Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease

• DOI: 10.1161/atvbaha.123.320382
• Publication Date: 2024-02-22T10:03:59Z
• Authors: Thassio Mesquita; Yen-Nien Lin; Shuang Chen; Youngho Lee; Rodrigo Miguel-do...; Asli E. Atici; Michael C. Fishbein; Magali Noval Rivas; Moshe Arditi; Eugenio Cingolani
• Keywords: Vasculitis; 0301 basic medicine; Tumor Necrosis Factor-alpha; Interleukin-1beta; Arrhythmias, Cardiac; Mucocutaneous Lymph Node Syndrome; Mice; Interleukin 1 Receptor Antagonist Protein; Disease Models, Animal; 03 medical and health sciences; Tachycardia, Ventricular; Humans; Animals; Cardiomyopathies

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis.

METHODS:

Lactobacillus casei cell wall extract–induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed.

RESULTS:

KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1β and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract–injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths.

CONCLUSIONS:

Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract–induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.