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Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure
Author(s) -
Arfsten Henrike,
Goliasch Georg,
Bartko Philipp E.,
Prausmüller Suriya,
Spinka Georg,
Cho Anna,
Novak Johannes,
Haslacher Helmuth,
Strunk Guido,
Struck Joachim,
Hülsmann Martin,
Pavo Noemi
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14442
Subject(s) - adrenomedullin , interquartile range , neprilysin , medicine , heart failure , natriuretic peptide , ejection fraction , endocrinology , sacubitril , trandolapril , valsartan , cardiology , angiotensin receptor , ace inhibitor , angiotensin ii , angiotensin converting enzyme , receptor , chemistry , blood pressure , enzyme , biochemistry
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.