ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
This article is part of the Research TopicGenetic and Immunological Insights into Angioedema Without WhealsView all 11 articles
Functional physiological, psychological, and biochemical Reactivity to Socially Evaluated Cold Pressor Test in Hereditary Angioedema Patients (FRoSEn)
Provisionally accepted
Beatrice De Maria1
Luca Ranucci2
Clara Gino1
Azzurra Cesoni Marcelli3Lorenza Chiara Zingale3
Aida Zulueta4
Laura Adelaide Dalla Vecchia5Alessandra Gorini2,6
Francesca Perego3*- 1Bioengineering Laboratory, Istituti Clinici Scientifici Maugeri SpA IRCCS Milano, Milan, Italy
- 2PsyCaRe Lab, Istituti Clinici Scientifici Maugeri SpA IRCCS Milano, Milan, Italy
- 3Department of Internal Medicine and Rehabilitation, Istituti Clinici Scientifici Maugeri SpA IRCCS Milano, Milan, Italy
- 4LaBioN, Istituti Clinici Scientifici Maugeri SpA IRCCS Milano, Milan, Italy
- 5Department of Cardiology, Istituti Clinici Scientifici Maugeri SpA IRCCS Milano, Milan, Italy
- 6Dipartimento di Eccellenza 2023-2027, Universita degli Studi di Milano Dipartimento di Scienze Cliniche e di Comunita, Milan, Italy
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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.
Keywords: Blood Pressure, Heart Rate, hereditary angioedema, Inflammation, rare disease, Secondary Prevention, socially evaluated cold pressor test, stress
Received: 31 Oct 2025; Accepted: 02 Dec 2025.
Copyright: © 2025 De Maria, Ranucci, Gino, Cesoni Marcelli, Zingale, Zulueta, Dalla Vecchia, Gorini and Perego. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Francesca Perego
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