**3. The pathophysiological mechanisms of viral myocarditis**

The current understanding of the immunopathologcial phases of myocarditis derives largely from enterovirus-induced myocarditis in murine models (Andréoletti et al, 1997; Cooper et al., 2007; Liu & Mason, 2001; Yajima & Knowlton, 2009). During the enterovirus (virus Coxsackie B) natural course of infection, the data obtained from experimental murine

Common human pathogenic DNA or RNA viruses can be responsible for acute or chronic endomyocardial tissue infection (Andréoletti et al., 1995; 2009; Kühl et al., 2005a). The detection of components (DNA or RNA genomes or viral proteins) of these viral agents by molecular techniques such as polymerase chain reaction (PCR) and/or immunohistochemical techniques demonstrating the viral protein expression in the cytoplasm of myocytes, was associated with an inflammation of the myocardium (acute myocarditis), arrhythmias, loss of contractility (Andréoletti et al., 2009; Cooper, 2009; Dennert et al., 2008). Moreover in serial of human cases, the presence of viral persistence was evidenced in the myocardium and associated with a left ventricular systolic dysfunction in relation to a reduction in the contractile function of the myocytes (Andréoletti et al., 2000; Badorff et al., 2001). Additional proofs of concept were that: (I) a longitudinal clinical investigation showed that the type of virus, the clinical presentation and the type of histological damage appeared to be related to the clinical course of the cardiac disease; (II) longitudinal clinical studies indicated that the immune clearance of the virus during or after the acute phase was correlated with an improvement of the left ventricular ejection fraction [LVEF] (Kühl et al. 2005b); (III) acute and chronic myocarditis as well as dilated cardiomyopathy (DCM) were reproduced in immunocompetent animal models following experimental viral infections (Andréoletti et al., 1997; Huber, 1993; Matsumori & Kawai, 1982). Altogether these clinical and experimental data supported the pathophysiological role of several human viruses in the genesis and the evolution of myocarditis and the DCM. Although up to 90% of people will be infected by at least one or more of these viruses in their life without getting their heart injured with associated clinical signs, only a few number will develop clinical symptoms. Therefore, it is highly suspected that a certain genetic background either related to immune alterations or to an improved susceptibility to viral cardiac infection (viral receptor or co-receptors polymorphisms) may be a prerequisite to develop clinical symptoms of myocarditis and/or progression to DCM following virus heart tissue infection. In addition, it has been shown that dystrophin mutations may make easier the development and progression of myocarditis and cardiac failure during coxsackievirus B3 infection, whereas dystrophin and/or sarcoglycan disruption by viral proteases account for myocardial injury (Andréoletti et al., 2007; Badorff et al., 2001; Lee et al., 2000). Human genetic studies of patients with myocarditis are rare and only 2 reports show an association between myocarditis and genetic factors such as HLA-DQ locus and CD45 polymorphism (Yajima & Knowlton, 2009). Future clinical investigations should therefore focus on the understanding of the underlying genetic susceptibility and related immune responses that explain why some patients are susceptible to develop clinical symptoms of acute myocarditis following viral infection, whereas other subjects clinically recover or progress to an 'idiopathic' DCM after the initial phase of the viral cardiac

**2. Human viral cardiac infection: proofs of concept and clinical relevance** 

infection.

**3. The pathophysiological mechanisms of viral myocarditis** 

The current understanding of the immunopathologcial phases of myocarditis derives largely from enterovirus-induced myocarditis in murine models (Andréoletti et al, 1997; Cooper et al., 2007; Liu & Mason, 2001; Yajima & Knowlton, 2009). During the enterovirus (virus Coxsackie B) natural course of infection, the data obtained from experimental murine models allowed the identification of three distinct pathophysiological phases defined as acute, sub-acute and chronic myocarditis (Cooper, 2003; Feldman & McNamara, 2000; Yajima & Knowlton, 2009) (Figure 1).

Fig. 1. Immunopathological phases of viral myocarditis.
