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Victoria and Victor: event-driven lessons for integrating vericiguat into practice and reducing residual risk in

Kalliopi Keramida1,2, Francesca Musella3, Magdy Abdelhamid4

  • 1Department of Cardiology, General Anticancer Oncological Hospital Agios Savvas, Alexandras Avenue 171, Athens, 111522, Greece. keramidakalliopi@hotmail.com.

Heart Failure Reviews
|December 11, 2025
PubMed

Insights

Vericiguat, a novel drug, targets impaired nitric oxide signaling in chronic heart failure with reduced ejection fraction (HFrEF). It stimulates soluble guanylate cyclase to restore cyclic guanosine monophosphate signaling, addressing unmet needs in HFrEF treatment.

Area of Science:

  • Cardiology
  • Pharmacology
  • Biochemistry

Background:

  • Chronic heart failure with reduced ejection fraction (HFrEF) presents significant morbidity and mortality despite current guideline-directed medical therapy (GDMT).
  • Impaired nitric oxide (NO) signaling, reduced soluble guanylate cyclase (sGC) responsiveness, and decreased cyclic guanosine monophosphate (cGMP) are key pathological mechanisms in heart failure progression.
  • Existing therapies for HFrEF, including ACEIs/ARBs/ARNIs, beta-blockers, MRAs, and SGLT2is, do not fully address these underlying signaling deficits.

Purpose of the Study:

  • To investigate the therapeutic potential of vericiguat, an oral sGC stimulator, in patients with HFrEF.
  • To evaluate vericiguat's ability to restore impaired NO-sGC-cGMP signaling pathways implicated in HFrEF pathogenesis.
  • To explore novel pharmacological targets for improving outcomes in chronic heart failure.

Main Methods:

  • Administration of vericiguat, an oral soluble guanylate cyclase (sGC) stimulator.
  • Assessment of vericiguat's mechanism of action, including sensitization of sGC to endogenous nitric oxide (NO) and direct stimulation of the enzyme.
  • Evaluation of the downstream restoration of cyclic guanosine monophosphate (cGMP) signaling in relevant cellular pathways.

Main Results:

  • Vericiguat effectively sensitizes soluble guanylate cyclase (sGC) to endogenous nitric oxide (NO).
  • The drug directly stimulates sGC activity, independent of NO levels.
  • Restoration of cGMP signaling was observed in vascular smooth muscle and cardiomyocytes, suggesting a potential benefit in HFrEF.

Conclusions:

  • Vericiguat represents a novel therapeutic approach for HFrEF by targeting the NO-sGC-cGMP pathway.
  • Its dual mechanism of action offers a promising strategy to address residual risk and improve outcomes in patients with chronic heart failure.
  • Further clinical investigation is warranted to establish the efficacy and safety of vericiguat in the HFrEF population.

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