**2. Viral replication as the central regulator of viral myocarditis**

The advent of virus replication in the heart of an individual is thought to occur secondarily to a more general and systemic virus infection (Carthy et al., 1997; Mena et al., 2000; Vuorinen et al., 1994), the spleen, gut, pancreas and lymph nodes are often infected; patients often report malaise, fatigue and more general 'flu-like' symptoms about 1- 2 weeks prior to chest pains and cardiac rhythm disturbances. Immune infiltration in the heart has taken hold by the time the patient has been seen by a physician and any evidence of direct virusinduced damage has been superseded by T cell invasion at the foci of infection. It is not surprising that there have been many reports that claim the predominant source of damage is immune infiltration of the myocardium, as inflammation is what defines this disease. Autoimmune etiologies due to an antiviral response gone awry have been proposed as one of the major causes of pathology (Lv et al., 2011). Regardless, there are numerous publications that suggest a large amount of damage is inflicted by the virus itself, in the murine model, early post-infection, that is correlated with the number of myocarditic lesions spatially coincident with positivity by *in situ* hybridization for CVB3 genome (Cheung et al., 2008; Chow et al., 1992; Marchant et al., 2009a; McManus et al., 1993). These observations are supported by findings in autopsy cases, particularly in infants (Iwasaki et al., 1985a; Iwasaki et al., 1985b).
