title: Soluble guanylate cyclase: a potential therapeutic target for heart failure.
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.
authors.affiliation: Center of Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Ave, Suite 1006, Chicago, IL 60611, USA. m-gheorghiade@northwestern.edu
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: Catherine N
authors.initials: CN
authors.lastname: Marti
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Lothar
authors.initials: L
authors.lastname: Roessig
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Greene
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Umberto
authors.initials: U
authors.lastname: Campia
authors.forename: John G F
authors.initials: JG
authors.lastname: Cleland
authors.forename: Sean P
authors.initials: SP
authors.lastname: Collins
authors.forename: Gregg C
authors.initials: GC
authors.lastname: Fonarow
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Levy
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.forename: Naoki
authors.initials: N
authors.lastname: Sato
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
mesh_terms: D006152:Cyclic GMP / Q000378:metabolism / Q000627:therapeutic use*; D006162:Guanylate Cyclase / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071756:Soluble Guanylyl Cyclase; D016896:Treatment Outcome
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP