Functional physiological, psychological, and biochemical reactivity to socially evaluated cold pressor test in hereditary angioedema patients (FRoSEn)

Abstract

Introduction: Stressful physical or psychological events can trigger acute swelling attacks in patients with Hereditary Angioedema due to C1 Inhibitor deficiency (HAE-C1INH), although the stress-disease relationship remains unclear. The Socially Evaluated Cold Pressor Test (SECPT) reliably induces acute stress under controlled conditions. This study aimed to compare perceived stress, inflammatory markers, and cardiovascular responses to SECPT between HAE-C1INH patients and healthy controls (HC).

Methods: Twenty HAE-C1INH patients (9 males, 44 ± 14 years) and age and sex matched HC underwent a 3-minute SECPT. Participants completed questionnaires assessing anxiety and depression (HADS), pain catastrophizing (PCS), and subjective stress (0-100 scale) before and after SECPT. Heart rate (HR) and arterial pressure (AP) were recorded. Blood samples for inflammatory cytokines (IL-6, IL-1ß, TNF-α) were collected at baseline, and 10 and 40 minutes after SECPT.

Results: Compared to HC, patients showed higher baseline HADS-A (7.3 ± 4.5 vs 4.7 ± 2.7), overall PCS (19.7 ± 12.6 vs 12.9 ± 8.7), and perceived stress during SECPT (60.6 ± 34.3 vs 34.6 ± 23.8). IL-6 levels were higher at baseline and 10 minutes post-test (2.63 ± 1.21 vs 1.84 ± 0.87; 2.78 ± 1.20 vs 1.91 ± 0.79 pg/ml), as were TNF-α levels across all phases (4.19 ± 1.38 vs 3.26 ± 1.55; 4.09 ± 1.39 vs 3.40 ± 1.48; 4.09 ± 1.28 vs 3.20 ± 1.57) while IL-1 ß remained unchanged. HR and AP variations were similar between groups.

Discussion: HAE-C1INH patients exhibited heightened perceived stress response to SECPT, and elevated baseline inflammation, despite comparable cardiovascular reactivity. These findings highlight a complex psychophysiological-inflammatory interplay in acute stress responses, suggesting the need to integrate psychological and biological frameworks in understanding HAE-C1INH triggers.

Clinical trials code: NCT06414252.

Keywords: Socially Evaluated Cold Pressor Test; blood pressure; heart rate; hereditary angioedema; inflammation; rare disease; secondary prevention; stress.

Figure 1

Schematic representation of the experimental protocol. Figure was created in Biorender.com.

Figure 2

Heart rate and arterial blood pressure in HC and HAE-C1INH patients. The bar graphs show the changes in heart rate (HR), systolic arterial blood pressure (SAP) and diastolic arterial blood pressure (DAP) during the different phases of the experimental protocol: supine resting position (REST), socially-evaluated cold pressure test (SECPT), in the 10 minutes following the SECPT (POST10) and in the 30 minutes following the POST10 (POST40) in HC (black bars) and HAE-C1INH (white bars). Data are presented as mean and standard deviation. * indicates p<0.05 vs HC, # p<0.05 vs SECPT.

Figure 3

Inflammatory cytokines in HC and HAE-C1INH patients. The bar graphs show the changes in Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-6 (IL-6) at the end of the REST, POST10 and POST40 phases of the experimental protocol in HC (black bars) and HAE-C1INH (white bars). Data are presented as mean and standard deviation. * indicates p<0.05 vs HC

Figure 4

Perceived stress in HC and HAE-C1INH patients. The bar graphs show the perceived level of stress during REST and SECPT in HC (black bars) and HAE-C1INH (white bars). Data are presented as mean and standard deviation. * indicates p<0.05 vs HC, $ p<0.05 vs REST.