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Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema: From Bed to Bench

Carucci L1, Bova M2, Petraroli A2, Ferrara AL2, Sutic A3, de Crescenzo G4, Cordisco G5, Margaglione M5, Gambardella J6, Spadaro G1,2, Genovese A1,2, Loffredo S2,7

1Post-Graduate Program in Clinical Immunology and Allergy, University of Naples Federico II, Naples, Italy
2Department of Translational Medical Sciences and Interdepartmental Center for Research in Basic and Clinical Immunology Sciences, University of Naples Federico II, Naples, Italy
3Division of Clinical Immunology, Allergology and Rheumatology, Department of Internal Medicine, University of Zagreb School of Medicine, University Hospital Dubrava, Zagreb, Croatia
4Division of Clinical Immunology and Allergy, Sant’Anna and San Sebastiano Hospital, Caserta, Italy
5Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
6Department of Medicine and Surgery, University of Salerno, Salerno, Italy
7Institute of Experimental Endocrinology and Oncology G. Salvatore, National Research Council, Naples, Italy

J Investig Allergol Clin Immunol 2020; Vol 30(4) : 272-280
doi: 10.18176/jiaci.0458

Background: Angiotensin-converting enzyme inhibitor–associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood.
Objective: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE.
Methods: The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients.
Results: A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed.
Conclusions: Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE.

Key words: Angiotensin-converting enzyme inhibitor, Angioedema, Vascular endothelial growth factor C, Vascular endothelial growth factor A, Phospholipases A2, Genetic analysis, C1-inhibitor, Biomarkers