5 (Fig. 2A and

B). It is noteworthy that the inflammatory disease in TCR-M mice was restricted exclusively to the heart indicating that this TCR is truly heart specific. At the age VX-770 nmr of 6–8 weeks, some TCR-M mice presented with severe clinical symptoms such as apathy and forced breathing so that these mice had to be euthanized (graded as lethal disease, severity grade 5). In a prospective study with 23 TCR-M mice, we determined the long-term effect of the spontaneous myocarditis on the survival of TCR-M mice. The highest incidence of severe disease was observed during the age of 8–12 weeks (Fig. 2C). However, after this critical time period, only very few mice succumbed and an overall survival rate of 40% was recorded (Fig. 2C). The lethal disease in TCR-M mice was mediated by CD4+ T cells because TCR-M mice crossed to the CD4-deficient background remained clinically healthy for more than 28 weeks (Fig. 2C) and did not show signs of myocarditis in histopathological examination (not shown). Macroscopic analysis of lethally diseased TCR-M hearts revealed classical signs of DCM such as significant enlargement of the heart muscle, substantial dilatation of the heart ventricles, and a remodeling process indicated by almost translucent ventricle walls (Fig. 2D). Histological

examination of TCR-M hearts revealed massive cardiomyocyte death around small and large foci of inflammatory cells indicated by condensed eosinophilic cytoplasm and accumulation of eosinophilic debris around ALK inhibitor histiocytic cells (not shown). In the advanced disease stages of the disease, histopathological analysis revealed massive leukocyte infiltration, almost complete loss of heart tissue and replacement of cardiomyocytes by fibrous connective tissue (Fig. 2E). We therefore conclude that the spontaneously developing myocarditis in TCR-M mice progressed to DCM whereby a fraction of the diseased animals was spared from the progressive disease. The fatal long-term consequence of myocarditis is marked by extensive cardiac remodeling that might foster DCM.

Such anatomical changes can be visualized by CMRI, the recommended diagnostic procedure to monitor myocarditis in humans [6]. Since the early anatomical and functional parameters Vorinostat chemical structure underlying the progression of myocarditis to DCM have remained enigmatic, we performed a CMRI study with groups of 5 and 12 weeks old male TCR-M and BALB/c control mice using a small animal MRI system and a self-gated parallel imaging strategy [26]. We found that 5 weeks old TCR-M mice displayed a significantly smaller end-systolic volume (ESV) and a substantial increase in the ejection fraction (EF) (Table 1 and Supporting Information Fig. 4). These early pathophysiological alterations were not due to differences in weight gain of TCR-M mice (Supporting Information Fig.