Complexity analysis of heart rate variability: application to Holter monitoring in patients with hereditary angioedema due to C1 inhibitor deficiency

Objective. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare condition characterized by unpredictable swelling attacks. Despite evidence of the involvement of the cardiac autonomic nervous system in the pathophysiology of HAE-C1INH, no studies have been conducted under real-life conditions. Approach. This study aims to investigate cardiac autonomic modulation in HAE-C1INH patients during attack-free period, via linear spectral and nonlinear complexity indexes (CIs) derived from 24 h Holter recordings of heart period variability in comparison with healthy controls (HCs). Main results. Twenty-five HAE-C1INH patients (13 males, age 43 ± 13 yrs) and 25 sex- and gender-matched HC (44 ± 15 yrs) were studied during a regular day. HAE-C1INH patients were divided into those who experience at least one HAE-C1INH attack in the last 6 months (ATT, n = 11, 6 males, 39 ± 14 yrs) and those who did not (NoATT, n = 14, 7 males, 47 ± 16 yrs). Power spectral indexes and markers of CIs estimated by sample entropy and two k-nearest-neighbour (KNN) techniques were derived during day-time (DAY) and night-time (NIGHT). All the calculated parameters showed a circadian rhythm and this time course was similar in HAE-C1INH and HC group. In HAE-C1INH patients, KNN complexity markers were significantly higher in ATT compared to NoATT during NIGHT. Significance. In HAE-C1INH patients, compared to HCs, cardiac autonomic modulation remains intact. However, in the ATT group, complexity analysis possibly suggests a more reactive vagal control compared to the NoATT one. Complexity indexes demonstrated superior sensitivity over traditional spectral measures in stratifying the risk of attack. The results are preliminary and need to be confirmed in larger samples.