New Therapeutics for Heart Failure Worsening: Focus on Vericiguat

Figure 1. Clinical progression of heart failure. Adapted from Bozkurt, 2024 [4].

Figure 2. Guidelines for pharmacological intervention at every phase of heart failure. Recommendations for pharmacological therapy across the spectrum of HF stages, from risk prevention to advanced HF (stages A to D), are delineated below. Each treatment is color-coded based on the class of recommendation and level of evidence as outlined in HF guidelines. ACEI (angiotensin-converting enzyme inhibitor), ARB (angiotensin receptor blocker), ARNI (angiotensin receptor–neprilysin inhibitor), CKD (chronic kidney disease), GDMT (guideline-directed medical therapy), HFmrEF (HF with mildly reduced ejection fraction), HFpEF (HF with preserved ejection fraction), HFrEF (HF with reduced ejection fraction), LVEF (left ventricular ejection fraction), MCS (mechanical circulatory support), MRA (mineralocorticoid receptor antagonist), SGLT2 (sodium–glucose cotransporter 2), uACR (urine albumin-to-creatinine ratio). Adapted from Bozkurt, 2024 [4].

Figure 3. Vericiguat.

Figure 4. Vericiguat metabolism.

Figure 5. NO synthesis. In living organisms, NO can be produced by L-arginine through the action of NO synthase (NOS) through the consumption of reduced nicotinamide adenine dinucleotide phosphate (NADPH+) and oxygen that converts L-arginine to L-citrulline with NO production. NOS-independent NO formation can be interpreted as a contingency mechanism, ensuring adequate NO production in situations of limited oxygen supply.

Figure 6. Summary of the mechanism of action of vericiguat. NO is produced in the endothelium and diffuses into the smooth muscle, where it binds to sGC. This binding causes a conformational change that catalyzes the production of cGMP. The cGMP then activates downstream kinases, leading to vasodilation. sGC stimulators and activators, including NO, bind to the reduced heme (Fe2+) form of sGC. This interaction catalyzes the conversion of GTP to cGMP, resulting in vasodilation. Vericiguat directly stimulates sGC by binding to a specific site on its β-subunit.