Impaired Cardiac Function in Viral Myocarditis

IntroductionViral 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 transplantation.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 management protocol (Baughman, 2006).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 assembly, and complete with viral progeny release. www.intechopen.comMyocarditis 294 CVB3 infection of myocarditis susceptible mice results in severe heart failure.The disease progression of viral myocarditis in the experimental infection model can be classified into three phases: acute (viremia), subacute (inflammatory), and chronic (remodeling) phases.The acute (viremia) phase is signified by active viral replication and direct virus-induced cardiomyocyte damage.The subacute (inflammatory) phase is characterized by the infiltration of immune cells that helps viral clearance but nonetheless adds to myocardial damage.The chronic (remodeling) phase is featured by the continual efforts of the impaired heart to meet the hemodynamic demand by remodeling the myocardium.Cardiac hypertrophy is triggered during remodeling to compensate for reduced contractile function due to myocyte loss and interstitial fibrosis in the earlier phases.However, such an adaption is unsustainable in the longer term in face of increasingly hostile environments, i.e. reduced blood supply and increased reactive oxidative stress, thus leading to cardiomyocyte death and triggering further inflammation and fibrosis.The pathological remodeling process eventually leads to DCM and heart failure.This book chapter focuses on the virus-host protein interactions in cardiomyocytes during viral myocarditis.We discuss the role of virus-induced protein cleavage and dysregulation of the host protein degradation systems in the pathogenesis of viral myocarditis and its subsequent progression to DCM. Host protein cleavages by coxsackieviral proteases contributing to cardiac dysfunction2.1 Viral proteases and dilated cardiomyopathy CVB3 encodes two viral proteases, 2A and 3C, both of which are cysteine proteases that have chymotrypsin-like activity and play critical roles in successful viral replication (Chau et al., 2007).First, the viral proteases are required to process the large viral polyprotein, a product of mono-cistronic translation of RNA genome, into the individual functional, structural and non-structural proteins.Second, the viral proteases facilitate viral replication by cleaving a number of host proteins that are involved in various cell functions such as transcription, translation, cell signaling, and cellular structure.Viral myocarditis is originally thought to be an immune response driven disorder.The initial observation that established the importance of direct virus-mediated myocardial damage in the pathogenesis of viral myocarditis was made in severe combined immunodeficient (SCID) mice, which lack functional T and B lymphocytes and yet developed early and severe myocyte damage upon enterovirus challenge (McManus et al., 1993).The significance of viral proteins in the development of viral myocarditis and DCM was further explored by Dr. Knowlton's research group.First, they showed that the cardiacspecific expression of a replication-restricted CVB3 mutant genome in transgenic mice, which only allows the expression of viral proteins without generating viral progenies and subsequent immune response, results in DCM phenotype (Wessely et al., 1998).Then, they demonstrated that mice with cardiac-restricted expression of viral protease 2A display a severe DCM phenotype (Xiong et al., 2007).These findings suggest that viral proteases play an important role in the development of viral-induced dilated cardiomyopathy. Cleavage of dystrophin during CVB3 infection may contribute to dilated cardiomyopathyThe observation that mouse cardiac expression of viral protease 2A induces DCM has been explained based on the landmark finding that dystrophin, which links the cytoskeleton to www.intechopen.com

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