Angiotensin Receptor–Neprilysin Inhibitors and the Natriuretic Peptide Axis

The purpose of this review is to describe the effects of angiotensin receptor neprilysin inhibitor (ARNI) therapy on the natriuretic peptide axis (NPA), with a particular focus on B-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and C-type natriuretic peptide (CNP) to better understand the biology behind the improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF). BNP, ANP, and CNP are the three main natriuretic peptides (NP); they share a common structure and ultimately mediate their actions by activating cyclic guanosine monophosphate (cGMP). ARNI therapy results in a decrease of N-terminal pro-BNP (NT-proBNP) and increase of BNP levels respectively. It is been questioned whether these changes may result from unique laboratory assays characteristics rather than actual biological implications. It appears to be that the prognostic accuracy of BNP for cardiovascular outcomes remains independent and comparable to that of NT-proBNP while on ARNI therapy. ANP levels also increase with ARNI therapy, but no consistent change has been described for CNP levels. There is evidence that the changes in BNP and NT-proBNP correlate with improvement in echocardiographic parameters of volume and function. The dual effect of neprilysin inhibition and angiotensin receptor blockade has substantial implications on the natriuretic peptide axis (NPA). The changes seen in BNP and NT-proBNP specifically have shown to correlate with improvement in echocardiographic parameters. Further results exploring the biologic effects of ARNI therapy on other NPs are still pending and likely will provide further insights in the mechanisms behind the improvement in cardiac function and clinical outcomes.