Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multiparametric quantitative cardiac magnetic resonance imaging

Abstract

Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the Toll-like receptor 7 (TLR-7) agonist Resiquimod induces auto-antibodies and systemic tissue damage, including in the heart, and is used as an inducible mouse model of systemic lupus erythematosus (SLE). Here, we show that overactivation of the TLR-7 pathway of viral recognition by Resiquimod treatment of CFN mice induces severe thrombocytopenia and internal bleeding, which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results with ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes. In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as an acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis improves diagnostic sensitivity and interpretation of disease mechanisms..

Cardiac magnetic resonance T2* mapping in patients with COVID-19 pneumonia is associated with serum ferritin level?

“…T2* mapping for non-COVID-19 myocarditis has been assessed in two MRI studies [ 27 , 28 ]. Helluy et al [ 27 ] assessed myocardial injury in murine models of acute and chronic viral myocarditis by T2* mapping [ 27 ].…”

“…It is also mentioned that T2* mapping has the capability to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was correlated histopathologically [ 27 ]. In another study by Baxan et al [ 28 ]] assessed acute hemorrhagic myocarditis in ex vivo histopathologic correlation with in vivo cardiac MRI using T2* sequence in the animal model and suggested that low T2 *detecting areas of increased levels of iron in the tissue suggestive of inflammatory changes including vascular damage, red blood cell extravasation, and tissue iron deposition.…”

“…For all that, recent studies have focused on T2* mapping for post-revascularization hemorrhage [ 23 , 24 ], hypertrophic cardiomyopathy [ 25 , 26 ], or myocardial fibrosis [ 21 ]. On the other hand, T2* mapping for non-COVID-19 myocarditis has become an area of great interest [ 27 , 28 ]. Although several studies have been published about the myocardial T1 mapping in COVID-19 related myocardial injury[ 29 ] myocardial T2* mapping in COVID-19 has not been evaluated yet.…”

Systemic Administration of the TLR7/8 Agonist Resiquimod (R848) to Mice Is Associated with Transient, In Vivo-Detectable Brain Swelling

“…The current study, therefore, tested the hypothesis that peripheral TLR7/8 stimulation of mice with R848 would similarly result in MR-detectable changes to the brain including modulation of the glutamate/glutamine balance and brain swelling consistent with edema. To the best of our knowledge, only a single study has previously evaluated the in vivo effects of R848 using MRI but focused on cardiac, not brain, tissue [ 44 ].…”

First person – Nicoleta Baxan

“…ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Nicoleta Baxan is first author on ‘Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multi-parametric quantitative cardiac magnetic resonance imaging’, published in DMM. Nicoleta conducted the research described in this article while in Dr Susanne Sattler's lab at Imperial College London, UK.…”