Статья
Значение сигнального пути “оксид азота — растворимая гуанилатциклаза — циклический гуанозинмонофосфат” в патогенезе сердечной недостаточности и поиске новых терапевтических мишеней
Сердечная недостаточность по-прежнему остается заболеванием с тяжелым течением и неблагоприятным прогнозом, что требует усиления терапии и поиска новых подходов к лечению. В настоящем обзоре подробно обсуждается физиологическое значение сигнального пути, ассоциированного с растворимой гуанилатциклазой, изложены причины снижения ее активности при сердечной недостаточности и возможные последствия в виде нарушения функции сердца и сосудов и прогрессирования заболевания. Рассматриваются фармакологические методы стимуляции образования циклического гуанозинмонофосфата при помощи препаратов с разными механизмами действия: приведены данные клинических исследований относительно их эффективности и безопасности. Перспективным подходом можно считать стимуляцию растворимой гуанилатциклазы, сопровождавшуюся благоприятными эффектами в доклинических исследованиях, а также в недавно завершившемся исследовании III фазы VICTORIA.
1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789-858. doi:10.1016/S0140-6736(18)32279-7.
2. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020;22(8):1342-56. doi:10.1002/ejhf.1858.
3. Фомин И. В. Хроническая сердечная недостаточность в Российской Федерации: Что сегодня мы знаем и что должны делать. Российский кардиологический журнал. 2016;(8):7-13. doi:10.15829/1560-4071-2016-8-7-13.
4. van Riet EE, Hoes AW, Wagenaar KP, et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail. 2016;18:242-52. doi:10.1002/ejhf.483.
5. Шляхто Е. В., Звартау Н. Э., Виллевальде С. В. и др. Значимость оценки распространенности и мониторинга исходов у пациентов с сердечной недостаточностью в России. Российский кардиологический журнал. 2020;25(12):4204. doi:10.15829/1560-4071-2020-4204.
6. Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart Failure With Reduced Ejection Fraction: A Review. JAMA. 2020;324(5):488-504. doi:10.1001/jama.2020.10262.
7. Felker GM, Mann DL. Heart Failure: A Companion to Braunwald's Heart Disease. 4th ed. Philadelphia, PA: Elsevier; 2020. ISBN-13: 978-0323609876, ISBN-10: 0323609872.
8. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303.
9. Chun S, Tu JV, Wijeysundera HC, et al. Lifetime analysis of hospitalizations and survival of patients newly admitted with heart failure. Circ Heart Fail. 2012;5:414-21. doi:10.1161/CIRCHEARTFAILURE.111.964791.
10. Виноградова НГ, Поляков Д. С., Фомин И. В. Риски повторной госпитализации пациентов с ХСН при длительном наблюдении в специализированном центре лечения ХСН и в реальной клинической практике. Кардиология. 2020;60(3):59-69. doi:10.18087/cardio.2020.3.n1002.
11. Ситникова М. Ю., Лясникова Е. А., Юрченко А. В. и др. Результаты 3 лет работы Российского госпитального регистра хронической сердечной недостаточности (RUssian hoSpital Heart Failure Registry-RUS-HFR): взаимосвязь менеджмента и исходов у больных хронической сердечной недостаточностью. Кардиология. 2018;58(S10):9-19. doi:10.18087/cardio.2483.
12. Lewis KS, Butler J, Bauersachs J, Sandner P. The Three-Decade Long Journey in Heart Failure Drug Development. Handb Exp Pharmacol. 2017;243:1-14. doi:10.1007/164_2016_101.
13. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020;382(20):1883-93. doi:10.1056/NEJMoa1915928.
14. Brutsaert DL. Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol Rev. 2003;83(1):59-115. doi:10.1152/physrev.00017.2002.
15. Boerrigter G, Lapp H, Burnett JC. Modulation of cGMP in heart failure: a new therapeutic paradigm. Handb Exp Pharmacol. 2009;(191):485-506. Handb Exp Pharmacol. 2009;(191):485-506. doi:10.1007/978-3-540-68964-5_21.
16. Balligand JL, Cannon PJ. Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences. Arterioscler Thromb Vasc Biol. 1997;17:1846-58. doi:10.1161/01.atv.17.10.1846.
17. Fulton DJR, Li X, Bordan Z, et al. Reactive Oxygen and Nitrogen Species in the Development of Pulmonary Hypertension. Antioxidants (Basel). 2017;6(3):54. doi:10.3390/antiox6030054.
18. Follmann M, Ackerstaff J, Redlich G, et al. Discovery of the soluble guanylate cyclase stimulator vericiguat (BAY 1021189) for the treatment of chronic heart failure. J Med Chem. 2017;60(12):5146-61. doi:10.1021/acs.jmedchem.7b00449.
19. Sandner P. From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators. J Biol Chem. 2018;399(7):679-90. doi:10.1515/hsz-2018-0155.
20. Sharina IG, Jelen F, Bogatenkova EP, et al. Alpha1 soluble guanylyl cyclase (sGC) splice forms as potential regulators of human sGC activity. J Biol Chem. 2008;283(22):15104-13. doi:10.1074/jbc.M710269200.
21. Bauersachs J, Widder JD. Endothelial dysfunction in heart failure. Pharmacol Rep. 2008;60:119-26.
22. Zhang M, Kass DA. Phosphodiesterases and cardiac cGMP: evolving roles and controversies. Trends Pharmacol Sci. 2011;32(6):360-5. doi:10.1016/j.tips.2011.02.019.
23. Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther. 2009;122(3):216-38. doi:10.1016/j.pharmthera.2009.02.009.
24. Breitenstein S, Roessig L, Sandner P, Lewis KS. Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure. Handb Exp Pharmacol. 2017;243:225. doi:10.1007/164_2016_100.
25. Kim JY, Yang HM, Lee JE, et al. Activation of Protein Kinase G (PKG) Reduces Neointimal Hyperplasia, Inhibits Platelet Aggregation, and Facilitates Re-endothelialization. Sci Rep. 2016;6:36979. doi:10.1038/srep36979.
26. Park M, Sandner P, Krieg T. cGMP at the centre of attention: emerging strategies for activating the cardioprotective PKG pathway. Basic Res Cardiol. 2018;113(4):24. doi:10.1007/s00395-018-0679-9.
27. Inserte J, Garcia-Dorado D. The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism. Br J Pharmacol. 2015;172(8):1996-2009. doi:10.1111/bph.12959.
28. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37:2129-200. doi:10.1093/eurheartj/ehw128.
29. Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling: mechanisms: part 1 of 2. Circulation. 2013;128(4):388-400. doi:10.1161/CIRCULATIONAHA.113.001878.
30. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15(7):387-407. doi:10.1038/s41569-018-0007-y.
31. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263-71. doi:10.1016/j.jacc.2013.02.092.
32. Higashi Y, Noma K, Yoshizumi M, Kihara Y. Endothelial function and oxidative stress in cardiovascular diseases. Circ J. 2009;73:411-8. doi:10.1253/circj.cj-08-1102.
33. Favero G, Paganelli C, Buffoli B, et al. Endothelium and its alterations in cardiovascular diseases: life style intervention. Biomed Res Int. 2014;2014:801896. doi:10.1155/2014/801896.
34. Wong MS, Vanhoutte PM. COX-mediated endothelium-dependent contractions: from the past to recent discoveries. Acta Pharmacol Sin. 2010;31(9):1095-102. doi:10.1038/aps.2010.127.
35. Cannan CR, McGoon MD, Holmes DR Jr, Lerman A. Altered coronary endothelial function in a patient with asymptomatic left ventricular dysfunction. Int J Cardiol. 1996;53:147-51. doi:10.1016/0167-5273(95)02513-8.
36. Mathier MA, Rose GA, Fifer MA, et al. Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1998;32:216-24. doi:10.1016/s0735-1097(98)00209-5.
37. Wu Z, Tian T, Ma W, et al. Higher urinary nitrate was associated with lower prevalence of congestive heart failure: results from NHANES. BMC Cardiovasc Disord. 2020;20(1):498. doi:10.1186/s12872-020-01790-w.
38. Gheorghiade M, Marti CN, Sabbah HN, et al. Soluble guanylate cyclase: a potential therapeutic target for heart failure. Heart Fail Rev. 2013;18:123-34. doi:10.1007/s10741-012-9323-1.
39. Taylor AL. Nitric oxide modulation as a therapeutic strategy in heart failure. Heart Fail Clin. 2012;8(2):255-72. doi:10.1016/j.hfc.2011.11.002.
40. Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol. 2009;7(1):65-74. doi:10.2174/157015909787602823.
41. Evgenov OV, Pacher P, Schmidt PM, et al. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov. 2006;5:755-68. doi:10.1038/nrd2038.
42. Greene SJ, Gheorghiade M, Borlaug BA, et al. The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction. J Am Heart Assoc. 2013;2(6):e000536. doi:10.1161/JAHA.113.000536.
43. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263-73. doi:10.1161/CIRCULATIONAHA.110.981738.
44. Janicki JS, Brower GL, Gardner JD, et al. The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling. Heart Fail Rev. 2004;9:33-42. doi:10.1023/B:HREV.0000011392.03037.7e.
45. Kruger M, Kotter S, Grutzner A, et al. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res. 2009;104:87-94. doi:10.1161/CIRCRESAHA.108.184408.
46. Vettel C, Lammle S, Ewens S, et al. PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways. Am J Physiol Heart Circ Physiol. 2014;306:H1246-52. doi:10.1152/ajpheart.00852.2013.
47. Borbely A, Falcao-Pires I, van Heerebeek L, et al. Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009;104:780-6. doi:10.1161/CIRCRESAHA.108.193326.
48. Fan D, Takawale A, Lee J, Kassiri Z. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair. 2012;5(1):15. doi:10.1186/1755-1536-5-15.
49. Rizzo NO, Maloney E, Pham M, et al. Reduced NO-cGMP signaling contributes to vascular inflammation and insulin resistance induced by high-fat feeding. Arterioscler Thromb Vasc Biol. 2010;30:758-65. doi:10.1161/ATVBAHA.109.199893.
50. Buys ES, Sips P, Vermeersch P, et al. Gender-specific hypertension and responsiveness to nitric oxide in sGCalpha1 knockout mice. Cardiovasc Res. 2008;79:179-86. doi:10.1093/cvr/cvn068.
51. Cawley SM, Kolodziej S, Ichinose F, et al. sGC{alpha}1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling. Am J Physiol Heart Circ Physiol. 2011;301:H157-63. doi:10.1152/ajpheart.01273.2010.
52. Leineweber K, Moosmang S, Paulson D. Genetics of NO Deficiency. Am J Cardiol. 2017;120:S80. doi:10.1016/j.amjcard.2017.06.013.
53. Emdin CA, Khera AV, Klarin D, et al. Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling. Circulation. 2018;137:222. doi:10.1161/CIRCULATIONAHA.117.028021.
54. Wobst J, Schunkert H, Kessler T. Genetic alterations in the NO-cGMP pathway and cardiovascular risk. Nitric Oxide. 2018;76:105. doi:10.1016/j.niox.2018.03.019.
55. Singh P, Vijayakumar S, Kalogeroupoulos A, Butler J. Multiple Avenues of Modulating the Nitric Oxide Pathway in Heart Failure Clinical Trials. Curr Heart Fail Rep. 2018;15(2):44-52. doi:10.1007/s11897-018-0383-y.
56. Российское кардиологическое общество. Хроническая сердечная недостаточность. Клинические рекомендации 2020. Российский кардиологический журнал. 2020;25(11):4083. doi:10.15829/1560-4071-2020-4083.
57. Elkayam U, Roth A, Mehra A, et al. Randomized study to evaluate the relation between oral isosorbide dinitrate dosing interval and the development of early tolerance to its effect on left ventricular filling pressure in patients with chronic heart failure. Circulation. 1991;84(5):2040-8. doi:10.1161/01.cir.84.5.2040.
58. Mehra A, Ostrzega E, Shotan A, et al. Persistent hemodynamic improvement with short-term nitrate therapy in patients with chronic congestive heart failure already treated with captopril. Am J Cardiol. 1992;70:1310-4. doi:10.1016/0002-9149(92)90767-s.
59. Munzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation. 2011;123:2132-44. doi:10.1161/CIRCULATIONAHA.110.981407.
60. Schwarz M, Katz SD, Demopoulos L, et al. Enhancement of endothelium-dependent vasodilation by low-dose nitroglycerin in patients with congestive heart failure. Circulation. 1994;89:1609-14. doi:10.1161/01.cir.89.4.1609.
61. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314:1547-52.
62. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303-10. doi:10.1056/NEJM199108013250502.
63. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049-57. doi:10.1056/NEJM198606123142404.
64. Gupta D, Georgiopoulou VV, Kalogeropoulos AP, et al. Nitrate therapy for heart failure: benefits and strategies to overcome tolerance. JACC Heart Fail. 2013;1(3):183-91. doi:10.1016/j.jchf.2013.03.003.
65. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015;373(24):2314-24. doi:10.1056/NEJMoa1510774.
66. Long W, Liao H, Liu Q, et al. Effect of nitrate treatment on functional capacity and exercise time in patients with heart failure: a systematic review and meta-analysis. J Int Med Res. 2020;48(8):300060520939742. doi:10.1177/0300060520939742.
67. Munzel T, Steven S, Daiber A. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vascul Pharmacol. 2014;63(3):105-13. doi:10.1016/j.vph.2014.09.002.
68. Thadani U, Ripley TL. Side effects of using nitrates to treat heart failure and the acute coronary syndromes, unstable angina and acute myocardial infarction. Expert Opin Drug Saf. 2007;6(4):385-96. doi:10.1517/14740338.6.4.385.
69. Michalak M, Armstrong PW. Exploring New Cardiovascular Pathways: Are Soluble Guanylate Cyclase Stimulators the Right Direction? Circ Heart Fail. 2018;11:e004813. doi:10.1161/CIRCHEARTFAILURE.118.004813.
70. Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. Randomized, double-blind, placebo-controlled study of carvedilol on the prevention of nitrate tolerance in patients with chronic heart failure. J Am Coll Cardiol. 1998;32:1194-200. doi:10.1016/s0735-1097(98)00392-1.
71. Guazzi M. Clinical use of phosphodiesterase-5 inhibitors in chronic heart failure. Circ Heart Fail. 2008;1:272-80. doi:10.1161/CIRCHEARTFAILURE.108.802116.
72. Barnes H, Brown Z, Burns A, Williams T. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database Syst Rev. 2019;1(1):CD012621. doi:10.1002/14651858.CD012621.pub2.
73. Bermejo J, Yotti R, Garda-Orta R, et al. Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, doubleblind, randomized clinical trial. Eur Heart J. 2018;39:1255-64. doi:10.1093/eurheartj/ehx700.
74. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phospho-diesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268-77. doi:10.1001/jama.2013.2024.
75. Hwang IC, Kim YJ, Park JB, et al. Pulmonary hemodynamics and effects of phosphodiesterase type 5 inhibition in heart failure: a meta-analysis of randomized trials. BMC Cardiovasc Disord. 2017;17(1):150. doi:10.1186/s12872-017-0576-4.
76. Volpe M, Carnovali M, Mastromarino V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci. 2016;130:57-77. doi:10.1042/CS20150469.
77. DiBianco R, Shabetai R, Kostuk W, et al. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med. 1989;320:677-83. doi:10.1056/NEJM198903163201101.
78. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325:1468-75. doi:10.1056/NEJM199111213252103.
79. Cuffe MS, Califf RM, Adams KF Jr, et al. Shortterm intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541-7. doi:10.1001/jama.287.12.1541.
80. Fifer MA, Molina CR, Quiroz AC, et al. Hemodynamic and renal effects of atrial natriuretic peptide in congestive heart failure. Am J Cardiol. 1990;65:211-6. doi:10.1016/0002-9149(90)90087-h.
81. Kasama S, Toyama T, Iwasaki T, et al. Evaluation of cardiac sympathetic nerve activity and aldosterone suppression in patients with acute decompensated heart failure on treatment containing intravenous atrial natriuretic peptide. Eur J Nucl Med Mol Imaging. 2014;41:1683-91. doi:10.1007/s00259-014-2754-2.
82. Matsue Y, Kagiyama N, Yoshida K, et al. Carperitide is associated with increased in-hospital mortality in acute heart failure: a propensity score-matched analysis. J Card Fail. 2015;21:859-64. doi:10.1016/j.cardfail.2015.05.007.
83. Packer M, O'Connor C, McMurray JJV, et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med. 2017;376:1956-64. doi:10.1056/NEJMoa1601895.
84. Fitzgerald RL, Cremo R, Gardetto N, et al. Effect of nesiritide in combination with standard therapy on serum concentrations of natriuretic peptides in patients admitted for decompensated congestive heart failure. Am Heart J. 2005;150:471-7. doi:10.1016/j.ahj.2004.11.021.
85. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med. 2000;343:246-53. doi:10.1056/NEJM200007273430403.
86. O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32-43. doi:10.1056/NEJMoa1100171.
87. Topol EJ. Nesiritide — not verified. N Engl J Med. 2005;353:113-6. doi:10.1056/NEJMp058139.
88. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077.
89. Bork NI, Nikolaev VO. cGMP Signaling in the Cardiovascular System-The Role of Compartmentation and Its Live Cell Imaging. Int J Mol Sci. 2018;19(3):801. doi:10.3390/ijms19030801.
90. Emdin M, Aimo A, Castiglione V, et al. Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure: JACC Review Topic of the Week. J Am Coll Cardiol. 2020;76(15):1795-807. doi:10.1016/j.jacc.2020.08.031.
91. Franssen C, Chen S, Hamdani N, Paulus WJ. From comorbidities to heart failure with preserved ejection fraction: a story of oxidative stress. Heart. 2016;102(4):320-30. doi: 10.1136/heartjnl-2015-307787.
92. Gheorghiade M, Greene SJ, Filippatos G, et al. Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes. Eur J Heart Fail. 2012;14:1056-66. doi:10.1093/eurjhf/hfs093.
93. Instructions for the medical use of the drug Adempas® (In Russ.) Инструкция по медицинскому применению лекарственного препарата Адемпас® https://pharma.bayer.ru/sites/g/files/vrxlpx3916/files/2020-10/Adempas.pdf.
94. Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation.2013;128:502-11. doi:10.1161/CIRCULATIONAHA.113.001458.
95. Bonderman D, Pretsch I, Steringer-Mascherbauer R, et al. Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study. Chest. 2014;146:1274-85. doi:10.1378/chest.14-0106.
96. Boettcher M, Loewen S, Gerrits M, Becker C. Safety, pharmacodynamics and pharmacokinetic characterisation of veri-ciguat: Key results from six phase I studies in healthy subjects. Eur J Heart Fail. 2019;21(S1):293. doi:10.1007/s00228-020-03023-7.
97. Frey R, Becker C, Saleh S, et al. Clinical pharmacokinetic and pharmacodynamic profile of riociguat. Clin Pharmacokinet 2018;57(6):647-61. doi:10.1007/s40262-017-0604-7.
98. Ruehs H, Klein D, Frei M, et al. Population Pharmacokinetics and Pharmacodynamics of Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. Clin Pharmacokinet. 2021. doi:10.1007/s40262-021-01024-y. Ahead of print.
99. Armitage ME, Wingler K, Schmidt HH, La M. Translating the oxidative stress hypothesis into the clinic: NOX versus NOS. J Mol Med. 2009;87:1071. doi:10.1007/s00109-009-0544-2.
100. Armstrong PW, Roessig L, Patel MJ, et al. A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: The VICTORIA trial. JACC Heart Fail. 2018;6(2):96-104. doi:10.1016/j.jchf.2017.08.013.
101. Hoffmann LS, Etzrodt J, Willkomm L, et al. Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue. Nat Commun. 2016;6:1-9. doi:10.1038/ncomms8235.
102. Hoffmann LS, Larson J, Pfeifer A. cGMP and brown adipose tissue. Handb Exp Pharmacol. 2015;233:283-99. doi:10.1007/164_2015_3.
103. Reverte-Salisa L, Sanyal A, Pfeifer A. Role of cAMP and cGMP signaling in brown fat. Handb Exp Pharmacol. 2019;251:161-82. doi:10.1007/164_2018_117.
104. Mathar I, Pavkovic M, Scheerer N, et al. The sGC stimulator vericiguat improved outcome in a rodent model of heart failure with preserved ejection fraction (HFpEF). Circulation. 2018;138(Suppl 1):A15553.
105. Irvine JC, Ganthavee V, Love JE, et al. The soluble guanylyl cyclase activator bay 58-2667 selectively limits cardiomyocyte hypertrophy. PLoS One. 2012;7(11):e44481. doi:10.1371/journal.pone.0044481.
106. Masuyama H, Tsuruda T, Kato J, 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.
107. Masuyama H, Tsuruda T, Sekita Y, et al. Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart. Hypertens Res. 2009;32:597-603. doi:10.1038/hr.2009.64.
108. Mathar I, Kretschmer A, Hartmann E, et al. Combination of Soluble Guanylate Cyclase Stimulation and Mineralocorticoid Receptor Antagonism as New Treatment Option for Heart Failure With Preserved Ejection Fraction (hfpef): Results From A Preclinical Study With Vericiguat and Finerenone. Circulation. 2017;136:A17778.
109. Sharkovska Y, Kalk P, Lawrenz B, et al. Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models. J Hypertens. 2010;28:1666-75. doi:10.1097/HJH.0b013e32833b558c.
110. Costell MH, Ancellin N, Bernard RE, et al. Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress. Front Pharmacol. 2012;3:128. doi:10.3389/fphar.2012.00128.
111. Reinke Y, Gross S, Eckerle LG, et al. The soluble guanylate cyclase stimulator riociguat and the soluble guanylate cyclase activator cinaciguat exert no direct effects on contractility and relaxation of cardiac myocytes from normal rats. Eur J Pharmacol. 2015;767:1. doi:10.1016/j.ejphar.2015.09.022.
112. Takimoto E, Belardi D, Tocchetti CG, et al. Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation. 2007;115:2159-67. doi:10.1161/CIRCULATIONAHA.106.643536.