Skip to main content
SpringerLink
Log in

Soluble Guanylate Cyclase Stimulators: a Novel Treatment Option for Heart Failure Associated with Cardiorenal Syndromes?

  • Pharmacologic Therapy (W H W Tang, Section Editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Heart failure in the setting of chronic kidney disease (CKD) is an increasingly common scenario and carries a poor prognosis. Clinicians lack tools for primary or secondary heart failure prevention in patients with cardiorenal syndromes. In patients without CKD, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) and statins mitigate cardiovascular risk in large part due to salutary effects on the endothelium. In the setting of CKD, use of these therapies is limited by adverse effects of hyperkalemia in pre-dialysis CKD (ACE-I/ARB), or potential increased risk of stroke in end-stage renal disease (statins). The soluble guanylate cyclase (sGC) stimulators are a novel class of medications that promote endothelial and myocardial function with no known risk of hyperkalemia or stroke. In this review, we discuss the evidence emerging from recent clinical trials of sGC stimulators in pulmonary hypertension and heart failure, the diseased pathways involved in cardiorenal syndromes likely to be restored by sGC stimulators, and several strategies for designing future clinical trials of cardiorenal syndromes that might shorten the timeline for discovery and approval of effective cardiovascular therapies in these high-risk patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Cardiovascular disease in patients with CKD, Vol.1 Ch. 4 [http://www.usrds.org/2014/view/v1_04.aspx]

  2. Adult population of the United States [http://www.census.gov].

  3. Damman K, Masson S, Hillege HL, Maggioni AP, Voors AA, Opasich C, et al. Clinical outcome of renal tubular damage in chronic heart failure. Eur Heart J. 2011;32(21):2705–12.

    Article  CAS  PubMed  Google Scholar 

  4. Rossignol P, Dobre D, McMurray JJ, Swedberg K, Krum H, van Veldhuisen DJ, et al. Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014;7(1):51–8.

    Article  CAS  PubMed  Google Scholar 

  5. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J. 2010;31(6):703–11.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Costs of chronic kidney disease [http://www.usrds.org/2010/view/v1_09.asp]

  7. Yildirim T, Arici M, Piskinpasa S, Aybal-Kutlugun A, Yilmaz R, Altun B, et al. Major barriers against renin-angiotensin-aldosterone system blocker use in chronic kidney disease stages 3–5 in clinical practice: a safety concern? Ren Fail. 2012;34(9):1095–9.

    Article  CAS  PubMed  Google Scholar 

  8. Park M, Hsu CY, Li Y, Mishra RK, Keane M, Rosas SE, et al. Associations between kidney function and subclinical cardiac abnormalities in CKD. J Am Soc Nephrol. 2012;23(10):1725–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Scialla JJ, Xie H, Rahman M, Anderson AH, Isakova T, Ojo A, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol. 2014;25(2):349–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Charytan DM, Fishbane S, Malyszko J, McCullough PA, Goldsmith D. Cardiorenal syndrome and the role of the bone-mineral axis and anemia. Am J Kidney Dis 2015.

  12. Yilmaz MI, Saglam M, Caglar K, Cakir E, Sonmez A, Ozgurtas T, et al. The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine. Am J Kidney Dis. 2006;47(1):42–50.

    Article  CAS  PubMed  Google Scholar 

  13. Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol. 2013;218:279–313.

    Article  CAS  PubMed  Google Scholar 

  14. Gheorghiade M, Marti CN, Sabbah HN, Roessig L, Greene SJ, Bohm M, et al. Soluble guanylate cyclase: a potential therapeutic target for heart failure. Heart Fail Rev. 2013;18(2):123–34.

    Article  CAS  PubMed  Google Scholar 

  15. Bolignano D, Rastelli S, Agarwal R, Fliser D, Massy Z, Ortiz A, et al. Pulmonary hypertension in CKD. Am J Kidney Dis. 2013;61(4):612–22.

    Article  PubMed  Google Scholar 

  16. Bolignano D, Lennartz S, Leonardis D, D’Arrigo G, Tripepi R, Emrich IE, et al. High estimated pulmonary artery systolic pressure predicts adverse cardiovascular outcomes in stage 2–4 chronic kidney disease. Kidney Int. 2015;88(1):130–6.

    Article  CAS  PubMed  Google Scholar 

  17. Di Lullo L, Floccari F, Rivera R, Barbera V, Granata A, Otranto G, et al. Pulmonary hypertension and right heart failure in chronic kidney disease: new challenge for 21st-century cardionephrologists. Cardiorenal Med. 2013;3(2):96–103.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Group. KDIGOKBPW: KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl. 2012(2):337–414.

  19. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211–21.

    Article  PubMed  Google Scholar 

  20. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014;63(6):528–36.

    Article  CAS  PubMed  Google Scholar 

  21. Zannad F, Kessler M, Lehert P, Grunfeld JP, Thuilliez C, Leizorovicz A, et al. Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int. 2006;70(7):1318–24.

    Article  CAS  PubMed  Google Scholar 

  22. Cice G, Di Benedetto A, D’Isa S, D’Andrea A, Marcelli D, Gatti E, et al. Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure a double-blind, placebo-controlled trial. J Am Coll Cardiol. 2010;56(21):1701–8.

    Article  CAS  PubMed  Google Scholar 

  23. Cardiovascular Disease Vol 2. Ch. 4 [http://www.usrds.org/atlas.aspx]

  24. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360(14):1395–407.

    Article  CAS  PubMed  Google Scholar 

  25. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353(3):238–48.

    Article  CAS  PubMed  Google Scholar 

  26. Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Assessment by bicoronary sodium nitroprusside infusion. Circulation. 1994;89(5):2070–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Kruger M, Kotter S, Grutzner A, Lang P, Andresen C, Redfield MM, et al. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res. 2009;104(1):87–94.

    Article  PubMed  Google Scholar 

  29. Zeiher AM, Krause T, Schachinger V, Minners J, Moser E. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation. 1995;91(9):2345–52.

    Article  CAS  PubMed  Google Scholar 

  30. Ito K, Chen J, Seshan SV, Khodadadian JJ, Gallagher R, El Chaar M, et al. Dietary arginine supplementation attenuates renal damage after relief of unilateral ureteral obstruction in rats. Kidney Int. 2005;68(2):515–28.

    Article  CAS  PubMed  Google Scholar 

  31. Wang-Rosenke Y, Neumayer HH, Peters H. NO signaling through cGMP in renal tissue fibrosis and beyond: key pathway and novel therapeutic target. Curr Med Chem. 2008;15(14):1396–406.

    Article  CAS  PubMed  Google Scholar 

  32. Stasch JP, Schlossmann J, Hocher B. Renal effects of soluble guanylate cyclase stimulators and activators: a review of the preclinical evidence. Curr Opin Pharmacol. 2015;21:95–104.

    Article  CAS  PubMed  Google Scholar 

  33. Kalk P, Godes M, Relle K, Rothkegel C, Hucke A, Stasch JP, et al. NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy. Br J Pharmacol. 2006;148(6):853–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang Y, Kramer S, Loof T, Martini S, Kron S, Kawachi H, et al. Stimulation of soluble guanylate cyclase slows progression in anti-thy1-induced chronic glomerulosclerosis. Kidney Int. 2005;68(1):47–61.

    Article  CAS  PubMed  Google Scholar 

  35. Geschka S, Kretschmer A, Sharkovska Y, Evgenov OV, Lawrenz B, Hucke A, et al. Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats. PLoS One. 2011;6(7), e21853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sharkovska Y, Kalk P, Lawrenz B, Godes M, Hoffmann LS, Wellkisch K, 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(8):1666–75.

    Article  CAS  PubMed  Google Scholar 

  37. Zoccali C. The endothelium as a target in renal diseases. J Nephrol. 2007;20 Suppl 12:S39–44.

    CAS  PubMed  Google Scholar 

  38. Stasch JP, Hobbs AJ. NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol. 2009;191:277–308.

    Article  CAS  PubMed  Google Scholar 

  39. Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–40.

    Article  CAS  PubMed  Google Scholar 

  40. Rubin LJ, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh A, Langleben D, Fritsch A, Menezes F et al.. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J. 2015.

  41. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319–29.

    Article  CAS  PubMed  Google Scholar 

  42. Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Hoeper MM, Jansa P, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J. 2015;45(5):1293–302.

    Article  CAS  PubMed  Google Scholar 

  43. Bonderman D, Pretsch I, Steringer-Mascherbauer R, Jansa P, Rosenkranz S, Tufaro C, 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(5):1274–85.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, 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(5):502–11.

    Article  CAS  PubMed  Google Scholar 

  45. Pieske B, Butler J, Filippatos G, Lam C, Maggioni AP, Ponikowski P, et al. Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES). Eur J Heart Fail. 2014;16(9):1026–38.

    Article  CAS  PubMed  Google Scholar 

  46. Gheorghiade M, Greene SJ, Butler J, Filippatos G, Lam CS, Maggioni AP, et al. 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):2251–62.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, Liu L, et al. Prognostic importance of impaired systolic function in heart failure with preserved ejection fraction and the impact of spironolactone. Circulation. 2015;132(5):402–14.

    Article  CAS  PubMed  Google Scholar 

  49. Kramann R, Erpenbeck J, Schneider RK, Rohl AB, Hein M, Brandenburg VM, et al. Speckle tracking echocardiography detects uremic cardiomyopathy early and predicts cardiovascular mortality in ESRD. J Am Soc Nephrol. 2014;25(10):2351–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu YW, Su CT, Sung JM, Wang SP, Su YR, Yang CS, et al. Association of left ventricular longitudinal strain with mortality among stable hemodialysis patients with preserved left ventricular ejection fraction. Clin J Am Soc Nephrol. 2013;8(9):1564–74.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Myerson SG, BelIenger NG, Pennell OJ. Assessment of left ventricular mass by cardiovascular magnetic resonance. Hypertension. 2002;39(3):750–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by research grants from the National Institutes of Health (K23 DK092354 and R03 DK104013 [to RFD]; and R01 HL107577 and R01 HL127028 [to SJS]).

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, San Francisco VA Medical Center/University of California, San Francisco, 4150 Clement St., Box 111A1, San Francisco, CA, 94121, USA

    Ruth F. Dubin

  2. Division of Cardiology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Sanjiv J. Shah

Authors
  1. Ruth F. Dubin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjiv J. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruth F. Dubin.

Ethics declarations

Conflict of Interest

Ruth F. Dubin declares that they have no conflict of interest.

Sanjiv J. Shah has received consulting fees from AstraZeneca, Bayer, Merck, and Novartis.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pharmacologic Therapy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dubin, R.F., Shah, S.J. Soluble Guanylate Cyclase Stimulators: a Novel Treatment Option for Heart Failure Associated with Cardiorenal Syndromes?. Curr Heart Fail Rep 13, 132–139 (2016). https://doi.org/10.1007/s11897-016-0290-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-016-0290-z

Keywords

Search

Navigation