**1. Introduction**

118 Myocarditis

[62] Soler-Soler J, Sagristà-Sauleda J, Permanyer-Miralda G. Relapsing pericarditis.

[63] Imazio M, Cecchi E, Demichelis B, Ierna S, Demarie D, Ghisio A, Pomari F, Coda L, Belli

R, Trinchero R. . Indicators of poor prognosis of acute pericarditis. Circulation. 2007

Heart. 2004 Nov;90(11):1364-8.

May 29;115(21):2739-44.

Chronic chagasic cardiomyopathy (CCC) is the most serious manifestation of the chronic phase of Chagas' disease and constitutes the most common type of chronic myocarditis in the world (Guerri-Guttenberg, et al., 2008, Milei, et al., 1996a, Milei, et al., 2009, Milei, et al., 1992a, Storino, et al., 1992). Chagas' disease, a chronic illness caused by the flagellate parasite *Trypanosoma cruzi* (*T. cruzi*), was first described in 1909 by the Brazilian physician Carlos Chagas (Chagas C, 1909). The insect vectors of the disease are present throughout most of South and Central America, and their zone of distribution extends across the southern United States (Rassi, et al., 2010). It was estimated by year 2000, that in endemic areas 40 million people were considered to be at risk of infection, being 20 million already infected. Every year near 200,000 new cases are expected to happen, and 21,000 deaths per year occur (WHO, 2005).

Although always considered to be confined to Latin America, due to migratory movements from endemic countries to Europe and North America, Chagas' disease is being detected more frequently in developed countries. Europe is estimated to have from 24,001 to 38,708 (lower or upper limit of estimate, respectively) immigrants with *T. cruzi* infection (Guerri-Guttenberg, et al., 2008). In the United States, six autochthonous cases, five transfusion related cases and five transplant related cases have been reported, but migratory movements still remain the main source of Chagas' disease. It has been estimated that around 89,221 to 693,302 infected Latin Americans migrated to the United States in the period 1981 to 2005 (Milei, et al., 2009).

Two phases of the disease can be distinguished: (1) acute phase, with transiently high concentration of parasites in tissue and blood, nonspecific symptoms, and a 5% myocarditis incidence, lasting 4 – 8 weeks; and (2) chronic phase, lasting lifelong. Chronic phase can be presented as indeterminate form, characterized by lack of symptoms and normal ECG and normal radiographic examination of the chest, esophagus and colon. Approximately 60 – 70% of patients remain in this form for the rest of their lives. Only 20-40% of infected individuals, 10-30 years after the original acute infection, will develop cardiac, digestive or mixed form of the disease, characterized by the appearance of megavicera (dilated cardiomyopathy, megaesophagus and/or megacolon). It poses a substantial public health burden due to high morbidity and mortality (Milei, et al., 2009, Rassi, et al., 2000, Rassi, et al., 2010).

Pathogenesis and Pathology of Chagas' Chronic Myocarditis 121

it excretes trypomastigotes with feces, which in turn reach blood torrent through bug's wound. Trypomastigotes can infect a wide variety of host cells, within them it differentiate into amastigotes and proliferate. Then, they can differentiate into trypomastigotes again, reach circulation and infect new cells. If an uninfected bug feeds from the animal in the

**2.1.2 Genetic variability of** *Trypanosoma cruzi* **and its relation to its pathogenesis**  The genetics of *T. cruzi* caught the attention of researchers in late 80' and early 90'. First studies on variability were performed analyzing electrophoretic variants on cellular enzymes. The groups resulting were called zymodemes and were named Z1, Z2, Z3. Only

The development of PCR based techniques, allowed the study of new variant regions and the characterization of multiple variants of a great number of genes. All these variants showed significant correlation with each other, suggesting the existence of two subtypes of *T. cruzi* based on these data (Macedo, et al., 2004). Moreover, *T. cruzi II* which is clearly linked to human pathology, being *T. cruzi I* mainly related to infection of wild sylvatic mammals. Even, applying LSSP-PCR to the study of the variable region of kinetoplast minicircle from *T. cruzi* provided evidence of a differential tissue distribution of genetically diverse *T. cruzi* populations in chronic Chagas' disease, suggesting that the genetic variability of the parasite is one of the determining factors of the clinical form of the disease

moment of parasitemia, cycle starts again (Tyler & Engman, 2001).

Fig. 1. Life cycle of *Trypanosoma cruzi.* 

(Vago, et al., 2000).

Z2 was associated with domestic transmission cycle.

CCC is manifested by a chronic, diffuse, progressive fibrosing myocarditis that involves not only the working myocardium but also the atrioventricular (AV) conduction system, autonomic nervous system and microcirculation (Andrade, 1985, Marin-Neto, et al., 2007, Milei, et al., 1991b). This leads to cardiomegaly, cardiac failure, arrhythmias, thromboembolism, and death (Milei, et al., 1991b). Colon and esophagus are also commonly affected by Chagas' disease, being megacolon with constipation and megaesofagus with achalasia also features of the disease (Rassi, et al., 2010).
