**4.1 Acute viral myocarditis**

Viruses generally infect human beings by fecal-oral (enteroviruses, *parvovirus* B19, *Herpesviruses*) or respiratory routes (enteroviruses, *influenza viruses A & B, parainfluenza viruses I II III*) and they usually perform a first phase of multiplication into the airway epithelial cells of the higher respiratory tract or tonsils; this can be followed by a potential rapid invasion of the lower respiratory tract as observed during influenza virus infection. After this initial and local replication phase, the viruses can diffuse by lymphatic way to the general circulation (viremic phase) allowing them to reach the cardiac tissues. In the heart, the virus infects and replicate actively into the cardiac myocytes but also into the cardiac fibroblasts that can play the role of reservoir cells for a persistent infection (Andréoletti et

Viral Myocarditis: Physiopathology and Diagnosis 93

of latent parvovirus B19 infection, the influence of immune activation triggering parvovirus B19 replication and chronic myocarditis, and immune-independent viral pathogenesis

In cases of *herpesviruses* (HSV1, HSV-2 , HCMV, HHV-6) cardiac infection a latent phase can occur subsequently to the acute phase of infection as demonstrated in a mice model (Grodums & Zbitnew, 1976). During this HSV experimental latent infection, HSV-DNA can be identified as agents of a persistent heart infection in cardiomyocytes, fibroblasts or Schwann cells, which has be seen in unmyelitinated axons in murine heart tissues. In human subjects, CMVH was detected in cardiomyocytes and in cardiac fibroblasts of patients with histological proven myocarditis (Schönian et al., 1995). Moreover, it was not possible to detect viral mRNA coding for structural proteins known as late proteins but only mRNA coding for viral enzymatic proteins (early proteins) related to the regulation of viral replication or associated with the HCMV DNA replication (Lenzo et al., 2002) Whatever, the cellular sites as well as the mechanisms of latency and reactivation of the *herpesviruses* (EBV, HCMV and HHV6) in human heart tissues remain to be assessed (Andréoletti et al., 2009;

Human Enteroviruses, (*picornaviridae*), specifically Coxsackie group B serotypes, Parvovirus B19, HHV6 of the B type and the adenovirus are the most frequently etiological viral agents implicated in the acute myocarditis of the child or the young adult (<35 year-old) (Andréoletti et al., 2009; Bowles et al., 2003; Feldman & McNamara, 2000; Kühl et al., 2005b; Magnani & Dec, 2006) (Table 2). Moreover HHV-1, Adenovirus, myxoviruses and also paramyxoviruses including respiratory syncytial virus (RSV), *influenza* and *parainfluenza*  strains can also induce an acute infection of cardiac tissue as previously demonstrated in reported acute myocarditis cases developed in immunocompetent patients (Bowles et al., 2003; Dennert et al., 2008). Other viruses as EBV or CMV are also associated with this pathology after heart transplantation. HIV or HCV can be also etiological agents of

Recent data showed that it was possible to detect viruses in 71% of the cases of acute myocarditis using molecular techniques for the virological analysis of cardiac biopsy samples (Table 2) (Kühl et al., 2003). Co-infections were found in more than 12% of the cases, generally associating HHV6 and Parvovirus B19. HHV6 seems to be an important cofactor of myocarditis due to Parvovirus B19. HHV6 may enhance the pathogenicity of Parvovirus B19 through alterations of the extracellular matrix and modulation of the expression levels of the PVB19) receptor (P-antigen) on endothelial cells facilitating

Concerning chronic myocarditis, there is no clinical data from transverse or longitudinal studies indicating the incidence of various viral causes of cardiac infection. However, viral persistence in the myocardium was associated with ventricular dysfunction whereas viral genome clearance was related to the hemodynamic improvement (Kühl et al. 2005a, 2005b). As in the cases of acute myocarditis, recent studies showed the interest to test a broad panel of cardiotropic viruses at the DCM stage. Thus, in a case series of 245 patients with clinically suggested DCM, one or more viruses were detected in 67% of the cases (Table 2) (Kühl et al.,

remains to be assessed (Bock et al., 2010).

Cooper, 2009; Dennert et al., 2008).

**5. Viral causes for human acute or chronic myocarditis** 

myocarditis (Matsumori et al., 2006; Sudano et al., 2006) (Table 2).

infections of the coronary vascular endothelium (Table 2) (Kühl et al., 2005a).

**4.3 The chronic latent viral cardiac infections** 

al., 2009). During this active phase of replication, the development of the classical clinical signs of myocarditis is usually observed (Andréoletti et al., 2007; Magnani & Dec, 2006).
