Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction

Abstract

BackgroundAttacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes.ObjectiveOur study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation.MethodsTwenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10’) and 75-degrees-head-up tilt (10’). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively.ResultsHAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls.At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01).ConclusionsOur data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.

Emotional processes and stress in children affected by hereditary angioedema with C1-inhibitor deficiency: a multicenter, prospective study

“…In recent years, several studies have suggested the interaction of the immune system with the central nervous system to explain the effects of mood and anxiety on inflammatory diseases [ 15 , 16 ]. A study in patients with C1-INH-HAE showing an increase in sympathetic activation at rest and a blunted response to experimentally induced stress have suggested that autonomous nervous system function may be altered [ 17 ]. Overall, studies addressing specifically the role of stress and psychological factors in C1-INH-HAE are still very limited, especially in children [ 10 , 18 , 19 ].…”

Impaired Endothelial Function in Hereditary Angioedema During the Symptom-Free Period

“…The present study has some limitations such as the small sample size. However, HAE is a rare disease, and groups of maximum 30 subjects were typically recruited in previous studies with similar design (Demirtürk et al, 2012 ; van Geffen et al, 2012 ; Wu et al, 2017 ). In addition, having studied HAE subjects only during inter-attack periods may have led to incomplete assessment of endothelial characteristics.…”

Molecular Dambusters: What Is Behind Hyperpermeability in Bradykinin-Mediated Angioedema?

“…In patients with angioedema, at some predisposed locations, together with elevated BK level or decreased activity of ANG-1, mental stress may trigger angioedema attacks. Although noradrenaline was shown to be elevated in a tilt-induced stress model of C1-INH-HAE patients [ 23 ], the pathogenetic role of noradrenaline in increasing permeability is controversial [ 132 – 134 ]. Glucocorticoids are also increased during stress; however, their effects are questionable similarly to catecholamines, as glucocorticoids decrease permeability directly [ 197 ] as well as indirectly by reducing pro-inflammatory cytokine production of T cells and other leukocytes.…”

“…BK-mediated angioedema involves a variety of plasma enzyme cascades (KKS, coagulation, fibrinolysis, and complement) [ 15 , 16 ], vascular endothelium [ 7 , 17 , 18 ], lymphatic endothelium [ 19 ], and cells of the immune system (e.g., neutrophil granulocytes) [ 20 ]. Various signaling pathways (such as ANGPT1-Tie2 signaling in HAE patients with ANGPT1 mutation) [ 21 ], hormonal effects [ 22 ], the autonomic nervous system [ 23 ], and other mechanisms yet to be discovered [ 24 ] may also contribute to the pathogenesis.…”