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

Arterioscler Thromb Vasc Biol. 2024 Apr;44(4):e117-e130. doi: 10.1161/ATVBAHA.123.320382. Epub 2024 Feb 22.


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.

Keywords: Kawasaki disease; cardiac arrhythmias; interleukin-1; interleukin-1 receptor antagonist protein; vasculitis.

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / etiology
  • Arrhythmias, Cardiac / prevention & control
  • Cardiomyopathies*
  • Disease Models, Animal
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Interleukin-1beta / metabolism
  • Mice
  • Mucocutaneous Lymph Node Syndrome* / complications
  • Mucocutaneous Lymph Node Syndrome* / drug therapy
  • Tachycardia, Ventricular* / complications
  • Tachycardia, Ventricular* / prevention & control
  • Tumor Necrosis Factor-alpha
  • Vasculitis*


  • Interleukin 1 Receptor Antagonist Protein
  • Tumor Necrosis Factor-alpha
  • Interleukin-1beta