Current and future therapeutic perspective in chronic heart failure.

The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin-Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1-7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development.