**3. A combined theory that could explain the pathogenic mechanism in chronic chagasic myocarditis**

With the perpetuation of inflammation, necrosis and scarring fibrosis, damage to all histological components of myocardium occurs. Damage to contracting myocardial fibers

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

Although proinflammatory cytokines seem to be necessary for controlling parasitemia during acute phase of the disease (Cunha-Neto E., et al., 2009), CCC patients display a rather proinflammatory cytokine while indeterminate patients display a down modulator one. CCC patients had higher levels of TNF- and CCL2 than indeterminate patients (Ferreira, et al., 2003, Talvani A., et al., 2004). Infiltrating macrophages from CCC patients expressed INF-, TNF- and IL-6 but showed low levels of IL-2, IL-4 and IL-10 (Abel, et al., 2001, Reis D. D., et al., 1993, Reis M. M., et al., 1997). Also CCR5, CXCR3 and CCR7 and their ligands were increased in hearts of CCC patients, as well as monocytes expressing CXCR3, CCR5, CXCL9 and CCL5 (Cunha-Neto E., et al., 2009). It has been shown that INF- and CCL2 induceed myocytes to secrete arial natriuretic factor and caused hypertrophy (Cunha-Neto E., et al., 2005), and IL-18 and CCR7 ligands, which are increased in CCC, caused cardiomyocyte hypertrophy and fibrosis (Reddy, et al., 2008, Riol-Blanco, et al., 2005, Sakai,

Fibrosis is one of the most striking characteristics of CCC. In our patients with CCC in endomyocardial biopsies, fibrosis had replaced between 8.2 and 49% of contractile myocardium, with only one patient having less than 10% (Milei, et al., 1992b). While in autopsies, fibrosis was more extensive reaching in the conduction system than in the

The deposition of laminin in extracellular and basement membranes has been implicated in the pathogenesis of inflammatory process, as laminin is able to bind proinflammatory citokines (Savino, et al., 2007). The inflammatory infiltrate in CCC was related to the production of citokines such as INF-, TNF-, IL-18, CCL2 and CCL21, that may have

With the perpetuation of inflammation, necrosis and scarring fibrosis, damage to all histological components of myocardium occurs. Damage to contracting myocardial fibers

contracting myocardium (51.5 ± 18% vs 43.4 ± 8%, p < 0.05) (Milei, et al., 1996a).

**3. A combined theory that could explain the pathogenic mechanism in** 

modulator actions on fibrotic process (Cunha-Neto E., et al., 2009).

Gene **Polymorphism** 

IL-1B - 31, + 3954, + 5810

CCL2/MCPI - 2518 CCR5 + 53029 TNF- - 308 LTA + 80, + 252 BAT-1 - 22, - 348 NFkBIL-1 - 62, - 262

IL-10 - 1082 IL-12B + 1188 MAL/TRIAP S180L

**2.2.5 The cytokines and chemokines** 

**2.3 The third ingredient: fibrosis** 

**chronic chagasic myocarditis** 

et al., 2006).

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 in the pathogenesis of CCC.

Fig. 3. Schematic representation of the integrated theory of multiple factors that determine myocardial damage in CCC.
