**2.2.4 Genetic factors**

Human leukocyte antigens (HLA) have shown some relation to the development of CCC. HLA-B40 and Cw3 combination was protective for CCC (Llop, et al., 1991), as resulted DRB1\*14, DQB1\*0303 (Fernandez-Mestre, et al., 1998), HLA-DQB1\*06 (Deghaide, et al., 1998) and HLA-A68 (Cruz-Robles, et al., 2004). On the other hand, HLA-C\*03 (Layrisse, et al., 2000), DRB1\*1503 (Garcia Borras, et al., 2009), DRB1\*01, DRB1\*08, DQB1\*0501 (Fernandez-Mestre, et al., 1998) and HLA-DR16 alelles (Cruz-Robles, et al., 2004) were positively related to the development of CCC.

A number of other genes related to immune system have been studied in order to determine their relation to a predisposition to develop CCC. In table 3 we list those positively related to the appearance of CCC (Cunha-Neto E., et al., 2009).

Pathogenesis and Pathology of Chagas' Chronic Myocarditis 131

determines contractile failure as well as electrophysiological disturbances. Conduction system, nervous autonomic system and microvasculature are also damaged and as a consequence they cause further damage to contractile myocardium and produce electrical instability. Figure 3 illustrates with a flow chart the interactive network of different elements

Fig. 3. Schematic representation of the integrated theory of multiple factors that determine

As early as 1922 Carlos Chagas noted that the chronotropic response to atropine was altered in chagasic patients (Chagas C. & Vilella, 1922), but it was not until late 1950's that Köberle published his works showing impressive neuronal depopulation in microscopic sections obtained from the intercaval atrial strip in chagasic patients using a standardized technique of cardiac intramural neuronal counting developed by himself (Köberle, 1956a, 1956b). These findings led to the "neurogenic hypothesis" (Köberle, 1959), which explained all

Although many other authors claimed to have confirmed this finding (Mott & Hagstrom, 1965, Oliveira J. S., 1985), other authors called to attention about the criteria used to diagnose neuronal depletion because of the great variability in the number of neurons in autonomic ganglia (Rossi L., et al., 1994) and they also remarked that the only right criterion to establish neuronal depletion is the presence of proliferation of satellite cells, with the formation of Terplan's nodules, a characteristic lesion described as proliferating satellite cells which replace degenerating neurons, forming nodular structures. These lesions, once considered patognomonic, can be found in other cardiomyopathies (Rossi L., et al., 1994). The same author could not confirm the loss of neurons or denervation in CCC (Rossi L., 1988). Finally, it was demonstrated that, using Terplan's nodules as diagnostic criterion,

**4. Pathophysiological consequences of organ damage** 

megas in Chagas' disease as a consequence of neuronal depletion.

in the pathogenesis of CCC.

myocardial damage in CCC.

**4.1 Dysautonomia** 


Table 3. Genetic polymorphisms related to CCC. Adapted from (Cunha-Neto E., et al., 2009).
