The significant morbidity and mortality associated with heart failure with 
reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for 
novel therapeutic agents. The nitric oxide (NO)-soluble guanylate cyclase 
(sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in 
the regulation of cardiovascular function. This pathway is disrupted in HF 
resulting in decreased protection against myocardial injury. The sGC activator 
cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, 
and may be particularly effective in conditions of increased oxidative stress 
and endothelial dysfunction, and then reduced NO levels, but this comes at the 
expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat 
and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more 
physiological action. The phase 3 VICTORIA trial found that vericiguat is safe 
and effective in patients with HFrEF and recent HF decompensation. Therefore, 
adding vericiguat may be considered in individual patients with HFrEF, 
particularly those at higher risk of HF hospitalization; the efficacy of the 
sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown.