Abstract
Heart failure (HF) is a life-threatening disease characterized by substantial morbidity and mortality. Yet despite recent advances, prognosis remains poor. Cyclic guanosine 3',5'-monophosphate (cGMP) mediates a wide range of physiological processes in various cell types. Its deficiency has been implicated in numerous pathological cardiovascular diseases, including HF, pulmonary hypertension (PH), and kidney disease. Therefore, restoring and enhancing the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cGMP signalling pathway appears to have far-reaching therapeutic potential. The discovery of sGC stimulators and activators marked a milestone in the field of NO-sGC-cGMP pharmacology, enabling NO-independent and long-acting enhancement of cGMP signalling without the formation of NO-derived radicals. Over a decade ago, the sGC stimulator riociguat was approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). More recently, the sGC stimulator vericiguat was approved for symptomatic chronic HF. A number of sGC activators are currently being investigated for the treatment of chronic kidney diseases. This review summarizes the evidence for NO-sGC-cGMP signalling in the regulation of cardiovascular and cardiac function, focusing on preclinical and clinical evidence for sGC stimulators and sGC activators in HF subtypes. Promising results have been observed in clinical trials of HF with reduced ejection fraction (HFrEF), but not in clinical trials of HF with preserved ejection fraction (HFpEF). Further studies are needed to determine the precise mechanisms of action of sGC agonists in HF and associated cardiorenal diseases to fully leverage their therapeutic potential and address the challenges of implementing these agents in routine clinical practice.
Summary of the preclinical findings
SGC stimulators and activators exhibit significant therapeutic potential in multiple preclinical models of CV diseases. Given the role of impaired NO–cGMP signalling in CV diseases, both sGC stimulators and sGC activators represent promising therapeutic classes due to their unique mode of action in restoring cGMP levels independently of NO.
One of the key mechanisms by which sGC stimulators and activators exert beneficial effects is through lowering BP, achieved through vascular smooth muscle relaxation mediated by cGMP-mediated vasodilation. HTN is considered the most common risk factor for the development of hypertensive heart disease and can exacerbate ventricular remodelling, fibrosis, and the progression of both HFrEF and HFpEF. By reducing afterload, these agents improve CO and LV performance, as demonstrated in numerous models of pressure-overload and HTN-induced HF. Importantly, this BP-lowering effect also contributes to improved survival in models of malignant hypertension and volume overload, indirectly relieving cardiac stress and preventing adverse remodelling. However, while BP reduction is beneficial in the earlier phases of HF progression, there is a risk of hypotension in patients with already established HF, particularly those with compromised cardiac function who are concurrently receiving other therapies (RAAS inhibitors and beta-blockers) with hypotensive effects.
Published: December 2025
