IL-1-dependent electrophysiological changes and cardiac neural remodeling in a mouse model of Kawasaki disease
M Abe1, D D Rastelli1,2, A C Gomez1
1Divisions of Infectious Diseases and Immunology, Departments of Biomedical Sciences and Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Insights
Kawasaki disease (KD) can cause heart problems in children. Blocking interleukin-1 (IL-1) signaling prevented ECG abnormalities and nerve changes in a mouse model, suggesting a new therapy for KD.
Area of Science:
- Cardiology
- Immunology
- Neuroscience
Background:
- Kawasaki disease (KD) is a leading cause of acquired heart disease in children.
- Acute KD is linked to electrocardiogram (ECG) abnormalities in 40-80% of patients.
- These ECG changes include coronary artery abnormalities, aneurysms, and myocarditis.
Purpose of the Study:
- To investigate ECG abnormalities and cardiac neuronal remodeling in a mouse model of KD.
- To explore the role of interleukin-1 (IL-1) signaling in KD-associated cardiac changes.
- To assess the therapeutic potential of blocking IL-1 signaling in KD.
Main Methods:
- Induction of KD vasculitis in mice using Lactobacillus casei cell wall extract (LCWE).
- Monitoring ECG parameters, cardiac ganglion inflammation, and serum nerve growth factor (NGF) levels.
- Utilizing anakinra (IL-1 receptor antagonist) and Il1r1 knockout mice to block IL-1 signaling.
Main Results:
- LCWE-injected mice exhibited elevated heart rate, decreased R wave amplitude, and prolonged ventricular repolarization.
- Cardiac ganglion inflammation and increased serum NGF were observed in LCWE-injected mice, mirroring human KD.
- Blocking IL-1 signaling with anakinra or in Il1r1-/- mice prevented ECG abnormalities and cardiac neural remodeling.
Conclusions:
- The LCWE-induced mouse model recapitulates KD's electrophysiological abnormalities and cardiac neuronal remodeling.
- IL-1 signaling plays a critical role in KD pathogenesis and associated cardiac changes.
- Blocking IL-1 signaling demonstrates therapeutic potential for KD patients, supporting anti-IL-1 therapy trials.
Abstract:
Kawasaki disease (KD) is the leading cause of acquired heart disease in children. In addition to coronary artery abnormalities, aneurysms and myocarditis, acute KD is also associated with echocardiogram (ECG) abnormalities in 40-80% of patients. Here, we show that these ECG changes are recapitulated in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. LCWE-injected mice developed elevated heart rate and decreased R wave amplitude, with significant differences in prolonged ventricular repolarization. LCWE-injected mice developed cardiac ganglion inflammation, that may affect the impulse-conducting system in the myocardium. Furthermore, serum nerve growth factor (NGF) was significantly elevated in LCWE-injected mice, similar to children with KD vasculitis, associated with increased neural remodeling of the myocardium. ECG abnormalities were prevented by blocking interleukin (IL)-1 signaling with anakinra, and the increase in serum NGF and cardiac neural remodeling were similarly blocked in Il1r1-/- mice and in wild-type mice treated with anakinra. Thus, similar to clinical KD, the LCWE-induced KD vasculitis mouse model also exhibits electrophysiological abnormalities and cardiac neuronal remodeling, and these changes can be prevented by blocking IL-1 signaling. These data support the acceleration of anti-IL-1 therapy trials to benefit KD patients.
