Contributing Role of Viruses

The inflammatory/infective theory does not exclude genetic aspects, although viral infections occur more rarely in familial cases. Myocarditis was found in members of the same family with ARVC/D leading to the hypothesis of genetic predisposition to viral infection (Table 9.3) [16, 56-58]. A more complete comprehension of disease pathogenesis can only be drawn if both genetic and environmental factors are considered. In this genome-environment interaction, viral infections may play a primary or secondary role, both crucial conditions for the development and progression of the disease.

Primary Role

Many DNA and RNA viruses, following infection, can cause genetic alterations in somatic genes. These genetic alterations, referred to as mutations, may include deletions, chromosomal translocations, inversions, or point mutations. These genomic modifications could occur during viral integration to the host genome or play a role during subsequent steps of viral replication [59, 60].

These aspects are well known in the study of neoplastic disorders. Many oncogenic viruses are able to cause genetic alteration responsible for structural cellular changes promoting malignant transformation. Among structural proteins, cellular junctions are frequently altered during viral infections. The alteration of structural junction proteins after viral infection is one of the first and principal mechanisms responsible for virus-induced cell dysfunction and viral immortalization.

Thus, viral infections could play a primary contributing role in the acquired forms of ARVC/D, affecting the desmosome primarily by direct disruption.

Secondary Role

Genome-environment interaction is the basis of many complex disorders. In the setting of cardiovascular diseases, DCM represents a typical example [43-49, 61]. Recent research suggests that car-diotropic viruses are important environmental factors in the pathogenesis of "idiopathic" cases and that DCM more frequently results from interactions between genetic and environmental factors, whereas

"pure" genetic forms may be uncommon. Genetic background could influence viral interaction at different levels: virus uptake, migration, and antiviral immunity. In other words, genetic defects of different types could be responsible for increased individual viral susceptibility (Fig. 9.4).

The majority of known cardiotropic viruses are taken up into the cell by receptor-mediated endocy-tosis and then further transported into the nucleus. The expression of viral receptors on target cells favor virus entry and migration. Overexpression of a common receptor for both coxsackievirus and aden-ovirus was detected in human DCM but not in other cardiomyopathies [62, 63] and is believed to potentially influence the pathogenesis of DCM.

Genetic abnormalities of immune pathways can also significantly alter the disease course in viral infection. Mice are protected from coxsackievirus B3 myocarditis by gene-targeted knockout of p56Lck, the Src family kinase essential for T-cell activation

Fig. 9.4 • Diagrams showing possible pathogenetic role of viral infection on genetic substrate:(a) contributing role primary, (b) contributing role secondary

[64]. On the other hand, coxsackievirus B3 infection ofINF-P deficient mice results in higher mortality as compared to controls [65].

Genetically altered structural proteins of car-diomyocytes could favor viral infection and could themselves represent a target for the viruses, which then cause a progression of the disease. Experimental studies have demonstrated the extent to which such mutations may aggravate the cardiac damage caused by the virus. Coxsackievirus B3 infection, for example, has been shown to grossly decrease cardiac function in dystrophin-deficient mice via enteroviral protease 2A-mediated cleavage of dystrophin [55, 66].

In complex genetic disorders with heterogenecity of phenotypes, a comprehensive picture of the pathogenesis can only be drawn if both genetic and environmental factors are considered. Broadened understanding of the pathogenesis may crucially modify the clinical risk assessment and treatment of these patients.

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