THE EFFICACY OF SILDENAFIL THERAPY IN PATIENTS WITH PULMONARY HYPERTENSION OF DIFFERENT ETIOLOGY: INFLUENCE ON THE CLINICAL, FUNCTIONAL, HEMODYNAMIC STATUS, STRUCTURE AND FUNCTION OF THE RIGHT AND LEFT HEART, RIGHT VENTRICULAR-ARTERIAL COUPLING

Aim: to study the efficacy of sildenafil therapy in pulmonary hypertension of different etiology, its influence on the clinical, functional, hemodynamic status, structure and function of the right and left heart, right ventricular-arterial coupling (RVAC) in pts with idiopathic pulmonary hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Materials and methods: in the study we included 29 IPAH pts aged 42.8±10.6 yrs, 28 CTEPH pts aged 43.4±10.4 yrs II-IV functional class (FC) (WHO), receiving stable standard therapy (anticoagulants, diuretics, glycosides) and calcium channel blockers for at least 3 months. Sildenafil was started at the dose of 10 mg TID to assess the tolerability for further titration after 1 wk to 20 mg 3 times a day. The treatment duration was 16 wks. At baseline and at wk 16 FC (WHO), 6-minute walking test (6-MWT), transthoracic echocardiography (Echo) and right heart catheterization (RHC) were performed.

Results: both groups were comparable in baseline functional parameters: FC, the distance in 6-MWT, Borg index. The analysis of baseline structural and functional cardiac parameters by Echo in IPAH and CTEPH pts revealed pronounced cardiac remodeling as compared to the control group. All pts had criteria precapillary PH by RHC with comparable systolic pulmonary artery pressure (SPAP), mean pulmonary artery pressure (PAPm), cardiac output (CO) and index (CI), pulmonary vascular resistance (PVR) except for diastolic PAP (DPAP), which was higher in IPAH group (38.3±13.7 mm Hg vs 31.5±8.9 mm Hg in CTEPH group (p<0.05). Sildenafil therapy resulted in the marked improvement of functional and hemodynamic status, cardiac remodeling parameters in both groups. To wk 16 IPAH pts achieved the 114m increase in 6-MWT as compared with 108m in CTEPH group. IPAH pts demonstrated the significant decrease in SPAP, PAPm, reduce of right ventricular (RV) size and improvement of contractile function - FAC and TAPSE, increase of RVAC by reducing LV stiffness. Eccentricity index of LV improved significantly only in CTEPH pts. Positive dynamic in RHC data (significant decrease of SPAP, PAPm, DPAP, PVR, increase of CO,CI, stroke volume). CTEPH pts showed a greater reduction in PVR, SPAP and significant SvO2 improvement.

Conclusion: 1. In pts with IPAH and CTEPH of comparable baseline clinical, functional and hemodynamic status we found no significant differences in the severity of cardiac remodeling, RV and LV systolic and diastolic function. Regardless of etiology RVAC was reduced due to the significant increase of LV stiffnessEs. 2. 16-wk sildenafil therapy in pts with IPAH and CTEPH resulted in the positive dynamic of 6-MWT distance, dyspnea index, Echo data including LV stiffness. 3. In CTEPH group as compared with IPAH pts we found the more marked reduction in PVR, PASP and significant improvement SvO2 by RHC. The significant decrease in Es was observed only in CTEPH pts.

1. Galiè N, Hoeper MM, Humbert M, 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 2016; 37(1): 67-119.

2. A. V. Volkov, E. V. Nikolaeva, N. N. Judkina, dr. Vlijanie terapii sildenafilom na vyzhivaemost' pacientov s legochnoj arterial'noj gipertoniej, associirovannoj s sistemnymi zabolevanijami soedinitel'noj tkani (rezul'taty prospektivnogo nabljudenija). Terapevticheskij arhiv 2015;11:62-67. [in Russian]

3. Volkov A.V., Martynjuk T.V., Judkina N.N., dr. Vyzhivaemost' pacientov s legochnoj arterial'noj gipertenziej, associirovannoj s sistemnoj sklerodermiej. Terapevticheskij arhiv 2012; 5:24-28. [in Russian]

4. Chazova I.E., Avdeev S.N., Careva N.A., dr. Klinicheskie rekomendacii po diagnostike i lecheniju legochnoj gipertenzii. Terapevticheskij arhiv 2014; 9:4–23. [in Russian]

5. Volkov A.V., Judkina N.N., Kurmukov I.A., dr. Vlijanie sildenafila na klinicheskie projavlenija i gemodinamicheskie pokazateli u bol'nyh legochnoj arterial'noj gipertenziej, associirovannoj s sistemnymi revmaticheskimi zabolevanijami. Sistemnye gipertenzii 2014;3:61-66. [in Russian]

6. Hoeper MM, Madani MM, Nakanishi N, et al. Chronic thromboembolic pulmonary hypertension. LancetRespirMed 2014; 2: 573–582.

7. Akchurin R.S., Chazova I.E., Mershin K.V., dr. Sluchaj sochetannogo lechenija tjazheloj formy hronicheskoj trobojembolicheskoj legochnoj gipertenzii. Medicinskij sovet 2015; 8:10-13. [in Russian]

8. Chazova I.E., Martynjuk T.V. ot imeni rabochej gruppy po razrabotke i podgotovki teksta Rossijskih rekomendacij po diagnostike i lecheniju HTJeLG. Klinicheskie rekomendacii po diagnostike i lecheniju hronicheskoj trombojembolicheskoj legochnojgipertenzii (II chast'). Terapevticheskij arhiv 2016; 10: 63-74. [in Russian]

9. Antonini- Canterin F., Carerj S., Di Bello V. et al. Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist's point of view. Eur J Echocardiogr 2009 10 (1): 36-43.

10. Valieva Z.S., Valeeva Je.G., Gluhova S.I., dr. Razrabotka skriningovogo oprosnika dlja uluchshenija rannej diagnostiki legochnoj arterial'noj gipertenzii. Sistemnye gipertenzii . 2014;11(4):62-67. [in Russian]

11. Andreeva Ju.A. Ocenka strukturno-funkcional'nogo sostojanija pravyh otdelov serdca po dannym tkanevoj mioka rdial'nojdopplerjehokardiografii i nejrogumoral'nogo statusa u bol'nyh s legochnoj gipertenziej razlichnoj jetiologii i opredelenie vlijanija na nih terapii ingibitorom APF mojeksiprilom. Avtoref. diss. kand. med. nauk- M., 2010. [in Russian]

12. Saxena N, Rajagopalan N, Edelman K, Lopez-Candales A. Tricuspid annular systolic velocity: a useful measurement in determining right ventricular systolic function regardless of pulmonary artery pressures. Echocardiography 2006;23:750–5.

13. Andreeva Ju.A., Saidova M.A., Martynjuk T.V., dr. Remodelirovanie serdca i legochnoj arterii v zavisimosti ot urovnja natrijureticheskih peptidov i aktivacii renin-angiotenzin-al'dosteronovoj sistemy u bol'nyh s legochnoj gipertenziej razlichnoj jetiologii. Kardiovaskuljarnaja terapija i profilaktika 2008, №7, s.62-68. [in Russian]

14. Gan CT, Lankhaar JW, Marcus JT, etal. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension. Am J Physiol Heart CircPhysiol 2006;290:H1528–33.

15. Andreeva Ju.A., Saidova M.A., Martynjuk T.V., dr. Tkanevaja miokardial'naja dopplerjehokardiografija v ocenke funkcii pravogo zheludochka u bol'nyh s legochnoj gipertenziej razlichnoj jetiologii. Kardiovaskuljarnaja terapija i profilaktika 2010, №4, 27-34. [in Russian]

16. 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: 1214-1219.

17. McGoon M.D. The assessment of pulmonary hypertension. Clin Chest Med 2001; 22: 493-508.

18. Gan CT, Lankhaar JW, Marcus JT, et al. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension. Am J Physiol Heart CircPhysiol 2006;290:H1528 –33.

19. Furchgott R.F., Vanhoutte P.M. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3: 2007-2018.

20. Galie N., Ghofrani H.A., Torbicki A., et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353:2148-2157.

21. Lang IM. Managing chronic thromboembolic pulmonary hypertension: pharmacological treatment options. EurRespirRev 2009; 18: 24–28.

22. H.A. Ghofrani, N. Galie, F. Grimminger, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330–340.

23. Reichenberger F., Voswinckel R., Enke B. et al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J 2007; 30:922–927.

24. Condliffe R., Kiely D.G., Gibbs J.S. etal. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension patients. AmJ Respir Crit Care Med 2008;177:1122–1127.