Use of soluble guanylyl cyclase stimulators in heart failure therapy-a mode of action perspective
Frank Ruschitzka1,2, Robert Lukowski3, Stefano Corda4
1Department of Cardiology, University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
Insights
New therapies targeting the nitric oxide-soluble guanylyl cyclase-cyclic guanosine monophosphate pathway, like vericiguat, show promise for treating chronic heart failure (HF). These treatments offer hope for patients with symptomatic heart failure with reduced ejection fraction (HFrEF).
Area of Science:
- Cardiovascular Pharmacology
- Heart Failure Pathophysiology
- Nitric Oxide Signaling
Background:
- Chronic heart failure (HF) remains a leading cause of morbidity and mortality despite current treatments.
- The nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is crucial for cardiovascular health.
- Dysfunction in the NO-sGC-cGMP cascade is implicated in the progression of HF.
Purpose of the Study:
- To review pharmacological therapies targeting the NO-sGC-cGMP pathway for HF treatment.
- To focus on NO-independent sGC stimulators, examining their mechanisms and cardiovascular benefits.
- To discuss the role of vericiguat in managing symptomatic heart failure with reduced ejection fraction (HFrEF).
Main Methods:
- Review of preclinical studies on NO-independent sGC stimulators.
- Analysis of clinical trial data, including the VICTORIA and VICTOR trials.
- Examination of vericiguat's efficacy in adult patients with symptomatic HFrEF post-worsening event.
Main Results:
- NO-independent sGC stimulators demonstrate cardiovascular benefits in preclinical models.
- Vericiguat, as an adjunct to standard therapy, is recommended for specific HFrEF populations.
- Clinical trials provide evidence supporting vericiguat's role in improving outcomes for symptomatic HFrEF patients.
Conclusions:
- Pharmacological modulation of the NO-sGC-cGMP pathway offers a novel therapeutic strategy for HF.
- Vericiguat represents a significant advancement for patients with symptomatic HFrEF.
- Further research is needed to fully elucidate the benefits and applications of vericiguat and related sGC stimulators.
Abstract:
Despite recent advances in pharmacological treatment, chronic heart failure (HF) is associated with significant morbidity and mortality, and further treatment options are needed. Intact nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signalling is a prerequisite of cardiovascular health. cGMP produced by NO/NO-sGC acts as a second messenger molecule via various downstream targets, which influence a broad spectrum of critical physiological parameters. Impairment of this cascade in the cardiovascular system is considered an important pathomechanism in HF. This review examines pharmacological therapies that act through the NO-sGC-cGMP signalling pathway. We will focus on the molecular mode(s) of action of NO-independent but haem-dependent sGC stimulators, and will examine evidence from preclinical studies demonstrating cardiovascular benefits of these therapies and their increasing number of effects on other susceptible tissues and organs, which together could contribute to clinical outcomes in HF. The sGC stimulator vericiguat may be considered, in addition to standard therapy, for adults with symptomatic HF with reduced ejection fraction following a worsening event. The findings from pivotal clinical trials that led to these recommendations will be outlined and classified in terms of their significance for different subpopulations. These include the Phase 3 VICTORIA and VICTOR trials. Finally, further research areas and ongoing studies designed to address existing gaps in our knowledge regarding vericiguat and related drugs will be highlighted.
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