Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart.

Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches

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

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.This article has an associated First Person interview with the first author of the paper

Mise en oeuvre de microantennes RMN en perspective d'étude in vivo de métabolites par spectroscopie

Dans ce travail, on aborde le problème de l'utilisation de capteurs miniaturisée pour spectroscopie RMN, résonateurs réalisés par des techniques d'intégration de circuits, et créés dans la perspective d'implantation in vivo des ces sondes à des fins d'application pré clinique. Un vue d'ensemble sur l'utilisation des microantennes RMN dans le contexte actuel est effectuée au cours d'un premier chapitre, introductif et qui fixera également les objectifs du travail. Le chapitre II présente la mise enoeuvre d'une série de capteurs RMN de dimensions sub-millimétriques réalisés sur un support de verre. Elle comporte le détermination de leur sensibilité spatiale, envisagées par simulation puis effectuée de manière concrète par Imageriee RMN. Dans le cas des structures utilisées l'estimation de leur volume utile de détection est de 2 microlitres environ si le capteur est utilisé en réception uniquement. Le chapitre III comprend une évaluation des performances des microantennes "monovoxel", l'étude permet de valider l'utilisation de micro antennes réceptrices en mesurant la sensiblité accessible à cette technique. Les résultats permettent d'envisager des détections à la concentrationde métabolites du proton rencontrées in vivo. le passage à l'expérimentation in vivo. Le passage à l'expérimention in vivo est préparé par le travail du chapitre IV qui présente notamment une voie possible pour l'implantation des microantennes au niveau cérébral chez le rat et il permet d'identifier les principales difficultés de ce type d'utilisation. Cette étude présente donc le concept et les performances d'une nouvelle génération de micro antennes pouvant fonctionner efficacement pour l'analyse locale de faibles volumes de biofluides et implantables in vivoConsidering the need to explore by MR spectroscopy small quantities of tissue, it is possible to create probes with a working volume compatible with such limitations. This work is centred on the research of efficient solutions to create implantable microsensors by microelectronic techniques especially for in vivo application in preclinical purposes. The first chapter of the theses is an overview on the MR microcoil utilisation on the international context. In the second chapter we describe the microcoil development, its spatial sensitivity estimated by simulation and further correlated by MRI enabling us to estimate the active volume close to 2 l when the microcoil is used as receiver only. The third chapter is dedicated to the evaluation of microcoil performances in tremes of limit of detection. The presented results made possible to validate the use of microcoils associated with MR spectroscopy sequences based on monovoxel techniques and to measure the sensivity of the technique. The last chapter describes a possible pathway to the microcoil implantation on living tissues and also identifying the difficulties of this approach. The example presented here covers the rat brain explorarion. this study presents the concept and the performances of a new generation of microcoils making possible to validate their performances in MR spectroscopy and largely opening innovative possibilities of highly spatial resolved explorationsLYON1-BU.Sciences (692662101) / SudocSudocFranceF