Increased Concentrations of bioactive Adrenomedullin subsequently to ARNi Treatment in Chronic Systolic Heart Failure.

AIMS The clinically investigated rationale for neprilysin (NEP)-inhibition by ARNi-therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in HFrEF. The effect of NEP-inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi. METHODS Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, sixty-seven patients on continuous ACEi/ARB therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-type-NP (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, and 1-year and 2-years follow-up (FUP). RESULTS Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term FUP [bio-ADM (pg/ml): 26.0 (interquartile range (IQR):17.7-37.5) vs 50.8 (IQR:36.5-78.1) vs 54.6 (IQR:42.0-97.1) vs 57.4 (IQR:48.5-161.6); MR-proADM (nmol/l): 0.87 (IQR:0.64-1.12) vs 1.25 (IQR:0.93-1.79) vs 1.42 (IQR:0.95-1.90) vs 1.60 (IQR:1.12-2.46), p 0.05 for all), indicating that activation of the ADM-axis arises particularly from NEP-inhibition. CONCLUSION The significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi.