Phenotype standardization of angioedema in the head and neck region caused by agents acting on the angiotensin system

Abstract

Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.

Figure 1

Theoretical effect of agents acting on the angiotensin system. (a) A simplified scheme of the angiotensin–bradykinin pathways.^, (b) Mechanism of action of angiotensin-converting enzyme (ACE) inhibitors.^, ACE inhibitors inhibit two pathways: the formation of angiotensin II from angiotensin I, and the degradation of bradykinin into inactive peptides. Aminopeptidase P (APP) and membrane metallo-endopeptidase (MME) are alternative pathways to inactivate bradykinin. Accumulation of bradykinin may contribute to the development of angioedema. (c) Mechanism of action of angiotensin II receptor type 1 blockers (ARBs).^,, ARBs block the type 1 receptor site for angiotensin II, which instead may bind to the type 2 receptor. Stimulation of the type 2 binding site results in a bradykinin cascade that inhibits ACE and metallo-endopeptidase (MME), which can lead to increased bradykinin levels. Bradykinin contributes to the therapeutic action of ARBs and may also contribute to the development of angioedema.