Sacubitril/Valsartan. Potential Impact of ARNi "Beyond the Wall" of ACE2 on Treatment and Prognosis of Heart Failure Patients With Coronavirus Disease-19

From the beginning of the SARS-CoV-2 pandemia, the type 2 angiotensin-converting enzyme (ACE2), probably the most “unloved and neglected” member of the renin-angiotensin-aldosterone (RAAS) family, has attracted increasing attention since it has been shown as the cell receptor through which the virus enters into the cells (1). The physiological action of ACE2, a membrane protein expressed in the heart, lungs, kidneys, liver, and intestine, consists in degrading angiotensin II (Ang II) to angiotensin (1-7), a heptapeptide with a potent vasodilator function through the Mas receptor able to counterbalance the Ang II effects on vasoconstriction, sodium retention, and fibrosis (1). Previous studies have shown that Ang II type 1 receptor (AT1R) blockers (ARBs), ACE inhibitors (ACEI), and mineralocorticoid receptor antagonists (MRA) may up-regulate the expression of ACE2 both in acute and chronic settings of cardiovascular diseases (CVDs), such as hypertension, heart failure (HF) and myocardial infarction (1). These data have generated concern during the early phases of the pandemia, since it has been speculated that the increase in ACE2 level may have contributed to disease virulence and to adverse outcomes particularly in subjects affected by chronic coexisting conditions, namely hypertension, coronary artery disease, HF, and diabetes, who commonly received treatment with RAAS inhibitors and who were characterized by a worse clinical course (2). On the other hand, it has been observed that the binding between coronavirus and ACE2 leads to ACE2 downregulation, resulting in an unopposed production of Ang II by ACE, contributing to lung damage as a consequence of AT1R mediated inflammation, fibrosis, thrombosis, vasoconstriction, and increased vascular permeability. According to these findings, RAAS inhibitors and, in particular, ARBs may even protect against COVID-19 acute lung injury (1). As a matter of fact, epidemiological studies conducted in large populations of COVID-19 patients demonstrated that ARBs or ACE inhibitors had no association with a severe or fatal course of the disease