Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease.
Publication Year:
2024
PubMed ID:
38385289
Funding Grants:
Public Summary:
Kawasaki disease (KD) is an illness that causes inflammation of blood vessels and can lead to heart problems like irregular heartbeats (arrhythmias). This study used a mouse model of KD to understand how certain immune signals, specifically IL-1 and TNFα, contribute to heart issues. They found that blocking IL-1 with a drug called IL-1Ra helped prevent heart function decline and arrhythmias, while blocking TNFα did not have the same effect. Both treatments helped reduce blood vessel inflammation, but only IL-1Ra improved heart electrical activity and structure. Mice with overactive IL-1 signaling had more severe heart problems and early death. These results suggest that targeting IL-1 might be a better treatment strategy for preventing heart complications in KD patients.
Scientific Abstract:
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 TNFalpha (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 TNFalpha 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-1beta and TNFalpha, 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 TNFalpha neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFalpha 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-TNFalpha therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.