
Sacubitril/valsartan (S/V) treatment is associated with clinical benefits in patients with heart failure with reduced ejection fraction (HFrEF). Still, its mode of action remains elusive, although it involves the increase of ANP (atrial natriuretic peptide). It was found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). These findings offer mechanistic evidence to the natriuretic peptide–a defective state in HFrEF, which is improved by S/V. These data also strongly suggest that S/V increases plasma ANP by multiple mechanisms that involve the indirect regulation of 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights into HFrEF pathophysiology and the mode of action of S/V.
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