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Soluble guanylate cyclase: a potential therapeutic target for heart failure

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Abstract

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)—soluble guanylate cyclase (sGC)—cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome. The impaired NO–sGC–cGMP pathway signaling in HF is secondary to reduced NO bioavailability and an alteration in the redox state of sGC, making it unresponsive to NO. Accordingly, increasing directly the activity of sGC is an attractive pharmacologic strategy. With the development of two novel classes of drugs, sGC stimulators and sGC activators, the hypothesis that restoration of NO–sGC–cGMP signaling is beneficial in HF patients can now be tested. Characterization of these agents in pre-clinical and clinical studies has begun with investigations suggesting both hemodynamic effects and organ-protective properties independent of hemodynamic changes. The latter could prove valuable in long-term low-dose therapy in HF patients. This review will explain the role of the NO–sGC–cGMP pathway in HF pathophysiology and outcomes, data obtained with sGC stimulators and sGC activators in pre-clinical and clinical studies, and a plan for the further clinical development to study these agents as HF therapy.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

AHF:

Acute heart failure

BP:

Blood pressure

CO:

Cardiac output

cGMP:

Cyclic guanosine monophosphate

eNOS:

Endothelial nitric oxide synthase

HF:

Heart failure

NO:

Nitric oxide

PCWP:

Pulmonary capillary wedge pressure

sGC:

Soluble guanylate cyclase

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Conflict of interest

Mihai Gheorghiade, MD, is consultant for Abbott Laboratories, Astellas, AstraZeneca, Bayer HealthCare AG, CorThera, Cytokinetics, DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Takeda Pharmaceutical, and Trevena Therapeutics. Hani N. Sabbah, PhD, received research grants from Bayer Healthcare and is consultant to Bayer Healthcare. Lothar Roessig, MD, is a full-time employee at Bayer HealthCare AG. Michael Böhm, MD, was supported by Boehringer-Ingelheim, Servier, Pfizer, and Medtronic. John C. Burnett, MD, received research grant from Bayer. Umberto Campia, MD, was supported by a National Institutes of Health grant (K12-HL083790). John G.F. Cleland, MD, received an honorarium from Bayer for an advisory board. Funding level is modest. Sean P. Collins, MD, MSc, received research grant and support from Abbott Point-of-Care, NIH/NHLBI. Consultation was made with Abbot Point-of-Care, Bayer, Trevena, Novartis, and The Medicines Company. Gregg C. Fonarow, MD, is consultant to Novartis, Medtronic, and Takeda. Phillip D. Levy, MD, MPH, received research grant/support from Corthera, Inc. and Bayer Schering AG; consultant for Corthera, Inc., The Medicines Company, Bayer Schering Pharma AG, Trevena, Inc., and EKR Therapeutics. Marco Metra, MD received honoraria for participation to advisory board meetings or speeches for Bayer, Corthera, and Novartis. Bertram Pitt, MD is consultant to Pfizer, Novartis, Bayer, Merck, Takeda, Astra Zeneca, GE-Healthcare, BG-medicine, and Relypsa. Stock options were made with BG-medicine and Relypsa. Grants were received from Forrest Laboratories and Novartis. Piotr Ponikowski, MD, PhD, is consultant to Bayer Schering AG, Corthera, Amgen, Johnson&Johnson. Naoki Sato, MD, PhD, is consultant to Chugai Pharmaceutical Company and honoraria from Daiichi-Sankyo, Otsuka, Philips Respironics, Astellas, Ono, Eisai, Chugai, Mitsubishi-Tanabe, Sanofi-Aventis, and Novartis pharmaceuticals. Adriaan A. Voors, MD, PhD, has received consulting fee from Bayer. Johannes-Peter Stasch, PhD, is a full-time employee at Bayer HealthCare AG. Javed Butler, MD, MPH, is consultant to Cardiomems, Trevena, Bayer Healthcare, Takeda, and Amgen and associated with Events Committee for WorldHeart and Corthera. Research support was provided by GE Healthcare and Medtronic. Catherine N. Marti, MD, and Stephen J. Greene, MD, did not received any support.

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Authors and Affiliations

  1. Center of Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Ave, Suite 1006, Chicago, IL, 60611, USA

    Mihai Gheorghiade, Stephen J. Greene & Umberto Campia

  2. Emory University, Atlanta, GA, USA

    Catherine N. Marti & Javed Butler

  3. Henry Ford Hospital, Detroit, MI, USA

    Hani N. Sabbah

  4. Global Clinical Development, Bayer HealthCare AG, Wuppertal, Germany

    Lothar Roessig

  5. Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Saar, Germany

    Michael Böhm

  6. Mayo Clinic, Rochester, MN, USA

    John C. Burnett

  7. Castle Hill Hospital, Hull York Medical School, Kingston-Upon-Hull, UK

    John G. F. Cleland

  8. Vanderbilt University, Nashville, TN, USA

    Sean P. Collins

  9. University of California, Los Angeles, CA, USA

    Gregg C. Fonarow

  10. Wayne State University, Detroit, MI, USA

    Phillip D. Levy

  11. University of Brescia, Brescia, Italy

    Marco Metra

  12. University of Michigan, Ann Arbor, MI, USA

    Bertram Pitt

  13. Wroclaw Medical University, Wroclaw, Poland

    Piotr Ponikowski

  14. Nippon Medical School, Tokyo, Japan

    Naoki Sato

  15. University Medical Center, Groningen, Groningan, The Netherlands

    Adriaan A. Voors

  16. Cardiology Research, Bayer HealthCare AG, Wuppertal, Germany

    Johannes-Peter Stasch

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  1. Mihai Gheorghiade
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  19. Javed Butler
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Corresponding author

Correspondence to Mihai Gheorghiade.

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On behalf of the Academic Research Team in Heart Failure (ART-HF).

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Gheorghiade, M., Marti, C.N., Sabbah, H.N. et al. Soluble guanylate cyclase: a potential therapeutic target for heart failure. Heart Fail Rev 18, 123–134 (2013). https://doi.org/10.1007/s10741-012-9323-1

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