The responses of B-type natriuretic peptide (BNP), mature BNP, proBNP, atrial natriuretic peptide, and N-terminal proBNP to sacubitril/valsartan differs between responders and non-responders

Background Previous studies showed that measured changes in plasma B-type natriuretic peptide (BNP) levels are inconsistent after sacubitril/valsartan administration. The reason remains unknown but may reflect the fact that BNP immunoreactivity measured with commercial BNP assays (BNPcom) includes both mature BNP and proBNP, and neprilysin degrades only mature BNP. In addition, the responsiveness to sacubitril/valsartan varies among heart failure patients. Purpose We investigated the mechanism underlying the inconsistency of BNP measurements after sacubitril/valsartan. Methods We measured plasma mature BNP, proBNP and total BNP (mature BNP + proBNP) levels with our immunochemiluminescent assay as well as NT-proBNP, ANP and BNPcom with conventional assays in 54 patients with heart failure (71±16 years, male 48%), before and after 2, 4, 8 and 12 weeks of sacubitril/valsartan administration. Responders were defined as having NT-proBNP levels at <70% of baseline after 12 weeks. Results Among all patients, total BNP and BNPcom did not change with sacubitril/valsartan treatment, whereas NT-proBNP and proBNP decreased, mature BNP modestly increased and ANP greatly increased. The %changes from baseline for all natriuretic peptides (NPs) after 2, 4, 8 and 12 weeks of Sac/Val treatment are presented in Figure 1. Although both ANP and mature BNP are substrates for neprilysin, ANP increased greatly after Sac/Val administration, while increase of mature BNP was mild. NT-proBNP and proBNP, which are not substrates for neprilysin, were both significantly reduced after Sac/Val administration. The %changes from baseline for each NP after 2, 4, 8 and 12 weeks of Sac/Val treatment in responders (n=31) and non-responders (n=23) are presented in Figure 2. At each measured time point, the %changes were all significantly smaller among the responders than non-responders (all P<0.01). ROC curves analysis to assess the ability of the %change in each NP at 4 weeks to detect responders showed that the AUCs for mature BNP, proBNP, total BNP, NT-proBNP, ANP and BNPcom at 4 weeks were 0.75, 0.81, 0.78, 0.89, 0.79 and 0.79, respectively (all p < 0.001). It is noteworthy that the NPs had similar AUCs, irrespective of their susceptibility to neprilysin inhibition. There were good correlations between NPs levels at baseline and throughout the sacubitril/valsartan administration, regardless of sensitivity to neprilysin inhibition. Conclusion These results suggest the magnitude and direction of change in each BNP form depends on its substrate specificity for neprilysin, that each BNP form is regulated mainly by cardiac production and neprilysin inhibition is only a modifying factor, that differences in plasma levels of each BNP form between responders and non-responders appear early and persist, and that BNPcom levels at 4 weeks can be applicable to prediction of the responders.