sGC Stimulators and Activators

Heli Tolppanen, Piotr Ponikowski


Nitric oxide (NO)-soluble guanylate cyclase(sGC)-cGMP signalling is impaired in HF syndromes, which could predispose to vascular oxidative stress. Nitrates directly stimulate cGMP, but are limited by tolerance. Therapeutic targets that aim at increasing cGMP concentrations have therefore been explored. Recently, two classes of drugs have been discovered, the sGC activators and the sGC stimulators, which target two different redox states of sGC: the NO-sensitive reduced (ferrous) sGC and NO-insensitive oxidized (ferric) sGC, respectively.  Cinaciguat is an activator and riociguat and vericiguat are sGC stimulators. Vericiguat is the most advanced agent in its clinical trial programme with two completed phase IIb studies, SOCRATES -REDUCED in HFrEF and SOCRATES-PRESERVED in HFpEF, with mixed results on NT-proBNP. The ongoing VICTORIA trial in HFrEF will study 4,872 participants with a mortality/morbidity end-point and VITALITY HFpEF trial will study  735 participants, with a quality of life end-point.


Heart Failure; sGC stimulators

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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.

Paulus WJ, Bronzwaer JG (2004) Nitric oxide’s role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol 287(1):H8–13

Mohan P, Brutsaert DL, Paulus WJ, Sys SU (1996) Myocardial contractile response to nitric oxide and cGMP. Circulation 93(6):1223–1229

Buys ES, Sips P, Vermeersch P, Raher MJ, Rogge E, Ichinose F, Dewerchin M, Bloch KD, Janssens S, Brouckaert P (2008) Gender-specific hypertension and responsiveness to nitric oxide in sGCalpha1 knockout mice. Cardiovasc Res 79(1):179–186

Lim SL, Lam CS, Segers VF, Brutsaert DL, De Keulenaer GW (2015) Cardiac endothelium- myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J 36(31):2050–2060.

Noireaud J, Andriantsitohaina R (2014) Recent insights in the paracrine

modulation of cardiomyocyte contractility by cardiac endothelial cells. Biomed Res Int 2014:923805.

Ahluwalia A, Foster P, Scotland RS, McLean PG, Mathur A, Perretti M, M o n c a d a S, Hobbs AJ (2004) Antiinflammatory activity of soluble guanylate cyclase: cGMP- dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc Natl Acad Sci USA 101 (5):1386–1391.

Jones SP, Greer JJ, van Haperen R, Duncker DJ, de Crom R, Lefer DJ (2003) Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci USA 100(8):4891–4896.

Vanhoutte PM, Shimokawa H, Tang EH, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196(2):193–222

Schmidt HH, Hofmann F, Stasch JP (2009) Handbook of experimental pharmacology. 191 cGMP generators, effectors and therapeuticimplications. Preface. Handb Exp Pharmacol 191:v–vi

Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschope C, Leite-Moreira AF, Musters R, Niessen HW, Linke WA, Paulus WJ, Hamdani N (2016) Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail 4(4):312–324.

Greene SJ, Gheorghiade M, Borlaug BA, Pieske B, Vaduganathan M, Burnett JC Jr, Roessig L, Stasch JP, Solomon SD, Paulus WJ, Butler J (2013) The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction. J Am Heart Assoc 2(6):e000536.

Hammond J, Balligand JL (2012) Nitric oxide synthase and cyclic GMP signaling in cardiac myocytes: from contractility to remodeling. J Mol Cell Cardiol 52(2):330–340.

Hamdani N, Krysiak J, Kreusser MM, Neef S, Dos Remedios CG, Maier LS, Kruger M, Backs J, Linke WA (2013) Crucial role for Ca2(+)/calmodulin-dependent protein kinase- II in regulating diastolic stress of normal and failing hearts via titin phosphorylation. Circ Res 112

Linke WA, Hamdani N (2014) Gigantic business: titin properties and function through thick and thin. Circ Res 114(6):1052–1068

Maxwell AJ, Schauble E, Bernstein D, Cooke JP (1998) Limb blood flow during exercise is dependent on nitric oxide. Circulation 98(4):369–374

van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, van der Velden J, Stienen GJ, Laarman GJ, Somsen A, Verheugt FW, Niessen HW, Paulus WJ (2012) Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126(7):830–839.

Redfield MM, Chen HH, Borlaug BA, et al. (2013) Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309(12):1268–1277.

Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, van Veldhuisen DJ, Voors AA (2015) Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 36(38):2565–2573.

Galie N, Humbert M, Vachiery JL, et al.(2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ ehv317. Epub 2015 Aug 29.

Damy T, Goode KM, Kallvikbacka-Bennett A, Lewinter C, Hobkirk J, Nikitin NP, Dubois- Rande JL, Hittinger L, Clark AL, Cleland JG (2010) Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure. Eur Heart J 31(18):2280–2290.

Lam CSP, Voors AA, de Boer RA, Solomon SD, van Veldhuisen DJ. Heart failure with preserved ejection fraction: from mechanisms to therapies. Eur Heart J. 2018 Aug 7;39(30):2780-2792. doi: 10.1093/eurheartj/ehy301.

Pradhan K, Sydykov A, Tian X, et al. (2016) Soluble guanylate cyclase stimulator riociguat and phosphodiesterase 5 inhibitor sildenafil ameliorate pulmonary hypertension due to left heart disease in mice. Int J Cardiol. 2016 Aug 1;216:85-91. doi: 10.1016/j.ijcard.2016.04.098.

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.

Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP (2006) NO- independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5(9):755–768.

Munzel T, Gori T, Bruno RM, Taddei S (2010) Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 31:2741–2748

Gheorghiade M, Greene SJ, Filippatos G, Erdmann E, Ferrari R, Levy PD, Maggioni A, Nowack C, Mebazaa A, Investigators C, Coordinators. 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(9):1056-1066.

Erdmann E, Semigran MJ, Nieminen MS, Gheorghiade M, Agrawal R, Mitrovic V, Mebazaa A. Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure. Eur Heart J. 2013;34(1):57-67.

Levy PD, Laribi S, Mebazaa A. Vasodilators in Acute Heart Failure: Review of the Latest Studies. Curr Emerg Hosp Med Rep. 2014;2(2):126-132.

Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, Oudiz RJ, Boateng F, Scalise AV, Roessig L, Semigran MJ, Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial Study G. 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(5):502-511.

Pieske B, Maggioni AP, Lam CSP, Pieske-Kraigher E, Filippatos G, Butler J, Ponikowski P, Shah SJ, Solomon SD, Scalise AV, Mueller K, Roessig L, Gheorghiade M. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J. 2017;38(15):1119-1127.

Gheorghiade M, Greene SJ, Butler J, Filippatos G, Lam CS, Maggioni AP, Ponikowski P, Shah SJ, Solomon SD, Kraigher-Krainer E, Samano ET, Muller K, Roessig L, Pieske B, Investigators S-R, Coordinators. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial. JAMA. 2015;314(21):2251-2262.

Armstrong PW, Roessig L, Patel MJ, Anstrom KJ, Butler J, Voors AA, Lam CSP, Ponikowski P, Temple T, Pieske B, Ezekowitz J, Hernandez AF, Koglin J, O’Connor CM. 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 Feb;6(2):96-104. doi: 10.1016/j.jchf.2017.08.013.

Shewan LG, Coats AJS, Henein MY. Authors’ Responsibilities and Ethical Publishing. International Cardiovascular Forum Journal 2018;13:3-4, DOI: 10.17987/icfj.v13i0.525


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