State of the art on angiotensin-neprilysin inhibitors

Angiotensin receptor neprilysin inhibitor (ARNI) decreases renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous systems (SNS) activity promoting vasodilation, decreasing myocardial hypertrophy and fibrosis. Beyond the SNS, RAAS and natriuretic peptide systems, ARNI results in increased circulatory and myocardial nitric oxide levels activating cGMP and protein kinase G, which reduces oxidative stress, myocyte hypertrophy, cell death and has anti-thrombotic effects. ARNIs have a class I indication by heart failure (HF) guidelines in HFrEF patients with NYHA class II to III symptoms. Beyond HFrEF, the use of ARNIs has also been expanded to other clinical settings including HF with preserved ejection fraction (EF, HFpEF), acute HF, advanced HF, hypertension, arrhythmias and chronic kidney disease. This paper reviews the clinical benefits of ARNIs in both HF and the aforementioned cardiovascular conditions. We also discuss the combined use of ARNI with SGLT2i and their potential synergistic benefits on cardiovascular outcomes.