**5.1 Gastronitestinal form of Chagas disease**

The gastrointestinal form of Chagas disease affects the whole digestive tract, with the esophagus and colon being the most altered. They present anatomic and motor disturbances as a result of chronic inflammatory lesions, focal myositis, fibrosis, and damage to intramural neurons [44], which in the esophagus could lead to dysphagia, odynophagia, epigastric or retrosternal pain, cough, and regurgitation. In advanced stages, the denervated esophagus is unable to transport the bolus, retaining it at the level of the cardia, which can cause weight loss, malnutrition, and repetitive aspiration pneumonitis [46]. On the other hand, the megacolon is characterized by prolonged constipation that could lead to fecaloma, abdominal distension, and intestinal obstruction. Despite treatment with laxatives, patients worsen and may suffer from volvulus due to intestine torsion [45, 47].

*Modulation of Host Cell Apoptosis by* Trypanosoma cruzi*: Repercussions in the Development… DOI: http://dx.doi.org/10.5772/intechopen.103740*

## **5.2 Chagasic chronic cardiomyopathy**

The chronic chagasic cardiomyopathy is the most critical clinical manifestation of Chagas disease due to its high morbidity and mortality in endemic regions [48, 49]. It is characterized by a complex pathogenesis, and many aspects are still under investigation. The causes for the colossal cardiac damage experienced by CCC patients have not been thoroughly explained, and different theories have been exposed throughout the years. It was previously thought that the cardiac damage was only caused by the direct action of the parasite over cardiomyocytes; however, it is now known that there are other contributing factors such as inflammatory response, autoimmunity, microvascular abnormalities, and nervous damage [50]. The cardiac tissue damage is progressive and characterized by chronic inflammation, myocytolysis, and fibrosis [51]. A recent study revealed that during a *T. cruzi* infection, activated macrophages release the metalloproteinases MMP2 and MMP9 that activate TGF-β signaling for cardiac extracellular remodeling and thus fibroblast differentiation to myofibroblasts that is a cellular phenotype present during damage and possesses characteristics that make it suitable for healing functions [51].

The most critical heart lesions are located in the myocardium and can lead to heart failure, arrhythmias, and thromboembolism. The heart excite-conducting system is also affected, blocking completely or incompletely some of the branches of the bundle of His (mainly the right) and sometimes a complete blockade of the atrioventricular node [50, 52].

The number of parasites in the cardiac tissue of CCC patients is scarce. This, together with the finding of immunoglobulins with affinity to muscarinic receptors and β-1 adrenergic expressed in the cardiomyocyte surface and the appearance of cytotoxic T lymphocytes with reactivity toward myocardial fibers, suggested that the etiology of CCC was autoimmune [53–57]. Investigations performed during the last 30 years in animal models infected with *T. cruzi* and patients with Chagas disease have modified this theory. Nowadays it is known that the amount of *T. cruzi* antigens correlates with the intensity of the inflammatory infiltrate that acts against the parasites that reside in the tissue [58]. Such infiltrate is mainly composed of macrophages and CD8+ and CD4+ T lymphocytes (2:1 ratio) that show a Th1 cytokine profile (TNF-α, IFN-γ, IL-1, IL-2) [59–61]. At first, this Th1 response protects the host, but its exacerbation produces diffuse myocarditis that over time causes myocytolysis and reparative fibrosis with interstitial deposition of collagen fibers, whose progression is directly correlated with cardiac dilatation and deterioration of systolic function. The growth of the left ventricle is common, although it is also possible to observe it in the right ventricle and auricles [52, 62]. In advanced stages of the disease, it is possible to find a cardiac apical aneurism, pathognomonic of CCC [49]. Studies carried out in patients and postmortem analysis have demonstrated the presence of intracavitary thrombi accompanied by infarcts in several organs such as the lungs, kidneys, and brain [63–65].

At present, the factors that contribute to the progression of patients from the indeterminate phase to the determinate phase of Chagas disease have not been fully elucidated. As for other infectious diseases, the prognosis of CD depends on factors attributable to the host and the pathogen. Being an intracellular parasite, *T. cruzi* needs to modulate the defense mechanisms of the host cell in order to guarantee its survival. One of these mechanisms is apoptosis.
