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

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 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.

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“…We observed systemic changes in circulating immune cells and positive correlations between frequencies and numbers of blood neutrophils and inflammatory monocytes during the acute phase of the disease with more severe vasculitis. We also observed an extensive fibrotic area around the aortitis and CA lesions early in the disease process, interstitial fibrosis in the myocardium later in the disease process, and a notable decline in cardiac function early in the disease as previously observed (37)(38)(39), which persists up to 16 weeks. Furthermore, there were substantial infiltrations of inflammatory cells in the aortic root and CA, with frequent severe or complete CA stenosis cases up to 16 weeks post-LCWE injection.…”

“…Myocarditis mainly affected the areas adjacent to sites of aortitis and coronary arteritis lesions (Figure 7B). Myocardial dysfunction, measured by decreased EF and increased LVID, was detected as early as 2 weeks post-LCWE injection (Figures 7C, D), in line with our previous observations (37)(38)(39). The decline in myocardial function and LV remodeling persisted and further deteriorated at weeks 12 and 16 post-LCWE injection (Figures 7C, D).…”

“…Here, we used the LCWE-induced KD-like vasculitis mouse model, which causes systemic vasculitis, aortitis, coronary arteritis, myocarditis, myocardial dysfunction, and myocardial fibrosis in mice (5,35,37,38). LCWE triggers the destruction of elastic layers, promotes intimal hypertrophy, and induces smooth muscle cell (SMC) proliferation towards the lumen, leading to myofibroblast proliferation and CA stenosis, as well as fibrotic remodeling and scarring also reported in children with KD (5,32,35,36,53).…”

Exploration of common genomic signatures of Systemic juvenile rheumatoid arthritis and Kawasaki disease

“…Recent studies indicate these two childhood in ammatory disorders share biochemical commonalities, including interleukin-1 beta (IL-Iβ) [7,8] . According to the ndings, SJIA and KD ought to share certain fundamental mechanisms.…”

Long-term cardiovascular inflammation and fibrosis in a murine model of vasculitis induced by Lactobacillus casei cell wall extract

“…As an alternative to patient samples, the Lactobacillus casei wall extract (LCWE)-induced mouse model of KD-like vasculitis is a well-described and widely accepted animal model (5,32). This model reproduces the key pathological features of KD, including coronary arteritis, aortitis, myocarditis, abdominal aorta aneurysms, myocardial dysfunction with mildly diminished ejection fraction (EF), and even electrocardiogram (EKG) changes and arrhythmias that may occur in clinical KD (5,(33)(34)(35)(36)(37)(38). Furthermore, it has also been successfully used to translate treatment responses to IVIG, anti-tumor necrosis factor (TNF)-a, and IL-1R antagonist (IL-1Ra; Anakinra) (35,36,39,40).…”