Cardiac and vascular autonomic control in patients with hereditary angioedema

Abstract

Background: Regulation of vascular permeability in hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is key to understanding the disease, but the role of the autonomic nervous system (ANS) in this mechanism remains unclear.

Purpose: The aim of this study was to compare the cardiovascular autonomic response to the head-up tilt test (HUTT) in HAE-C1INH patients and matched healthy controls (HCs).

Methods: HAE-C1INH patients were evaluated during a 1-week symptom-free period. Electrocardiogram (ECG) and beat-to-beat non-invasive arterial blood pressure (BP) were recorded in the supine position (REST) and during 70° tilt (TILT). Heart rate and systolic BP (SBP) variability indices were derived. Variance (σ² _SBP) and low-frequency power (LF_SBP) of SBP variability were used as markers of sympathetic vascular control.

Results: Twenty-five HAE-C1INH patients [13 male individuals, 44 (28.8-57.5) years] and 25 HCs [13 male individuals, 44 (30.8-54.3) years] were enrolled and divided into <45 and ≥45 age groups. Eighteen patients were on long-term prophylaxis (LTP). In the younger group, LF_SBP increased from REST to TILT in both groups, with no differences. In older subjects, HAE-C1INH patients showed higher σ² _SBP [21.2 (9.3-59.2) vs. 7.5 (1.9-14.6) mmHg²] and a greater LF_SBP increase [9.4 (4.6-22.4) vs. 0.9 (0.2-7.6) mmHg²] than HCs during TILT, suggesting sympathetic hyperactivation. No significant group differences in cardiac autonomic control were observed during REST or TILT, regardless of age. Findings in the LTP subgroup mirrored those of the full cohort.

Conclusion: Older HAE-C1INH patients display altered vascular autonomic regulation, with an exaggerated sympathetic response during orthostatic stress. Further studies are needed to assess the role of LTP in these alterations.

Clinical trial registration: https://clinicaltrials.gov/study/NCT06408805?cond=Hereditary%20Angioedema&term=autonomic&rank=1.

Keywords: autonomic nervous system; heart rate variability; hereditary angioedema; long-term prophylaxis; rare disease; secondary prevention; systolic arterial pressure variability.

FIGURE 1

Flowchart of the enrolled population. Legend: HAE, hereditary angioedema.

FIGURE 2

Comparison of the cardiovascular neural control indices in HAE patients and HCs during HUTT. Boxplots show µ_RR (a), σ² _RR (b), HF_RR (c), µ_SBP (d), σ² _SBP (e), and LF_SBP (f) in HAE patients (dark gray boxes) and HCs (white boxes) during REST and TILT. Data are presented as the median [IQR]. *p < 0.05 REST vs. TILT, #p < 0.05 HAE patients vs. HCs, based on two-way analysis of variance with Holm–Sidak post hoc test.

FIGURE 3

Comparison of the vascular neural control indices in HAE patients and HCs who were younger and older than 45 years during HUTT. Line plots show σ² _SBP and LF_SBP of HAE patients and their age- and sex-matched HCs who were younger (left) and older (right) than 45 years *p < 0.05 REST vs. TILT, #p < 0.05 HAE patients vs. HCs, based on two-way analysis of variance with Holm–Sidak post hoc test.