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. 2021 Mar;87(3):916-924.
doi: 10.1111/bcp.14442. Epub 2020 Jul 20.

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

Henrike Arfsten  1 , Georg Goliasch  1 , Philipp E Bartko  1 , Suriya Prausmüller  1 , Georg Spinka  1 , Anna Cho  1 , Johannes Novak  1 , Helmuth Haslacher  1 , Guido Strunk  2 , Joachim Struck  3 , Martin Hülsmann  1 , Noemi Pavo  1
Affiliations

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

Henrike Arfsten et al. Br J Clin Pharmacol. 2021 Mar.

Abstract

Aims: 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 [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 < .0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition.

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.

Keywords: adrenomedullin; angiotensinreceptor-neprilysin inhibitor; bioactive adrenomedullin; heart failure; neprilysin.

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Conflict of interest statement

Joachim Struck is employed by sphingotec GmbH, a company, which commercializes and has patent rights in several of the assays used in this study (bio‐ADM,).

Figures

FIGURE 1
FIGURE 1
Short‐term, 1‐year and 2‐year follow‐up changes in plasma bio‐ADM, MR‐proADM, BNP and NT‐proBNP levels after initiation of angiotensin‐receptor/neprilysin‐inhibitor therapy. Individual values as well as geometric mean and 95% confidence interval of serum concentrations of biomarkers are displayed. Biomarkers were compared by the Mann–Whitney U test. ns, nonsignificant with P ≥ .05, * for P < .05 and **** for P < .0001. bio‐ADM, bioactive adrenomedullin; BNP, B‐type natriuretic peptide; MR‐proADM, mid‐regional pro‐adrenomedullin; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide
FIGURE 2
FIGURE 2
Fold changes in plasma bio‐ADM, MR‐proADM, BNP and NT‐proBNP, levels after initiation of angiotensin‐receptor/neprilysin‐inhibitor therapy compared to continuous ACEi/ARB therapy. Fold changes of long‐term FUP samples respective to baseline levels are displayed as geometric mean and 95% CI. Biomarker levels for each timepoint were compared by the Wilcoxon test, statistical significance is indicated. Ns for nonsignificant with P ≥ .05, * for P < .05, ** for P < .01 and *** for P < .001. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor‐neprilysin inhibitor; FUP, follow‐up; bio‐ADM, bioactive adrenomedullin; MR‐proADM, mid‐regional pro‐adrenomedullin; BNP, B‐type natriuretic peptide; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide
FIGURE 3
FIGURE 3
Relationship of plasma concentrations of the inactive cleavage product and the biologically active peptide for BNP and ADM following angiotensin‐receptor/neprilysin‐inhibitor therapy switch compared to controls. Results of the linear regression analysis are displayed and the slope of the curve is indicated. kBL, slope of the curve of the linear regression at baseline; k1a, slope of the curve of the linear regression at 1‐year FUP; k2a, slope of the curve of the linear regression at 2‐year FUP; 1a, 1 year; 2a, 2 years; ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor‐neprilysin inhibitor; bio‐ADM, bioactive adrenomedullin; BL, baseline; BNP, B‐type natriuretic peptide; FUP, follow‐up; MR‐proADM, mid‐regional pro‐adrenomedullin; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide
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