The significant morbidity and mortality associated with heart failure with 
reduced ejection fraction (HFrEF) or heart failure with preserved ejection 
fraction (HFpEF) justify the search for novel therapeutic agents. Reduced cyclic 
guanosine monophosphate levels contribute to HF progression. Among molecules 
modulating the nitric oxide (NO)-GMP-phosphodiesterase (PDE) pathway, the 
evaluation of nitrates, synthetic natriuretic peptides (NP), and NP analogs has 
yielded mixed results. Conversely, sacubitril/valsartan, combining NP 
degradation inhibition through neprilysin and angiotensin receptor blockade, has 
led to groundbreaking findings in HFrEF. Other strategies to increase tissue 
cyclic guanosine monophosphate have been attempted, such as PDE-3 or PDE-5 
inhibition (with negative or neutral results), NO-independent soluble guanylate 
cyclase (sGC) activation, or enhancement of sGC sensitivity to endogenous NO. 
Following the positive results of the phase 3 VICTORIA (A Study of Vericiguat in 
Participants With Heart Failure With Reduced Ejection Fraction) trial on the sGC 
stimulator vericiguat in HFrEF, the main open questions are the efficacy of the 
sacubitril/valsartan-vericiguat combination in HFrEF and of vericiguat in HFpEF.