Autonomic Nervous System Profile in Hereditary Angioedema (ANS-HAE)

Hereditary Angioedema Due to C1 Inhibitor Deficiency: Evaluation of the Cardiac Autonomic Nervous System Profile in Patients With and Without Prophylactic Treatment

The goal of this study is to compare the autonomic nervous system control of patients with hereditary angioedema to healthy individuals.

The main questions it aims to answer are:

Are there differences in the autonomic nervous system control between patients with hereditary angioedema and healthy individuals during short-term resting period and during orthostatic challenges?

Are there differences in the autonomic nervous system control recorded over long-term periods (i.e. 24 hours)?

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 60

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20138
    • Istituti Clinici Scientifici Maugeri

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The group of patients with hereditary angioedema were recruited during a out-patient visit in a tertiary care center. The group of healthy individuals were volunteers recruited from community.

Description

Inclusion Criteria:

• Age between 18 and 65 years
• Diagnosis of hereditary angioedema due to C1 inhibitor deficiency (for the group of patients only)

Exclusion Criteria:

• Any type of chronic diseases requiring chronic treatment.
• Active acute disease
• Sars-Cov2 infection in the previous three months
• Acute attacks experiences within the previous week and within 72 hours after the enrollment
• Patients in prophylaxis treated off-label.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients with hereditary angioedema; Patients with documented diagnosis of hereditary angioedema due to C1 inhibitor deficiency with or without prophylactic treatment and aged between 18 and 65 years.
Healthy individuals; Healthy individuals with an age between 18 and 65 and matched with patients with hereditary angioedema by age and gender.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short-term heart rate variability	Changes in heart rate variability indices analyzed during tilt test	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term heart rate variability	Changes in heart rate variability indices analyzed during holter ECG recordings	Baseline
Concentration of catecholamines	Changes in the concentration of catecholamines, quantified in the blood plasma	Baseline

Collaborators and Investigators

• Sponsor: Istituti Clinici Scientifici Maugeri SpA

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2023
• Primary Completion (Actual): March 18, 2024
• Study Completion (Actual): March 18, 2024

Study Registration Dates

• First Submitted: May 7, 2024
• First Submitted That Met QC Criteria: May 7, 2024
• First Posted (Actual): May 10, 2024

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Autonomic Nervous System; Heart Rate Variability; Rare disease; Hereditary angioedema
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary
• Other Study ID Numbers: 2746CE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No