Autonomic Nervous System Profile in Hereditary Angioedema

Angioedema (AE) without wheals is a localized self-limiting edema associated with different mechanisms. The best-known form is hereditary angioedema (HAE) due to C1 inhibitor deficiency (C1-INH), a rare disease with a prevalence of 1:65000 in Italy. Symptoms include swelling of the extremities, genitals, bowel mucosa, face, and upper airway including the larynx. Laryngeal attacks, if not treated, can lead to death. AE attacks are unpredictable and occur episodically upon release of the main mediator of the attack, namely bradykinin, resulting from hyperactivation of the contact system lacking its main control protein C1-INH.

The overall result is an impairment of the endothelial function associated with increased vascular permeability. The release of bradykinin occurs locally, in an unpredictable way, at times facilitated by trauma and different triggers such as stress.

In C1-INH-HAE patients, the autonomic nervous system (ANS) has a role in the regulation of vascular permeability, for example via the baroreflex mechanism. It is also known that sympathetic nervous system inhibition by the α2 agonist clonidine reduces microvascular permeability in endotoxemic animals, suggesting that antagonizing the sympathetic nervous system might prove beneficial in stabilizing capillary leakage during inflammation. Similarly, the vagus nerve has a protective role in models of inflammation such as ischemia-reperfusion injury. The parasympathetic tone, acting on the B2-receptors in the nucleus ambiguous, can also be modulated by bradykinin. The ANS could be investigated using the tilt test and Holter ECG monitoring in current clinical practice when its impairment is suspected. Power spectral analysis of heart rate variability (HRV), i.e. the analysis of the spontaneous fluctuations of the heart period, is exploited to analyze data collected during the tilt test and Holter-ECG, deriving indices of the autonomic control.

In C1-INH-HAE patients the cardiac ANS was investigated during a remission period, during the AE attack and its prodromal phase.

It has been demonstrated that HRV analysis, extended to multiday ECG recordings, may furnish an early marker of an angioedema attack.

In this perspective, the identification of markers, like HRV parameters, could play a crucial role in helping patients and physicians to characterize the ANS control in each patient and individualize treatment based on the ANS balance.

This study aims to compare the cardiovascular ANS control in healthy subjects and HAE patients by head-up tilt test monitoring and evaluate the differences in long-term ANS between healthy controls and HAE patients by Holter ECG monitoring.