Adrenomedullin in heart failure: pathophysiology and therapeutic application - PubMed (original) (raw)

Review

. 2019 Feb;21(2):163-171.

doi: 10.1002/ejhf.1366. Epub 2018 Dec 28.

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Review

Adrenomedullin in heart failure: pathophysiology and therapeutic application

Adriaan A Voors et al. Eur J Heart Fail. 2019 Feb.

Abstract

Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin-angiotensin-aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio-ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio-ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non-neutralizing ADM-binding antibody with a half-life of 15 days. Adrecizumab binds at the N-terminal epitope of ADM, leaving the C-terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM-binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

Keywords: Adrenomedullin; Congestion; Decompensation; Heart failure; Vascular permeability.

© 2018 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

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Figures

Figure 1

Figure 1

Simplistic representation of the mode of action of intravascular vs. interstitial adrenomedullin. (1) Adrenomedullin present within the blood vessels improved vascular integrity, thereby putatively reducing vascular permeability. (2) Adrenomedullin present in the interstitium acts on the vascular smooth muscle cells and causes dilatation of the vascular resistance and capacitance vessels.

Figure 2

Figure 2

Bio‐adrenomedullin (ADM) as a marker and inhibitor of tissue congestion. Brain natriuretic peptide (BNP) as a marker and inhibitor of intravascular congestion.

Figure 3

Figure 3

Mode of action of adrecizumab. Administration of adrecizumab leads to a dose‐dependent increase of plasma adrenomedullin (ADM) bound to the administered antibody. Circulating adrecizumab cannot leave the blood compartment due to its high molecular weight (160 kDa), whereas ADM (with a much lower molecular weight of 6 kDa) can freely cross the endothelial barrier between the interstitium and the circulation. Binding of ADM by adrecizumab (present in the circulation in a large excess over ADM) prevents ADM from leaving the blood vessel, effectively ‘trapping’ ADM in the circulation.

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