Figure 1. Cardiovascular effects of vericiguat.

In a heart failure setting, an increased oxidative stress, inflammation and endothelial dysfunction reduce nitric oxide (NO) bioavailability, which results in soluble guanylate cyclase (sGC) deficiency with a subsequent reduction in cyclic guanosine monophosphate (cGMP) synthesis (orange arrows). A lower sGC activity is associated with coronary microvascular dysfunction, altered diastolic relaxation, inflammation, fibrosis, hypertrophy and apoptosis of cardiomyocytes in response to cardiac injury.12–17 Vericiguat directly stimulates sGC (independent of NO involvement) and it also sensitizes this enzyme to endogenous NO by the stabilization of its binding site. Consequently, by restoring cGMP deficiency (green arrows), myocardial function and vascular tone improve.18

Vericiguat is a poorly soluble and highly permeable agent that, once ingested, requires a median time of <2.5 hours to reach its maximum plasma concentration (half-life 18–22 hours). It is approximately 98% bound to plasma proteins (essentially albumin) and is not affected by renal or hepatic insufficiency. In healthy subjects, 53.1% and 45.2% of the administered dose is excreted in the urine and faeces, respectively.19

eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate.