In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis

Helluy, Xavier; Sauter, Martina; Ye, Yuxiang; Lykowsky, Gunthard; Kreutner, Jakob; Yılmaz, Ali; Boivin, Valérie; Kandolf, Reinhard; Jakob, Peter M.; Hiller, K. H.; Klingel, Karin

doi:10.1371/journal.pone.0172084

Cited by 11 publications

(13 citation statements)

References 25 publications

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“…As many lines of evidence suggest, iron dysmetabolism is involved in wide array of cardiac diseases, including I/R injury, drug cardiotoxicity, HF, TM and FA. In other diseases, such as infective myocarditis, research concerning the role of iron is still in early stages and remains to be elucidated . The problem with our knowledge concerning the role of iron in different heart conditions is that in some diseases we do not fully understand temporal changes during cardiac iron dysmetabolism, while in others, we are not sure if iron dysmetabolism is a primary feature or a consequence of the disease.…”

Section: Resultsmentioning

confidence: 99%

Keeping heart homeostasis in check through the balance of iron metabolism

Vela

2019

Acta Physiologica

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Highly active cardiomyocytes need iron for their metabolic activity. In physiological conditions, iron turnover is a delicate process which is dependent on global iron supply and local autonomous regulatory mechanisms. Though less is known about the autonomous regulatory mechanisms, data suggest that these mechanisms can preserve cellular iron turnover even in the presence of systemic iron disturbance.Therefore, activity of local iron protein machinery and its relationship with global iron metabolism is important to understand cardiac iron metabolism in physiological conditions and in cardiac disease. Our knowledge in this respect has helped in designing therapeutic strategies for different cardiac diseases. This review is a synthesis of our current knowledge concerning the regulation of cardiac iron metabolism. In addition, different models of cardiac iron dysmetabolism will be discussed through the examples of heart failure (cardiomyocyte iron deficiency), myocardial infarction (acute changes in cardiac iron turnover), doxorubicin-induced cardiotoxicity (cardiomyocyte iron overload in mitochondria), thalassaemia (cardiomyocyte cytosolic and mitochondrial iron overload) and Friedreich ataxia (asymmetric cytosolic/mitochondrial cardiac iron dysmetabolism). Finally, future perspectives will be discussed in order to resolve actual gaps in knowledge, which should be helpful in finding new treatment possibilities in different cardiac diseases. K E Y W O R D Scardiomyocyte, heart failure, iron chelation, iron metabolism, mitochondria, transferrin receptor 1

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Section: Resultsmentioning

confidence: 99%

Keeping heart homeostasis in check through the balance of iron metabolism

Vela

2019

Acta Physiologica

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“…Compared to macrophage imaging, LIBS-MPIO might be more suitable for early time points of the inflammation, when macrophages are not present in a high number. www.nature.com/scientificreports/ Another interesting experimental myocarditis imaging approach by Helluy et al focused on imaging of tissue damage by iron depositions with T2* MRI in a viral myocarditis model 29 . In-vivo imaging of cell damage causing iron deposition was possible 14 days after induction of myocarditis whereas our LIBS-MPIO approach can image platelets at a much earlier time point.…”

Section: Discussionmentioning

confidence: 99%

“…Another interesting experimental myocarditis imaging approach by Helluy et al focused on imaging of tissue damage by iron depositions with T2* MRI in a viral myocarditis model 29 . In-vivo imaging of cell damage causing iron deposition was possible 14 days after induction of myocarditis whereas our LIBS-MPIO approach can image platelets at a much earlier time point.…”

Section: Discussionmentioning

confidence: 99%

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice

Braig

Jakob

Bienert

et al. 2020

Sci Rep

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MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes. Besides myocardial ischemia, myocarditis is one of the most common causes of heart failure. The prevalence among young patients with sudden cardiac death is described within a range of 2-42%, and among patients with non-ischemic dilated cardiomyopathy within a range of 9-16%. The prognosis of progressing myocarditis is poor, symptoms are unspecific and diagnosis is challenging 1. Myocarditis is defined as an inflammatory process of the myocardium established by histological and immunohistochemical criteria associated with cardiac dysfunction. Several pathophysiological causes for myocarditis are known including infectious agents such as viruses, immune-mediated and toxic causes. Clinical symptoms, laboratory values, ECG and echocardiography are very often unspecific or inconclusive 1. To date, the diagnostic gold standard for diagnosis of myocarditis is endomyocardial biopsy (EMB). The Dallas criteria define myocarditis as histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of non-ischemic origin 2. There are also immunohistochemical criteria, namely abnormal inflammatory infiltrate defined as ≥ 14 leucocytes/mm 2 , including up to 4 monocytes/mm 2 with the presence of CD3 positive T-lymphocytes ≥ 7 cells/mm 21 .

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“…In the brain, hemoglobin-derived iron plays a major role in secondary damage following hemorrhage (Stephenson et al, 2014) and iron-overload cardiomyopathy is caused by iron deposition in the tissue, induction of cardiomyocyte cell death and an ensuing inflammatory reaction (Gammella et al, 2015). A recent study of CVB3-induced myocarditis in mice detected iron deposits within infected cardiomyocytes (Helluy et al, 2017), suggesting that, albeit due to a different mechanism, deposition of iron in the heart could be more prominent during pathological inflammatory processes than previously appreciated.…”

Section: Discussionmentioning

confidence: 99%

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

Baxan

Papanikolaou

Salles‐Crawley

et al. 2019

Disease Models &Amp; Mechanisms

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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..

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In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis

Cited by 11 publications

References 25 publications

Keeping heart homeostasis in check through the balance of iron metabolism

Keeping heart homeostasis in check through the balance of iron metabolism

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice

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

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