**2. Clinical course of myocarditis**

Myocarditis is defined as a heterogeneous common disease pathway for myocardial inflammation resulting from a variety of infectious, immune and non-immune insults. The histopathologic hallmark of the disease is characterized by inflammatory infiltrates of the myocardium with concomitant necrosis or degeneration of adjacent cardiomyocytes in the absence of predominant ischemia. Despite this clear definition, the classification and diagnosis of myocarditis continue to present clinical problems. In recent years our understanding of the pathophysiology and natural clinical course of the disease has improved, probably because histological findings obtained from endomyocardial biopsies have routinely been combined with modern molecular biological and immunological tools in the detection of viral genomes persisting in the heart (Heidecker et al., 2011).

From epidemiological studies, it is known that viruses are the most frequent cause of myocarditis in Europe and North America although in rare cases bacteria, protozoa, and even fungi have also been implicated as infectious agents (Ellis and Di Salvo, 2007). Among the more common cardiotropic viruses are enteroviruses including Coxsackie virus, adenoviruses, parvovirus B19, hepatitis C virus, and human immunodeficiency virus (Kühl et al., 2005; Magnani and Dec, 2006; Mahrholdt et al., 2006; Noutsias et al., 2009; Rose, 2009; Pankuweit and Maisch, 2010). Other non-infectious etiologies of myocardial inflammation include hypersensitivity reactions against drugs, unexplained toxic reactions, and immunological syndromes including Churg-Strauss syndrome, giant cell myocarditis, systemic lupus erythematosus, sarcoidosis, Wegener´s granulomatosis, and others (Magnani and Dec, 2006; Ellis and Di Salvo, 2007; Rose, 2009). Although infections with cardiotropic viruses are believed to be the most common cause of acute lymphocytic myocarditis, a large number of patients have no identifiable source of the illness (Liu and Mason, 2001; Rose, 2009). Particularly, when the inflammatory process in the myocardium is moderate, the diagnosis frequently remains a challenge for clinicians. The diagnostic sensitivity for viral

establishing an anti-viral state and influencing the activation of various immune cells. These potent anti-viral cytokines are best known for their role as innate immune mediators (Yajima and Knowlton, 2009). In the course of viral myocarditis, apoptotic signalling pathways are activated and modulate disease pathogenesis. However, cardiotropic viruses have evolved a battery of highly specific strategies to circumvent this innate protective response of the host and successfully replicate in cardiomyocytes (Versteeg and García-Sastre, 2010). Viral factors with or without homology to host proteins specifically target key components of the anti-viral defense machinery, some of which are transcription factors

In the present review we focus on the contribution of pattern-recognition receptors engaged in the early response cascade against cardiotropic viruses. In particular, we report on different signal transduction pathways emerging from membrane-associated and cytosolic receptors that inhibit viral dissemination and, furthermore, give a brief overview of the various adaptor molecules involved in these pathways. Not covered in this review are the diverse viral mechanisms for antagonizing the innate immune response and the precise cellular actions of cytokines in executing this anti-viral defense. Understanding the exact mechanisms by which viral components activate pattern-recognition receptors in the heart and modify gene expression profiles may help to improve novel therapeutic regimes for the

Myocarditis is defined as a heterogeneous common disease pathway for myocardial inflammation resulting from a variety of infectious, immune and non-immune insults. The histopathologic hallmark of the disease is characterized by inflammatory infiltrates of the myocardium with concomitant necrosis or degeneration of adjacent cardiomyocytes in the absence of predominant ischemia. Despite this clear definition, the classification and diagnosis of myocarditis continue to present clinical problems. In recent years our understanding of the pathophysiology and natural clinical course of the disease has improved, probably because histological findings obtained from endomyocardial biopsies have routinely been combined with modern molecular biological and immunological tools

From epidemiological studies, it is known that viruses are the most frequent cause of myocarditis in Europe and North America although in rare cases bacteria, protozoa, and even fungi have also been implicated as infectious agents (Ellis and Di Salvo, 2007). Among the more common cardiotropic viruses are enteroviruses including Coxsackie virus, adenoviruses, parvovirus B19, hepatitis C virus, and human immunodeficiency virus (Kühl et al., 2005; Magnani and Dec, 2006; Mahrholdt et al., 2006; Noutsias et al., 2009; Rose, 2009; Pankuweit and Maisch, 2010). Other non-infectious etiologies of myocardial inflammation include hypersensitivity reactions against drugs, unexplained toxic reactions, and immunological syndromes including Churg-Strauss syndrome, giant cell myocarditis, systemic lupus erythematosus, sarcoidosis, Wegener´s granulomatosis, and others (Magnani and Dec, 2006; Ellis and Di Salvo, 2007; Rose, 2009). Although infections with cardiotropic viruses are believed to be the most common cause of acute lymphocytic myocarditis, a large number of patients have no identifiable source of the illness (Liu and Mason, 2001; Rose, 2009). Particularly, when the inflammatory process in the myocardium is moderate, the diagnosis frequently remains a challenge for clinicians. The diagnostic sensitivity for viral

in the detection of viral genomes persisting in the heart (Heidecker et al., 2011).

involved in establishing an anti-viral state.

treatment of viral myocarditis (Topkara et al., 2010).

**2. Clinical course of myocarditis** 

myocarditis is comparably low, even when applying modern molecular biological techniques, probably because, due to sampling error, the diagnostic accuracy of endomyocardial biopsy remains a significant limitation (Magnani and Dec, 2006; Ellis and Di Salvo, 2007). The Dallas criteria, originally proposed in an effort to standardize the histopathologic diagnosis of myocarditis, have been shown to be of limited use for epidemiological investigations (Magnani and Dec, 2006; Ellis and Di Salvo, 2007). Thus, despite recent advances in the recognition of myocardial inflammation, the true incidence and prevalence of acute viral myocarditis is still unknown.

The spectrum of clinical manifestations of viral myocarditis is extensive, ranging from asymptomatic infection to fever, myalgias, palpitations, exertional dyspnea, and hemodynamic collapse. Fulminant myocarditis may lead to systolic failure, malignant ventricular arrhythmias and sudden cardiac death (Baughman, 2005; Magnani and Dec, 2006; Rose, 2009, Blauwet and Cooper, 2010). The cardiac symptoms may also be present in more chronic forms of DCM, therefore contributing much to the difficulties in establishing the correct diagnosis. The main reason for the clinical variability appears to lie in the characteristics of the viral agent, together with the host´s innate immune system and genetic susceptibility to infection. Given the diversity and insidious onset of clinical manifestations, endomyocardial biopsy in combination with other techniques such as immunohistochemistry, serological analyses, PCR and *in situ* hydridization remains the gold standard for the detection of virus-induced myocardial inflammation (Magnani and Dec, 2006; Rose, 2009).

Although, in severely affected individuals, fulminant viral myocarditis can lead to rapid progressive heart failure, the disease usually resolves spontaneously without persisting ventricular dysfunction (Baughman, 2005; Magnani and Dec, 2006; Rose, 2009, Blauwet and Cooper, 2010). Continuing cardiovascular symptoms in the absence of ventricular compromise may indicate that chronic persistent myocarditis has developed, which is characterized by the maintenance of lymphocytic infiltrates combined with foci of myocyte necrosis. Whereas it has been well-established that chronic active myocarditis can induce heart failure, there is still a controversy with respect to the causal relationship of asymptomatic viral infections for the pathogenesis of idiopathic DCM (Yajima and Knowlton, 2009). Several studies have suggested an association between viral persistence in the myocardium and the development of DCM. However, the etiologic significance of viral genomes detected in endomyocardial biopsies from DCM patients is currently unknown (Bock et al., 2010).
