев С.Н., Царева Н.А., Неклюдова Г.В., Чучалин А.Г. Первый клинический опыт применения антагониста рецепторов эндотелина бозентана у пациентов с легочной артериальной гипертензией: результаты 1-годичного исследования. Терапевтический архив. 2013; 85 (3): 38–43.

63. Rubin L., Badesch M., Barst R. et al. Randomized trial of endothelin antagonist therapy. N. Engl. J. Med. 2002; 346 (12): 896–903. DOI: 10.1056/NEJMoa012212.

64. Galie N., Olschewski H., Oudiz R.J. 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. 2008; 117 (23): 3010–3019. DOI: 10.1161/CIRCULATIONAHA.107.742510.

65. Oudiz R.J., Galie N., Olschewski H. et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2009; 52 (21): 1971–1981. DOI: 10.1016/j.jacc.2009.07.033.

66. Badesch D.B., Feldman J., Keogh A. et al. ARIES3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension. Cardiovasc. Ther. 2012; 30 (2): 93–99. DOI: 10.1111/j.1755-5922.2011.00279.x.

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

68. Galie N., Manes A. New treatment strategies for pulmonary arterial hypertension: hopes or hypes? J. Am. Coll. Cardiol. 2013; 62 (12): 1101–1102. DOI: 10.1016/j.jacc.2013.06.032.

69. Rubin L.J., Mendoza J., Hood M. et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann. Intern. Med. 1990; 112 (7): 485–491.

70. Barst R.J., Rubin L.J., Long W.A. et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension [see comments]. N. Engl. J. Med. 1996; 334 (5): 296–302. DOI: 10.1056/NEJM199602013340504.

71. Sitbon O., Humbert M., Nunes H. et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J. Am. Coll. Cardiol. 2002; 40 (4): 780–788. DOI: 10.1016/S0735-1097(02)02012-0.

72. McLaughlin V.V., Shillington A., Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002; 106 (12): 1477–1482. DOI: 10.1161/01.CIR.0000029100.82385.58.

73. Sitbon O., Delcroix M., Bergot E. et al. EPITOME-2: an openlabel study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension. Am. Heart J. 2014; 167 (2): 210–217. DOI: 10.1016/j.ahj.2013.08.007.

74. Galie N., Manes A., Branzi A. Prostanoids for pulmonary arterial hypertension. Am. J. Respir. Med. 2003; 2 (2): 123–137.

75. Simonneau G., Barst R.J., Galie N. et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. A double-blind, randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 2002; 165 (6): 800–804. DOI: 10.1164/ajrccm.165.6.2106079.

76. Hiremath J., Thanikachalam S., Parikh K. et al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J. Heart Lung Transplant. 2010; 29 (2): 137–149. DOI: 10.1016/j.healun.2009.09.005.

77. Tapson V.F., Gomberg-Maitland M., McLaughlin V.V. et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006; 129 (3): 683–688. DOI: 10.1378/chest.129.3.683.

78. Barst R.J., McGoon M., McLaughlin V.V. et al. Beraprost therapy for pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2003; 41 (12): 2119–2125. DOI: 10.1016/S0735-1097(03)00463-7.

79. Olschewski H., Simommeau G., Galie N. et al. Inhaled iloprost in severe pulmonary hypertension. N. Engl. Med. 2002; 347 (5): 322–329. DOI: 10.1056/NEJMoa020204.

80. 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): 1257–1263. DOI: 10.1164/rccm.200603-358OC.

81. Ghofrani H.A., Rose F., Schermuly R.T. et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2003; 42 (1): 158–164. DOI: 10.1016/S0735-1097(03)00555-2.

82. Michelakis E., Tymchak W., Lien D. et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation. 2002; 105 (20): 2398–2403. DOI: 10.1161/01.CIR.0000016641.12984.DC.

83. Evgenov O.V., Pacher P., Schmidt P.M. et al. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat. Rev. Drug Discov. 2006; 5 (9): 755–768. DOI: 10.1038/nrd2038.

84. Schermuly R.T., Stasch J.P., Pullamsetti S.S. et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur. Respir. J. 2008; 32 (4): 881–891. DOI: 10.1183/09031936.00114407.

85. Stasch J.P., Evgenov O.V. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb. Exp. Pharmacol. 2013; 218 (1): 279–313. DOI: 10.1007/978-3-642-38664-0-12.

86. Ghofrani H.A., Grimminger F. Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy. Eur. Respir. Rev. 2009; 18 (111): 35–41. DOI: 10.1183/09059180.00011112.

87. Stasch J.P., Hobbs A. NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb. Exp. Pharmacol. 2009; (191): 277–308. DOI: 10.1007/978-3-540-68964-5-13.

88. Ghofrani H.A., Galie N., Grimminger F. et al. Riociguat for the treatment of pulmonary arterial hypertension. N. Engl. J. Med. 2013; 369 (4): 330–340. DOI: 10.1056/NEJMoa1209655.

89. Ghofrani H.A., D'Armini A., Grimminger F. et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N. Engl. J. Med. 2013; 369 (4): 319–329. DOI: 10.1056/NEJMoa1209657.

90. Царева Н.А., Авдеев С.Н., Неклюдова Г.В. Последовательная комбинированная терапия у больной идиопатической легочной артериальной гипертензией. Кардиология. 2016; 56 (3): 97–100. DOI: 10.18565/cardio.2016.3.97-100.

91. McLaughlin V.V., Channik R., Chin K.M. et al. Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: results of the GRIPHON study. J. Am. Coll. Cardiol. 2015; 65 (10): 1538–1588. DOI: 10.1016/S0735-1097(15)61538-8.