The Heart Failure Knights

The 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure (HF) have abandoned the sequential approach for optimal drug therapy and proposed four drug classes, the so-called 4 “pillars” (angiotensin-converting enzyme inhibitors; angiotensin receptor-neprilysin inhibitors; beta-blockers; mineralocorticoid receptor antagonists and sodium-glucose co-transporter 2 inhibitors) to be initiated and titrated in all patients with reduced ejection fraction HF (HFrEF). In addition, new molecules have been considered, derived from recently reported advances from trials in HFrEF. In this review, Authors examine in particular these new molecules, as further “knights” for HF. In particular, vericiguat, a novel oral soluble guanylate cyclase stimulator, has proved effective in patients with HFrEF who had recently been hospitalized or had received intravenous diuretic therapy. The selective cardiac myosin activator omecamtiv mecarbil and the cardiac myosin inhibitors aficamten and mavacamten are under investigation. Cardiac myosin stimulator, omecamtiv mecarbil, has shown efficacy in HFrEF, lowering HF related events or cardiovascular death, while the 2 inhibitors, mavacamten and aficamten have been shown to reduce hypercontractility and left ventricular outflow obstruction improving functional capacity in randomized trials targeting hypertrophic cardiomyopathy. These agents are the prototypes of active pipelines promising to deliver an array of molecules against HF in the near future.