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IL-1β is not critical to chronic heart dysfunction in mice with Chagas disease
Camila Victória Sousa Oliveira1, Oscar Moreno-Loaiza2, Daniel Figueiredo-Vanzan3
1Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
Insights
Interleukin-1 beta (IL-1β) does not appear to drive chronic chagasic cardiomyopathy (CCC) or its associated cardiac issues in a mouse model. Blocking IL-1β signaling did not prevent or reverse key cardiac abnormalities in Chagas disease.
Area of Science:
- Immunology
- Cardiology
- Infectious Diseases
Background:
- Chronic Chagas disease (CCC) affects 40% of infected individuals, causing progressive cardiac dysfunction.
- Elevated Interleukin-1 beta (IL-1β) levels are observed in Chagas disease patients.
- Previous studies implicated IL-1β in cardiac dysfunction in other conditions.
Purpose of the Study:
- To investigate the role of IL-1β signaling in the development of chronic chagasic cardiomyopathy (CCC).
- To determine if IL-1β blockade is a viable therapeutic strategy for CCC.
Main Methods:
- Utilized a mouse model of chronic Trypanosoma cruzi infection.
- Compared wild-type (WT) mice with IL-1 receptor knockout (Il-1r) mice.
- Administered an IL-1R antagonist (anakinra) to infected WT mice.
- Assessed cardiac function, arrhythmias, and electrophysiological parameters.
Main Results:
- Il-1r mice showed increased parasitemia but no weight loss during acute infection.
- Chronic Il-1r mice had normal ventricular repolarization (QJ) compared to WT.
- Absence of IL-1R signaling or anakinra treatment did not improve stroke volume or reduce arrhythmias.
- Anakinra treatment shortened QJ intervals but did not affect other cardiac parameters.
Conclusions:
- IL-1β/IL-1R signaling is not a critical mechanism in the development or maintenance of CCC.
- Targeting IL-1β blockade may not be an effective therapeutic strategy for Chagasic cardiomyopathy.
Abstract:
Long after Trypanosoma cruzi infection, 40% of individuals develop a progressive chronic chagasic cardiomyopathy (CCC), with systolic dysfunction and arrhythmias. Since we previously showed IL-1β mediates the development of systolic dysfunction and cardiac arrhythmias in diabetes mellitus and cardiorenal syndrome, and IL-1β remains elevated in Chagas disease patients, here we tested the role of IL-1β in CCC using a mouse model. Mice deficient in IL-1R expression (Il-1r ) survived acute T. cruzi infection with greater parasitemia than controls but did not lose weight as wild-type (WT) did. At the chronic stage, WT presented prolonged ventricular repolarization intervals (QJ), while Il-1r presented intervals like noninfected controls. Infected Il-1r and WT did not differ in stroke volume (SV), the incidence of cardiac arrhythmias on electrocardiography (EKG), whole heart action potential duration (APD), or the incidence of triggered activity after S1-S2 protocol, which is a measure of susceptibility to cardiac arrhythmias. We also treated chronically infected WT mice with an IL-1R antagonist, anakinra. Treatment shortened the QJ interval but did not improve the SV or the incidence of cardiac arrhythmias on EKG. Anakinra failed to reduce triggered activity following the electrical extra-stimulation protocol. In conclusion, the absence of functional IL-1β/IL-1R signaling did not prevent or reverse the decrease of SV or the incidence of cardiac arrhythmias induced by chronic T. cruzi infection, implying this is not a critical mechanism in generating or maintaining CCC. Since similar cardiac abnormalities were previously credited to IL-1β signaling, ruling out this mechanism is important to discourage further attempts of IL-1β blockade as a therapeutical measure.
