Nailfold Videocapillaroscopy Findings in Bradykinin-Mediated Angioedema

Abstract

Background: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and acquired angioedema related to ACE inhibitors (ACEI-AAE) are types of bradykinin-mediated angioedema without wheals characterized by recurrent swelling episodes. Recent evidence suggests that a state of "vascular preconditioning" predisposes individuals to attacks, but no data are available on the possible structural alterations of the vessels. Objective: This study aims at evaluating the features of the nailfold capillaries to highlight possible structural anomalies in patients affected by C1-INH-HAE in comparison with the healthy population and ACEI-AAE patients in comparison with hypertensive controls. Methods: With nailfold videocapillaroscopy (NVC), we assessed: apical, internal, and external diameter, loop length, intercapillary distance, capillary density, distribution, and morphology. Plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, angiopoietin (Ang)1, and Ang2 were also measured. Results: C1-INH-HAE patients (n = 34) had significant structural alterations of the capillaries compared to healthy controls (n = 28): greater intercapillary distance (216 vs 190 µm), increased apical, internal, and external diameter (28 vs 22 µm; 22 vs 20 µm; and 81 vs 65 µm, respectively), decreased density (4 vs 5 capillaries/mm 2), more irregular capillary distribution, and more tortuous morphology. Apical diameter was enlarged in patients with ≥12 attacks/year. In ACEI-AAE patients, NVC showed no alterations versus hypertensive controls. NVCs performed in two C1-INH-HAE patients during attacks showed no changes compared to the remission phase. Conclusions: C1-INH-HAE patients have important structural capillary alterations, confirming the involvement of microcirculation in the pathogenesis of angioedema.

Angiotensin-Converting Enzyme Inhibitor-Induced Non-allergic Perioral Angioedema: A Case-Based Scoping Review

“…It arises from a mutation in the SERPING1 gene, which encodes C1-INH. 13,14) Recurrent DINAAE is another form of non-histaminergic angioedema. African-Americans are at higher risk of DINAAE, probably due to the C-2399A genetic polymorphism of the bradykinin-degrading enzyme aminopeptidase (encoded by the X-linked XPNPEP2 gene).…”

“…These morphological changes confirm endothelial dysfunction in angioedema from C1-INH deficiency, but not ACEIs-induced angioedema. 14) Table 1 summarizes the classification of angioedemas, 2,8,12) and Table 2 concludes risk factors of DINAAE due to ACEIs. 4,6,7,[16][17][18][19] Although angioedema has many subtypes, the core pathogenesis is a temporary increase in endothelial permeability of postcapillary veins, which in turn leads to plasma extravasation in the deeper layers of the dermis and submucosa.…”

“…Moreover, DINAAE due to ACEIs is also linked to an impairment of cytokine degradation with an increase in the level of C-reactive protein (Figure 2). 2,6,[8][9][10][12][13][14]16,[21][22][23] This adverse reaction is medication-specific, but not dependent upon dosage. 2,5) The different pathogenesis of DINAAE are presented in Table 3.…”

“…Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency is a rare autosomal dominant disease (ORPHA:91378), with a prevalence of 1:50,000. It arises from a mutation in the SERPING1 gene, which encodes C1-INH [ 13 , 14 ]. Recurrent DINAAE is another form of non-histaminergic angioedema.…”

A novel pathogenetic factor of laryngeal attack in hereditary angioedema? Involvement of protease activated receptor 1

“…They observed the presence of capillary and venular dilatation as well as mononuclear cell accumulation in edematous tissues [ 9 ]. Cesoni et al demonstrated capillary alteration in patients with C1-INH-HAE using nailfold videocapillaroscopy [ 10 ]. Complement C4 and fibrin have been detected in the non-edematous skin of C1-INH-HAE patients [ 11 ]; however, no other immunohistological assessment was performed.…”