Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Abstract

The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (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, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up. Results: Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0

Relevance of Neutrophil Neprilysin in Heart Failure

“…NEP is critical for the processing and catabolism of numerous vasoactive peptides involved in natriuresis and diuresis, e.g., natriuretic peptides, adrenomedullin, angiotensin II, and endothelin [ 4 , 5 , 6 ]. It has been hypothesized that the mechanism of action of NEPi in HFrEF is based on a beneficial net effect on vasoactive peptide homeostasis.…”

“…NEP, also known as cluster of differentiation 10 (CD10), neutral endopeptidase, enkephalinase, or common acute lymphoblastic leukemia antigen, is a zinc-dependent transmembrane metalloendoprotease that is involved in the breakdown of a plethora of vasoactive peptides, including natriuretic peptides, adrenomedullin, angiotensin II, and endothelin-1 [ 4 , 5 , 6 ]. Predominantly, NEP is found in the plasma membrane of cells in the kidneys, lungs, intestine, brain, and liver and has been shown to be identical to CD10, which is expressed on several distinct hematopoietic cell lineages including neutrophils [ 4 , 7 ].…”

Neprilysin inhibition does not alter dynamic of proenkephalin‐A 119‐159 and pro‐substance P in heart failure

“…However, BNP is a rather humble NEP substrate. Ad interim, first data on the effects of NEPi on further vasoactive NEP substrates with significance in HFrEF exist 9,20,21 . For NEPi, a significant increase in atrial natriuretic peptide (ANP), substance P, adrenomedullin (ADM) and glucagon‐like peptide 1 (GLP‐1) at short‐term follow‐up of 90 days has been reported 20 .…”

“…The changes in NT-proBNP and BNP levels have been described previously. 9 A more detailed overview of assessed biomarker (PENK, pro-SP; BNP, NT-proBNP 9 ) concentrations at baseline and different follow-up timepoints for the respective patients is provided in Table 2. Supporting Information, Table S1 lists biomarker concentrations at baseline and different follow-up timepoints for the respective patients with available data comparing medians by a paired test.…”

“…Ad interim, first data on the effects of NEPi on further vasoactive NEP substrates with significance in HFrEF exist. 9,20,21 For NEPi, a significant increase in atrial natriuretic peptide (ANP), substance P, adrenomedullin (ADM) and glucagon-like peptide 1 (GLP-1) at short-term follow-up of 90 days has been reported. 20 Early dynamics in blood levels of these neurohormones after NEPi initiation, partly even exceeding the observed changes in BNP, substantiate the assumption of a more complex mechanism of action.…”