Soluble Guanylate Cyclase Modulation in Heart Failure Management
Summary
Heart failure remains a global health challenge, with impaired cardiac output and frequent hospitalisations despite advances in neurohormonal blockade. Central to emerging therapies is the nitric oxide–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signalling axis, which mediates vasodilation, myocardial relaxation and protection against remodelling. In heart failure, reduced nitric oxide bioavailability and oxidative alteration of sGC diminish cGMP generation, exacerbating endothelial dysfunction and myocardial stress. Pharmacological modulation of sGC encompasses two strategies: stimulators that sensitize the enzyme to endogenous nitric oxide, and activators that directly engage oxidised sGC independently of nitric oxide. By restoring cGMP levels, these agents aim to improve vascular tone, attenuate fibrotic pathways and enhance cardiac performance. Recent clinical development has centred on oral sGC stimulators, which offer once-daily dosing and a favourable safety profile, and on novel activators with potential in conditions of heightened oxidative stress. The integration of sGC modulators into existing treatment regimens promises to address residual risk in patients with reduced or preserved ejection fraction, with ongoing research exploring optimal timing, dosing and combination strategies.
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Soluble Guanylate Cyclase Modulation in Heart Failure Management publication trend
The graph below shows the total number of articles in soluble guanylate cyclase modulation in heart failure management across all publications each year (not limited to Nature Index journals).
Technical terms
Soluble guanylate cyclase (sGC): A cytosolic enzyme that produces cGMP upon activation by nitric oxide or pharmacological agents.
Cyclic guanosine monophosphate (cGMP): A second messenger that mediates vasodilation, anti-remodelling and cardioprotective signalling.
Heart failure with reduced ejection fraction (HFrEF): A subtype of heart failure characterised by left ventricular ejection fraction below normal thresholds.
Heart failure with preserved ejection fraction (HFpEF): A form of heart failure where ejection fraction remains within normal limits despite impaired diastolic function.
sGC stimulator: A compound that enhances the sensitivity of sGC to endogenous nitric oxide.
sGC activator: An agent that directly activates oxidised or haem-free sGC independently of nitric oxide.
Endothelial dysfunction: Impairment of the vascular endothelium’s ability to regulate vasomotion and maintain barrier integrity.
References
- Current Modulation of Guanylate Cyclase Pathway Activity—Mechanism and Clinical Implications. Molecules (2021).
- Safety, pharmacodynamic, and pharmacokinetic characterization of vericiguat: results from six phase I studies in healthy subjects. European Journal of Clinical Pharmacology (2020).
- Development of vericiguat: The first soluble guanylate cyclase (sGC) stimulator launched for heart failure with reduced ejection fraction (HFrEF). Biomedicine & Pharmacotherapy (2022).
- A Systematic Review of the Effect of Vericiguat on Patients with Heart Failure. International Journal of Molecular Sciences (2023).
- Practical Patient Care Considerations With Use of Vericiguat After Worsening Heart Failure Events. Journal of Cardiac Failure (2022).
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