**6. References**

284 Myocarditis

**4.2 Proposing novel therapeutic targets for viral myocarditis through systems biology** 

As we have already discussed, cardio-tropic viruses like CVB3 can directly and indirectly further the progression of viral myocarditis to heart failure [(McManus et al., 1993) reviewed in (Marchant et al., 2008)]. To date, there is no curative treatment beyond heart transplantation for viral myocarditis-associated heart failure. Therapies that have been used in patients with myocarditis are immune serum globulin and pleconaril (Pevear et al., 1986; Rotbart, 1999). The anti-picornaviral agent, pleconaril perturbs viral uncoating and in turn blocks viral attachment to host cell receptors. Although, directly targeting viruses has been successful in controlling viral diseases, it suffers from some serious weaknesses, including failure to eliminate chronic viral myocarditis, narrow spectrum of action, and the inherent capacity to force outgrowth of drug resistance mutations (Tan et al., 2007). Thus, the discovery of novel antiviral targets, host cell-based antiviral agents is a more promising

At the cellular level, studies have shown that host cell phospho-proteins essential for viral replication, are potentially targetable [(Marchant 2009) reviewed in (Marchant et al., 2008)]. It is known, however, that phospho-protein networks embrace a system that contains redundant, convergent and even distinct signaling pathways (Borisy et al., 2003). Such combinative properties of signaling networks may counteract the therapeutic efficacy of highly selective drugs due to signalling pathway redundancy. Thus, combination therapy may be necessary to achieve efficacy due to less treatment resistance (Fitzgerald et al., 2006). However, motivation for this initiative, therapeutic synergy of a combination is tempered by concerns about introducing synergistic side effects. Nevertheless, an *in vivo* study that has emerged from recent studies of the healing process in a rat asthma model showed that

Together, to propose novel and promising drugs and therapies requires us to understand network mechanisms at the cellular, tissue and organism level. Using high-throughput technologies in genomics, proteomics, phosphoproteomics, metabolomics and lipidomics, we can develop interactome network models, in that these models ultimately translate to network analysis and data-driven questions in a specific disease context, that can be used to analyse a broad range of different states and disease contexts. There have been recent reports that used systems biology analysis tools in an attempt to untangle the web of kinase signalling pathways that are activated during CVB3 infection of cardiomyocytes (Garmaroudi et al., 2010). There is a current unclaimed niche of research that exists to use similar systems biology tools to analyse the pathways of cell death in order to better understand not only the dominant pathways of virus induced cell death but to also characterise the type of cell death that causes necrotic rupture of infected cells. To perturb specific molecules or biological processes in a combination as directed by network models

In every facet of CVB3 replication there are a large number of pathways and proteins involved, forming a large network of pathways and complexity too large to analyse by conventional means. The large number of death pathways activated by CVB3 may not all be required to mediate lysis of the infected host cell. The question still remains as to whether there are pathways activated as a matter of coincidence or whether death pathways are all

**analysis of host cell signal-transduction networks** 

approach and deserves more attention (Saladino et al., 2010).

combining drugs performed better than single ones (Lehar et al., 2009).

can be a capable strategy to treat complex diseases.

**5. Conclusion** 


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**14** 

*Canada* 

Jerry Wong and Honglin Luo

*University of British Columbia, Vancouver, BC,* 

**Impaired Cardiac Function in Viral Myocarditis** 

Viral myocarditis, the inflammation of the myocardium caused by viral infection, is an important cause of dilated cardiomyopathy (DCM) – a major cause of morbidity and mortality worldwide (Mason, 2003; Esfandiarei & McManus, 2008; Cooper, 2009). In North America, viral myocarditis and DCM together account for 20% of the sudden deaths and heart failure in children and adolescents (Okuni *et al.*, 1975; Drory *et al.*, 1991). To date, there is no effective therapeutic against these diseases. Patients diagnosed with late stage DCM are limited to supportive treatments such as ventricular assist device implantation and heart

The clinical presentation of viral myocarditis comes in various severities. Most people have contracted and subsequently recovered from multiple viral infections of the heart without overt symptoms. Yet, retrospective studies revealed that ~20% of subclinical cases later develop congestive heart failure. In addition, some may experience acute fulminant viral myocarditis or persistent chronic myocarditis symptoms. About one-third of these patients with viral myocarditis subsequently develop DCM (Esfandiarei & McManus, 2008). A combination of new diagnostic technologies for viral myocarditis such as cardiovascular magnetic resonance techniques with conventional diagnostics including clinical presentation, histopathological examination, cardiac antibody assessment, and viral polymerase chain reaction (PCR), now helps better define disease stage and its respective

The presence of viral genome in the myocardium is associated with significantly worse outcome over two years (Why *et al.*, 1994). Analysis of human failing hearts by PCR unveiled trails of previous viral infection. The identified viruses include enterovirus, adenovirus, parvovirus B19, herpes simplex virus 6, cytomegalovirus, hepatitis C virus, and human immunodeficiency virus, which are clinically associated with viral myocarditis (Grist & Reid, 1997; Calabrese *et al.*, 2010). Among them, coxsackievirus B3 (CVB3), an enterovirus in the picornavirus family, is highly implicated in clinical cases of viral myocarditis, particularly in neonates and young children, and is the most thoroughly studied causative agent in experimental viral myocarditis models (Froeschle *et al.*, 1966; Abelmann, 1971; Reyes & Lerner, 1985; McManus *et al.*, 1988). CVB3 replicates rapidly in short infection cycles that begin with viral receptor engagement and subsequent internalization, followed by translation of viral RNA, amplification of viral genome, viral

**1. Introduction** 

transplantation.

management protocol (Baughman, 2006).

assembly, and complete with viral progeny release.

*James Hogg ResearchCenter, Providence Heart and Lung Institute,* 

*St. Paul's Hospital and Department of Pathology and Laboratory Medicine,* 

