Potential role of Sacubitril/valsartan
Sacubitril/valsartan is the first of a new class of drugs with a therapeutic indication for the treatment of chronic symptomatic heart failure with reduced ejection fraction. Sacubitril is a neprilisin inhibitor (NEPi), valsartan an angiotensin II receptor antagonist (ARBs) (64). Based on the considerations described above, the association sacubitril/valsartan could be an important therapeutic solution to combat COVID-19 infection. The use of the sacubitril/valsartan association could be of clinical benefit for several reasons, in particular the antagonism on the AT-1 receptor mediated by valsartan would lead to increased receptor occupation by the Ang II of the AT-2 receptor with antifibrotic, antiflammatory, antihyperproliferative and vasodilating effects with potential benefits on both pulmonary lesions caused by fibrotic tissue and cardiac damage caused by COVID-19. In addition, the actions of Ang-II on the AT-1 receptor, which mediates vasoconstriction, profibrotic and hyperproliferative effects, are blocked. Finally
Angiotensin II can cause increased inflammation through production of IL-6, TNF-α and other inflammatory cytokines mediated by AT-1. (65)(66)(67) It is known that in the more severe stages of COVID-19 infection there is a decrease in ACE-2 which plays a protective role. In fact, ACE-2 synthesizes Ang 1-7 and Ang 1-9 with known anti-inflammatory, vasodilating, antifibrotic and antihyperproliferative effects. (68)(69) The antagonism on AT-1 receptors leads to a compensatory increase of ACE-2. (70) Finally, after ARBs administration the response to hypertrophic growth induced by TNF-a is significantly attenuated (71) (Figure 1 ).