Multiplicity of Nitric Oxide and Natriuretic Peptide Signalling in Heart Failure.

Heart failure (HF) is a common consequence of several cardiovascular diseases, and is understood as a vicious cycle of cardiac and haemodynamic decline. The current inventory of treatments either alleviate the pathophysiological features (e.g., cardiac dysfunction, neurohumoral activation, ventricular remodelling) and/or target any underlying pathologies (e.g., hypertension, myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine 3',5'-monophosphate (cGMP), synthesised by nitric oxide (NO)- and natriuretic peptide (NP)- responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signalling, which can occur following GC deactivation and the upregulation of cyclic nucleotide-hydrolysing phosphodiesterases (PDEs), promotes cardiac dysfunction. Herein we review the role that NO/cGMP and NP/cGMP signalling plays in HF. After considering disease aetiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from pre-clinical models and patients that compromised cGMP signalling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.