Effect of sildenafil on clinical evidence and hemodynamic parameters in patients with pulmonary arterial hypertension, associated withsystemic rheumaticdiseases

Timeliness of the topic: Pulmonary arterial hypertension(PAH), associated with systemic rheumaticdiseases(SRD),in particular with diffuse scleroderma, is a progressive disorder characterized by adverse outcomeespecially in lack of adequate treatment. Sildenafil 20 mg relaxes blood vessels and shows antiproliferative effect in patients with SRD.The aim of this paperis to study efficiency and safety of sildenafil in patients with PAH, associated with systemic rheumatic diseases.Material and methods:we have been monitoring the 16-week therapyin 14 patients with PAH, associatedwith systemic scleroderma (12 patients) and systemic lupus erythematosus (2 patients). The efficiency was assessed by the dynamics of clinico-laboratorial indices, central hemodynamics were evaluated using the right heart catheterization before the study and after 16 weeks of treatment.Results:We marked thatthe walkeddistancehad been increased by 31 meterinsix-minute walking testduring the therapy;we also saw the improvement of thefunctional classin 29% of patients.The significant improvement achieved in evaluating the hemodynamic parameters.A significant reduction of mean pulmonary arterial pressure was determined from 50.4 ± 9.2 mm Hg to 40.7 ± 10.2 mm. (p = 0.002), the pulmonary vascular resistance fell from 9.5 ± 5.9 to 6.4 ± 3.7 Wood units(p = 0.05),as well assome of the other indicators decreased.Right atrial pressurefell from8.3 ± 5.5 mm Hg. to 6.5 ± 3.1 mm Hg,we noticedthe stabilizationof left ventricle systolic function indices, thus,cardiac indexin all 14 patients,participatingin our study,had not been undergoingsignificant changes (3.1 ± 0.9 l/min/m2at the beginning of the study and 3.1 ± 0.7 l/min/m 2after 16 weeks of the therapy).The risk level, using scale register REVEAL, significantly decreased frommoderate high (9.0 ± 2.0)to medium (8.2 ± 1.9), (p = 0.04).There were no serious adverse events during the 16-week treatment using sildenafil. Three patients showed predisposition to hypotension, but, the blood pressuredecreased within the normal rangesin total group. Skin changes characterized bydermahemia ("blush") were observed in 4 patients and did not significantly impact on the general well-being of patients.Conclusion: Thus, Sildenafil 20 mgshowedefficiency and safety and could be used in treatment patients with PAH, associated with SRD.

легочная артериальная гипертензия, системные заболевания соединительной ткани, системная склеродермия, силденафил, катетеризация правых отделов сердца, pulmonary arterial hypertension, systemicconnective tissuediseases, diffuse scleroderma, sildenafil, right heart catheterization

1. Humbert M, Morrell N.W, Archer S.L et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 13S-24S.

2. Fagan K.A, Badesch D.B. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis 2002; 45: 225-34.

3. Koh E.T, Lee P, Gladman D.D, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996; 35: 989-93.

4. Волков А.В., Мартынюк Т.В., Юдкина Н.Н. и др. Выживаемость пациентов с легочной артериальной гипертензией, ассоциированной с системной склеродермией. Терапевт арх. 2012; 5: 24-8.

5. Kawut S.M, Taichman D.B, Archer-Chicko C.L et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003; 123: 344-50.

6. Mukerjee D, St.George D, Coleiro B et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: Application of a registry approach. Ann Rheum Dis 2003; 62: 1088-93.

7. Corbin J.D, Francis S.H. Cyclic G.M.P phosphodiesterase-5: Target of sildenafil. J Biol Chem 1999; 274: 13729-32.

8. Ghofrani H.A, Voswinckel R, Reichenberger F et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: A randomized prospective study. J Am Coll Cardiol 2004; 44: 1488-96.

9. Tantini B, Manes A, Fiumana E et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 2005; 100: 131-8.

10. Sastry B.K, Narasimhan C, Reddy N.K, Raju B.S. Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo - controlled, double - blind, crossover study. J Am Coll Cardiol 2004; 43: 1149-53.

11. Watanabe H, Ohashi K, Takeuchi K et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002; 71 (5): 398-402.

12. Galie N, Ghofrani H.A, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148-57.

13. Rubin L.J, Badesch D.B, Barst R.J et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903.

14. Gruenig E, Michelakis E, Vachiéry J.L et al. Acute hemodynamic effects of single - dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS- 1 study. J Clin Pharmacol 2009; 49 (11): 1343-52.

15. Badesch D.B, Tapson V.F, Mc Goon M.D et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132: 425-34.

16. 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): 158-64.

17. D'Alto M. An update on the use of ambrisentan in pulmonary arterial hypertension. Ther Adv Respir Dis 2012; 6 (6): 331-43.

18. Чазова И.Е., Мартынюк Т.В., Авдеев С.Н. и др. Российские рекомендации: Диагностика и лечение легочной артериальной гипертензии. Кардиоваск. терапия и профилактика. 2007; 6 (6), Прил. 2: 1-20.

19. Launay D, Remy-Jardin M, Michon-Pasturel U et al. High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol 2006; 33: 1789-801.

20. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six - minute walk test. Am J Respir Crit Care Med 2002; 166: 111-7.

21. Chemla D, Castelain V, Hervé P et al. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J 2002; 20: 1314-31.

22. Benza R.L, Gomberg-Maitland M, Miller D.P et al. The REVEAL Registry Risk Score Calculator in Patients Newly Diagnosed With Pulmonary Arterial Hypertension. Chest 2012; 141 (2): 354-62.

23. 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: 2493-537.

24. Cea-Calvo L, Escribano Subias P, Tello de Menesses R et al. Sildenafil as a substitute for subcutaneous prostacyclin in pulmonary hypertension [Spanish]. Arch Bronconeumol 2003; 39: 476-7.

25. Rosenkranz S, Diet F, Karasch T et al. Sildenafil improved pulmonary hypertension and peripheral blood flow in a patient with scleroderma - associated lung fibrosis and the Raynaud phenomenon. Ann Intern Med 2003; 139: 871-3.

26. Molina J, Lucero E, Luluaga S et al. Systemic lupus erythematosus - associated pulmonary hypertension: Good outcome following sildenafil therapy. Lupus 2003; 12: 321-3.

27. Badesch D.B, Hill N.S, Burgess et al. Sildenafil for Pulmonary Arterial Hypertension Associated with Connective Tissue Disease. J Rheumatol 2007; 34: 2417-22.