Adrenomedullin: A Double-edged Sword in Septic Shock and Heart Failure Therapeutics?

To the Editor:

In a recent issue of the Journal, Filewod and Lee eloquently demystified the prospects of vascular leakage in sepsis, highlighting novel therapeutic avenues (1). The authors appropriately mentioned adrenomedullin (ADM) as a prominent example among approaches to harness vascular leakage (1). Given the interdisciplinary therapeutic potential of the ADM pathway, further focused discussion is warranted.

ADM is a vasoactive peptide synthesized by endothelial and vascular smooth muscle cells, has diverse multiorgan roles, and diffuses freely between the circulation and the interstitium (2, 3). In the circulation, it exerts endothelial barrier–stabilizing effects, thereby mitigating vascular leakage, whereas in the interstitium, it modulates vascular tone, exerting vasodilatory effects (2, 3). As a biomarker, ADM improves prognostication in heart failure and chronic obstructive pulmonary disease (3, 4).

Among the currently available therapies for heart failure, sacubitril-based therapy potentiates ADM by inhibiting its degradation by neprilysin (5). Adrecizumab is a monoclonal nonneutralizing antibody against the N terminus of ADM. Adrecizumab is bound to the blood compartment by virtue of its high molecular weight and leads to a dose-dependent increase of plasma ADM by compartmentalizing ADM in the circulation, and also potentially by increasing its translocation from the interstitium (3). Although a study of adrecizumab in hospitalized patients with heart failure is currently being prepared (3), a phase 2 study of adrecizumab in patients with early septic shock is already underway (6). Indeed, harnessing vascular leakage in inflammation is no longer science fiction, but an active focus of interdisciplinary scientific investigation.