Pathogenesis Virus and Myocyte Death

Over the past two decades, the use of molecular-based studies have enabled viral genomes to be analyzed in the hearts of human subjects with cardiac dysfunction. Bowles and colleagues were the first to identify coxsackievirus in myocardial specimens of patients with myocarditis and dilated cardiomyopathy (DCM) using molecular techniques [42,43]. Towbin and colleagues later showed the high incidence of adenovirus in myocarditis and DCM [44-48] as well as par-

Fig. 9.2 • Viral genomes frequency in 36 endomyocardial biopsies from clinical and histological proven ARVC/D cases. Viral positivity was found in 7 (19%) of 36 cases vovirus B19 [49]. Viruses cause myocyte damage either by direct cytopathic effects or indirectly by immune-mediated mechanisms. Apoptosis is the principal type of cell death involved in the progressive myocyte loss of ARVC/D and evidence supporting this view has been collected both at autopsy [19] and from biopsy material [20]. The biochemical mechanisms involved in the high rate of apoptosis observed in ARVC/D are poorly understood. Overexpression of caspase CPP32, a cysteine protease required for apoptosis, has been observed in the RV of ARVC/D patients [1]. Interestingly, the presence of apoptosis was found in the early and acute symptomatic phase of the disease [20]. Apoptosis is involved in the pathogenesis of several viral infections in a dual fashion, as viruses have both apoptosis-inducing and apoptosis-sup-pressing functions during their replication in host cells [50]. Myocardial apoptosis might be directly associated with the viral presence or be mediated by inflammation (i.e., activation of the Fas receptor pathway, release of apoptotic cytokines) [51]. Perforin, granzyme B, or other cytotoxic-T-related products can, by themselves or by activating effector caspases, induce apoptosis [52]. Perforin-containing cells have been detected in the myocardium after coxsackievirus infection [53] and circumstantial evidence has indicated that perforin is involved in coxsackievirus-in-duced myocarditis [54].

Cytotoxic T lymphocytes have been frequently observed in samples from patients with ARVC/D and the association of this lymphocyte subset with apop-totic myocyte is a frequent event (Fig. 9.3).

Although apoptotic myocyte death is believed by many to be the main mechanism of myocardial loss, the association of necrotic cell death cannot be excluded. Enteroviral protease 2A directly cleaves human dystrophin in the hinge 3 region of this large cy-toskeletal protein, leading to functional dystrophin impairment and loss of sarcolemmal integrity [55].

Table 9.3 • Familial ARVC/D and myocarditis

Arvc Myocytes Apoptose

Table 9.3 • Familial ARVC/D and myocarditis

Fig.9.3 • Endomyocardial biopsy from patient with ARVC/D. Double staining showing a strict relation of CD8 T lymphocyte (cytoplasm marked in brown) and apoptotic myocytes (marked in blue) TUNEL/IHC for CD8, original magnification, x100

Author

N. patients

Sabel et al., 1990 [56]

2

Hisaoka et al.,1990 [57]

2

Pinamonti et al., 1996 [16]

2

D'Amati et al., 1998 [58]

2

Fig.9.3 • Endomyocardial biopsy from patient with ARVC/D. Double staining showing a strict relation of CD8 T lymphocyte (cytoplasm marked in brown) and apoptotic myocytes (marked in blue) TUNEL/IHC for CD8, original magnification, x100

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