**1. Introduction**

86 Myocarditis

Zagrosek, A., Wassmuth, R., Abdel-Aty, H., et al. (2008). Relation between myocardial

myocarditis: a CMR study. *J Cardiovasc Magn Reson,* 10,19.

edema and myocardial mass during the acute and convalescent phase of

In Europe and the USA, viral aetiologies largely prevail over other causes of myocarditis as previously indicated by recent data demonstrating the molecular detection of cardiotropic viruses in human cardiac biopsy samples (Kühl et al., 2005a). Clinical presentations of the myocarditis range from non-specific systemic symptoms (fever, myalgias, palpitations, or exertional dyspnea) to fulminant hemodynamic collapse (5 to 10 cases per million inhabitants and per year) and sudden cardiac death (Feldman & McNamara, 2000; Magnani & Dec, 2006).

Acute myocarditis remains a complex and challenging diagnosis in cardiology (Magnani & Dec, 2006). This cardiomyopathy is defined histologically by the Dallas criteria as an''inflammation of the myocardium'' associated with necrosis and an absence of ischaemia (Aretz et al., 1987; Cooper, 2009; Dennert et al., 2008; Felmann & McNamara, 2000). The use of the Dallas criteria in the diagnosis of myocarditis is associated with poor sensitivity and specificity, mainly because of the sampling error related to the often focal distribution of the specific histological lesions in cardiac tissue and because of the variability in pathological interpretation (Baughman, 2006; Mahrholdt et al., 2004). Moreover, the Dallas classification does not consider local quantification and differentiation of inflammatory cells and does not take into account viral infection and autoimmune regulation in cardiac tissues (Dennert et al., 2008). To improve the histological diagnosis, additional virological and immunological evaluations of cardiac tissues are required using immunohistochemical and PCR techniques, which allow identification and quantification of inflammatory cells and viral infection markers (Dennert et al., 2008). The diagnostic gold standard is endomyocardial biopsy with the histological Dallas criteria in association with new immunohistochemical and viral PCR analyses of cardiac tissues (Cooper et al., 2007). This new diagnostic approach can lead to better identification of the aetiological cause of the myocarditis and can improve the clinical management of viral myocarditis. This chapter chronicles the advances in understanding the physiopathology of viral acute and chronic myocarditis and in the development of new molecular techniques for an accurate and valuable virological diagnosis.

Viral Myocarditis: Physiopathology and Diagnosis 89

models allowed the identification of three distinct pathophysiological phases defined as acute, sub-acute and chronic myocarditis (Cooper, 2003; Feldman & McNamara, 2000;

**Subacute myocarditis**

**Mononuclear cell infiltrate**

**Chronic myocarditis**

**B**

**(A) Clinical stage of dilated cardiomyopathy; (B) Human cardiac heart tissue with large fibrosis areas (arrows)**

**A**

**<sup>90</sup> <sup>0</sup> 4 days 14 days Viremia Viral clearance Viral persistence**

During the period of active viremia, cardiotropic RNA or DNA viruses interact with specific vascular endothelial cell receptors before to be translated in the endomyocardial target cells to produce viral proteins (Huber, 1993; Li et al., 2000) (Table 1). Mechanisms of viral entry into the host cell remains crucial and are of major interest because each of them is putative target for novel therapeutics. Before to interact specifically with the virus, expression of levels of the virus receptors for CVB3, PVB19, HVV6 (CAR/DAF, P-Antigen/ Alpha5-beta1 integrin and CD46, respectively) on endovascular endothelial cells of coronary vessels modulate the diffusion of these viral agents into the vessels and their subsequent translation into the endomyocardial target cells (Khül et al., 2005a; Yajima & Knowlton, 2009). Some inflammatory mechanisms as a primary persistent infection by HHV6 or PVB19 may modulate cell membrane receptors and /or immune suppression and preventing virus clearance; altogether these mechanisms could facilitate an endomyocardial super infection by a second viral agent as described in 27 % of virus positive DCM patients (Khül et al.,

**CTL**

**NK cells**

**Perforine**

**NO, NO.**

Fig. 1. Immunopathological phases of viral myocarditis.

**3.1 Acute myocarditis during the initial Virus invasion** 

**Dendritic cells**

**B lymphocytes**

**Neutralizing antibodies + antimyosin antibodies**

Yajima & Knowlton, 2009) (Figure 1).

**Myocyte lysis Macrophages activation**

**Cytokines** •**IL-1** •**IL-2** •**TNFs** •**INFs**

**Acute myocarditis**

**Viral antigens Cellular antigens**

2005a) (Table 1).

**Viral infection**
