150.00 rub.
Buy article

Effect of the phosphodiesterase type 5 inhibitor sildenafil on clinical status, pulmonary hemodynamics, and heart diastolic function in patients with diastolic heart failure and reactive pulmonary hypertension

Gavryushina S. V., Ovchinnikov A. G., Ageev F. T.
Russian Cardiology Science and Production Center, 3rd Cherepkovskaya 15a, Moscow 121552, Russia

Keywords: diastolic heart failure, reactive pulmonary hypertension, phosphodiester ase type 5 inhibitor, sildenafil

DOI: 10.18087/rhfj.2017.4.2378

Background. One third of diastolic heart failure (DHF) cases is complicated with reactive pulmonary hypertension (PH). The treatment of reactive PG should provide an influence on both the reactive component and the disturbed LV diastolic function (DF). Both tasks can be solved using sildenafil, a phosphodiesterase type 5 inhibitor (PDE5). Aim. To evaluate the effect of sildenafil on functional status, pulmonary hemodynamics, and heart DF in patients with DHF and reactive PH. Materials and methods. The study included 50 patients with FC II–III CHF, LV EF >50%, hi gh LV filling pressure, and reactive PH (pulmonary vascular resistance >3 Wood units and/or transpulmonary pressure gradient >15 mm Hg). Patients were randomized to a PDE5 sildenafil treatment group (n=30) and a control group (n=20). Beside the study drug, all patients received a standard therapy for CHF. Sildenafil was administered at a dose of 25 mg 3 times daily for the first three months followed by 50 mg 3 times daily for the next three months till the end of study. General clinical evaluation, 6‑min walk test (6MWT), and transthoracic EchoCG were performed for all patients at baseline and at 3 and 6 months. Results. The PDE5 sildenafil treatment was safe, resulted in a rapid decrease in mean heart failure FC, and increased the 6MWT distance by 49±8 m (р<0.05) due to decreases in pulmonary artery systolic pressure by 17±1 mm Hg (р<0.01) and pulmonary artery wedge pressure by 2.9±1 mm Hg (р<0.05). Conclusion. Sildenafil 75–150 mg/day effectively improved the functional status and reduced pulmonary artery pressure in patients with DHF at the stage of reactive PH. In this process, the increased left heart blood flow is compensated by improved LV relaxation processes, which allows avoiding an increase in left atrial pressure.
  1. Беленков Ю. Н., Мареев В. Ю., Агеев Ф. Т. Эпидемиологическое исследование сердечной недостаточности: состояние вопроса. Журнал Сердечная Недостаточность. 2002;3(2):57–8 [Belenkov Yu. N., Mareev V. Yu., Ageev F. T. E`pidemiologicheskoe issledovanie serdechnoj nedostatochnosti: sostoyanie voprosa. Zhurnal Serdechnaya Nedostatochnost`. 2002;3(2):57–8].
  2. Shah RV, Desai AS, Givertz MM. The Effect of Renin‑Angiotensin System Inhibitors on Mortality and Heart Failure Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction: A Systematic Review and Meta‑Analysis. Journal of Cardiac Failure. 2010;16(3):260–7. DOI:10.1016/j.cardfail.2009.11.007.
  3. van Veldhuisen DJ, Cohen‑Solal A, Böhm M, Anker SD, Babalis D, Roughton M et al. Beta‑Blockade With Nebivolol in Elderly Heart Failure Patients With Impaired and Preserved Left Ventricular Ejection Fraction. Journal of the American College of Cardiology. 2009;53(23):2150–8. DOI:10.1016/j.jacc.2009.02.046.
  4. Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction. Journal of the American College of Cardiology. 2009;53(13):1119–26. DOI:10.1016/j.jacc.2008.11.051.
  5. Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence and Risk Factors of Pulmonary Hypertension in Patients With Elevated Pulmonary Venous Pressure and Preserved Ejection Fraction. The American Journal of Cardiology. 2010;106(2):284–6. DOI:10.1016/j.amjcard.2010.02.039.
  6. Drazner MH, Prasad A, Ayers C, Markham DW, Hastings J, Bhella PS et al. The Relationship of Right‑and Left‑Sided Filling Pressures in Patients With Heart Failure and a Preserved Ejection Fraction. Circulation: Heart Failure. 2010;3(2):202–6. DOI:10.1161/CIRCHEARTFAILURE.108.876649.
  7. Овчинников А. Г., Агеев Ф. Т., Азизова А. Г. Сравнительное влияние торасемида и фуросемида на клинический статус и диастолическую функцию левого желудочка у больных с компенсированной сердечной недостаточностью и высоким давлением наполнения левого желудочка. Журнал Сердечная Недостаточность. 2011;12(6):326–32 [Ovchinnikov A. G., Ageev F. T., Azizova A. G. Sravnitel`noe vliyanie torasemida i furosemida na klinicheskij status i diastolicheskuyu funkcziyu levogo zheludochka u bol`ny`x s kompensirovannoj serdechnoj nedostatochnost`yu i vy`sokim davleniem napolneniya levogo zheludochka. Zhurnal Serdechnaya Nedostatochnost`. 2011;12(6):326–32].
  8. Gavazzi A, Ghio S, Scelsi L, Campana C, Klersy C, Serio A et al. Response of the right ventricle to acute pulmonary vasodilation predicts the outcome in patients with advanced heart failure and pulmonary hypertension. American Heart Journal. 2003;145(2):310–6. DOI:10.1067/mhj.2003.146.
  9. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2001;37(1):183–8.
  10. Grigioni F, Potena L, Galie N, Fallani F, Bigliardi M, Coccolo F et al. Prognostic Implications of Serial Assessments of Pulmonary Hypertension in Severe Chronic Heart Failure. The Journal of Heart and Lung Transplantation. 2006;25(10):1241–6. DOI:10.1016/j.healun.2006.06.015.
  11. Kalra PR, Moon JCC, Coats AJS. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non‑selective endothelin antagonism in heart failure? Int J Cardiol. 2002;85(2–3):195–7.
  12. Anand I, McMurray J, Cohn JN, Konstam MA, Notter T, Quitzau K et al. Long‑term effects of darusentan on left‑ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double‑blind, placebo‑controlled trial. The Lancet. 2004;364(9431):347–54. DOI:10.1016/S0140‑6736(04)16723‑8.
  13. Kaluski E, Cotter G, Leitman M, Milo‑Cotter O, Krakover R,  Kobrin I et al. Clinical and Hemodynamic Effects of Bosentan Dose Optimization in Symptomatic Heart Failure Patients with Severe Systolic Dysfunction, Associated with Secondary Pulmonary Hypertension – A Multi‑Center Randomized Study. Cardiology. 2007;109(4):273–80. DOI:10.1159/000107791.
  14. Kaluski E, Kobrin I, Zimlichman R, Marmor A, Krakov O, Milo O et al. RITZ‑5: randomized intravenous TeZosentan (an endothelin‑A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double‑blind, placebo‑controlled study. J Am Coll Cardiol. 2003;41(2):204–10.
  15. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase‑5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. Journal of the American College of Cardiology. 2004;44(12):2339–48. DOI:10.1016/j.jacc.2004.09.041.
  16. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A et al. Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves Contractility. Circulation. 2007;116(3):238–48. DOI:10.1161/CIRCULATIONAHA.106.655266.
  17. Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME et al. Sildenafil Improves Exercise Hemodynamics and Oxygen Uptake in Patients With Systolic Heart Failure. Circulation. 2006;115(1):59–66. DOI:10.1161/CIRCULATIONAHA.106.626226.
  18. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL et al. Sildenafil Stops Progressive Chamber, Cellular, and Molecular Remodeling and Improves Calcium Handling and Function in Hearts With Pre‑Existing Advanced Hypertrophy Caused by Pressure Overload. Journal of the American College of Cardiology. 2009;53(2):207–15. DOI:10.1016/j.jacc.2008.08.069.
  19. Guazzi M, Arena R. Pulmonary hypertension with left‑sided heart disease. Nature Reviews Cardiology. 2010;7(11):648–59. DOI:10.1038/nrcardio.2010.144.
  20. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Target of Phosphodiesterase‑5 Inhibition in a 1‑Year Study. Circulation. 2011;124(2):164–74. DOI:10.1161/CIRCULATIONAHA.110.983866.
  21. Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T, Ogut O et al. Sildenafil and B‑Type Natriuretic Peptide Acutely Phosphorylate Titin and Improve Diastolic Distensibility In Vivo. Circulation. 2011;124(25):2882–91. DOI:10.1161/CIRCULATIONAHA.111.048520.
  22. Yin J, Kukucka M, Hoffmann J, Sterner‑Kock A, Burhenne J, Haefeli WE et al. Sildenafil Preserves Lung Endothelial Function and Prevents Pulmonary Vascular Remodeling in a Rat Model of Diastolic Heart Failure. Circulation: Heart Failure. 2011;4(2):198–206. DOI:10.1161/CIRCHEARTFAILURE.110.957050.
  23. Shan X, Quaile MP, Monk JK, French B, Cappola TP, Margulies KB. Differential Expression of PDE5 in Failing and Nonfailing Human Myocardium. Circulation: Heart Failure. 2012;5(1):79–86. DOI:10.1161/CIRCHEARTFAILURE.111.961706.
  24. Redfield MM, Borlaug BA, Lewis GD, Mohammed SF, Semigran MJ, LeWinter MM et al. PhosphdiesteRasE‑5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) Trial: Rationale and Design. Circulation: Heart Failure. 2012;5(5):653–9. DOI:10.1161/CIRCHEARTFAILURE.112.969071.
  25. Гаврюшина С. В., Овчинников А. Г., Агеев Ф. Т. Эффективность и безопасность терапии ингибитором фосфодиэстеразы типа 5 силденафилом у пациентов с диастолической сердечной недостаточностью и реактивной легочной гипертонией. Журнал Сердечная Недостаточность. 2016;17(3 (96)):173–80. DOI:10.18087/rhfj.2016.3.2225 [Gavryushina S. V., Ovchinnikov A. G., Ageev F. T. E`ffektivnost` i bezopasnost` terapii ingibitorom fosfodie`sterazy` tipa 5 sildenafilom u paczientov s diastolicheskoj serdechnoj nedostatochnost`yu i reaktivnoj legochnoj gipertoniej. Zhurnal Serdechnaya Nedostatochnost`. 2016;17(3 (96)):173–80. DOI:10.18087/rhfj.2016.3.2225].
  26. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 Inhibition With Sildenafil Improves Left Ventricular Diastolic Function, Cardiac Geometry, and Clinical Status in Patients With Stable Systolic Heart Failure: Results of a 1‑Year, Prospective, Randomized, Placebo‑Controlled Study. Circulation: Heart Failure. 2011;4(1):8–17. DOI:10.1161/CIRCHEARTFAILURE.110.944694.
  27. Katz SD, Parker JD, Glasser DB, Bank AJ, Sherman N, Wang H et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure. The American Journal of Cardiology. 2005;95(1):36–42. DOI:10.1016/j.amjcard.2004.08.060.
  28. Webster LJ, Michelakis ED, Davis T, Archer SL. Use of Sildenafil for Safe Improvement of Erectile Function and Quality of Life in Men With New York Heart Association Classes II and III Congestive Heart Failure: A Prospective, Placebo‑Controlled, Double‑blind Crossover Trial. Archives of Internal Medicine. 2004;164(5):514. DOI:10.1001/archinte.164.5.514.
  29. Fink HA, Mac Donald R, Rutks IR, Nelson DB, Wilt TJ. Sildenafil for male erectile dysfunction: a systematic review and meta‑analysis. Arch Intern Med. 2002;162(12):1349–60.
  30. Kloner RA, Mullin SH, Shook T, Matthews R, Mayeda G, Burstein S et al. Erectile Dysfunction in the Cardiac Patient: How Common and Should We Treat? The Journal of Urology. 2003;170(2):S46–50. DOI:10.1097/01.ju.0000075055.34506.59.
  31. Zusman RM. Cardiovascular data on sildenafil citrate: introduction. Am J Cardiol. 1999;83(5A):1C–2C.
  32. Wharton J, Strange JW, Møller GMO, Growcott EJ, Ren X, Franklyn AP et al. Antiproliferative Effects of Phosphodiesterase Type 5 Inhibition in Human Pulmonary Artery Cells. American Journal of Respiratory and Critical Care Medicine. 2005;172(1):105–13. DOI:10.1164/rccm.200411‑1587OC.
  33. Li B, Yang L, Shen J, Wang C, Jiang Z. The Antiproliferative Effect of Sildenafil on Pulmonary Artery Smooth Muscle Cells Is Mediated via Upregulation of Mitogen‑Activated Protein Kinase Phosphatase‑1 and Degradation of Extracellular Signal‑Regulated Kinase 1/2 Phosphorylation: Anesthesia & Analgesia. 2007;105(4):1034–41. DOI:10.1213/01.ane.0000278736.81133.26.
  34. Tantini B, Manes A, Fiumana E, Pignatti C, Guarnieri C, Zannoli R et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Research in Cardiology. 2005;100(2):131–8. DOI:10.1007/s00395‑004‑0504‑5.
  35. Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R. How Prostacyclin Improves Cardiac Output in Right Heart Failure in Conjunction with Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine. 2007;175(8):846–50. DOI:10.1164/rccm.200611‑1615OC.
  36. Kuehne T. Magnetic Resonance Imaging Analysis of Right Ventricular Pressure‑Volume Loops: In Vivo Validation and Clinical Application in Patients With Pulmonary Hypertension. Circulation. 2004;110(14):2010–6. DOI:10.1161/01.CIR.0000143138.02493.DD.
  37. Guazzi M, Gatto P, Giusti G, Pizzamiglio F, Previtali I, Vignati C et al. Pathophysiology of cardiorenal syndrome in decompensated heart failure: Role of lung–right heart–kidney interaction. International Journal of Cardiology. 2013;169(6):379–84. DOI:10.1016/j.ijcard.2013.09.014.
  38. Robbins IM, Hemnes AR, Pugh ME, Brittain EL, Zhao DX, Piana RN et al. High Prevalence of Occult Pulmonary Venous Hypertension Revealed by Fluid Challenge in Pulmonary Hypertension. Circulation: Heart Failure. 2014;7(1):116–22. DOI:10.1161/CIRCHEARTFAILURE.113.000468.
  39. Kohr MJ, Davis JP, Ziolo MT. Peroxynitrite increases protein phosphatase activity and promotes the interaction of phospholamban with protein phosphatase 2a in the myocardium. Nitric Oxide. 2009;20(3):217–21. DOI:10.1016/j.niox.2009.01.003.
  40. Masuyama H, Tsuruda T, Kato J, Imamura T, Asada Y, Stasch J‑P et al. Soluble Guanylate Cyclase Stimulation on Cardiovascular Remodeling in Angiotensin II‑Induced Hypertensive Rats. Hypertension. 2006;48(5):972–8. DOI:10.1161/01.HYP.0000241087.12492.47.
  41. Masuyama H, Tsuruda T, Sekita Y, Hatakeyama K, Imamura T, Kato J et al. Pressure‑independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure‑overloaded rat heart. Hypertension Research. 2009;32(7):597–603. DOI:10.1038/hr.2009.64.
  42. Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC et al. Impaired Chronotropic and Vasodilator Reserves Limit Exercise Capacity in Patients With Heart Failure and a Preserved Ejection Fraction. Circulation. 2006;114(20):2138–47. DOI:10.1161/CIRCULATIONAHA.106.632745.
  43. Borlaug BA, Nishimura RA, Sorajja P, Lam CSP, Redfield MM. Exercise Hemodynamics Enhance Diagnosis of Early Heart Failure With Preserved Ejection Fraction. Circulation: Heart Failure. 2010;3(5):588–95. DOI:10.1161/CIRCHEARTFAILURE.109.930701.
  44. Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. European Journal of Heart Failure. 2013;15(7):776–85. DOI:10.1093/eurjhf/hft026.
  45. Melenovsky V, Al‑Hiti H, Kazdova L, Jabor A, Syrovatka P, Malek I et al. Transpulmonary B‑Type Natriuretic Peptide Uptake and Cyclic Guanosine Monophosphate Release in Heart Failure and Pulmonary Hypertension. Journal of the American College of Cardiology. 2009;54(7):595–600. DOI:10.1016/j.jacc.2009.05.021.
  46. Mahmud A, Hennessy M, Feely J. Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. Journal of Human Hypertension. 2001;15(10):707–13. DOI:10.1038/sj.jhh.1001244.
  47. Oliver JJ, Melville VP, Webb DJ. Effect of Regular Phosphodiesterase Type 5 Inhibition in Hypertension. Hypertension. 2006;48(4):622–7. DOI:10.1161/01.HYP.0000239816.13007.c9.
  48. Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow‑mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 2000;36(3):845–51.
Gavryushina S. V., Ovchinnikov A. G., Ageev F. T. Effect of the phosphodiesterase type 5 inhibitor sildenafil on clinical status, pulmonary hemodynamics, and heart diastolic function in patients with diastolic heart failure and reactive pulmonary hypertension. Russian Heart Failure Journal. 2017;18(4):254–263

To access this material please log in or register

Register Authorize
Ru En