Adrenomedullin in heart failure: pathophysiology and therapeutic application

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.

Biomarker guidance allows a more personalized allocation of patients for remote patient management in heart failure: results from the TIM‐HF2 trial

“…The other biomarker measured was mid‐regional pro‐adrenomedullin (MR‐proADM), a strong independent prognostic marker in HF . As a marker of vascular function and endothelial integrity, MR‐proADM has complimentary predictive effects to natriuretic peptides …”

“…6 The other biomarker measured was mid-regional pro-adrenomedullin (MR-proADM), a strong independent prognostic marker in HF. 7 -10 As a marker of vascular function and endothelial integrity, 11 MR-proADM has complimentary predictive effects to natriuretic peptides. 12 -14 In the current study, we analysed how both biomarkers were associated with the two major endpoints of TIM-HF2: percentage of days lost due to unplanned cardiovascular (CV) hospital admission or all-cause death (primary endpoint), and time to all-cause death (the first secondary endpoint).…”

Dipeptidyl peptidase 3, a biomarker in cardiogenic shock and hopefully much more

“…It is noteworthy that the time line for the development of a new specific assay of circulating DPP3, to that of a blocking antibody for the same molecule is short, and all has been performed by the same company, to which two of the Authors belong (AB and OH). The same team has developed a humanized non‐neutralizing antibody against adrenomedullin (bio‐ADM), adrecizumab, on which they are now running a Phase 2 clinical trial in septic shock (http://clinicaltrials.gov identifier: NCT03085758).…”

February 2019 at a glance: pathophysiology, exercise capacity, diuretics and valve disease

“…4 summarize its characteristics and describe a novel immunoassay measuring its biological activity as well as adrecizumab, a humanized, monoclonal, non‐neutralizing, adrenomedullin‐binding antibody with a half‐life of 15 days. Adrecizumab cannot cross the endothelial barrier and thus, when infused, can bind circulating adrenomedullin and drain it from the interstitium into the circulation, thus enhancing its intravascular effects …”

“…Adrenomedullin, a peptide synthesized by endothelial and vascular smooth muscle cells, has natriuretic and vasodilatory effects and preserves endothelial barrier function, inhibiting vascular leakage. 3 In his review, Voors et al 4 summarize its characteristics and describe a novel immunoassay measuring its biological activity as well as adrecizumab, a humanized, monoclonal, non-neutralizing, adrenomedullin-binding antibody with a half-life of 15 days. Adrecizumab cannot cross the endothelial barrier and thus, when infused, can bind circulating adrenomedullin and drain it from the interstitium into the circulation, thus enhancing its intravascular effects.…”