Primary abnormalities of the autonomic nervous system had been postulated as the pathogenic mechanisms of myocardial damage, in patients with Chagas disease. However, recent investigations indicate that these abnormalities are secondary and amenable to treatment with beta-adrenergic blockers. Moreover, muscarinic cardiac autoantibodies appear to enhance parasympathetic activity on the sinus node. Therefore, the purpose of this paper is to analyze how knowledge on Chagas' disease evolved from being initially considered as a primary cardioneuromyopathy to the current status of a congestive cardiomyopathy of parasitic origin. 1. Introduction The natural history of Chagas disease is characterized by an acute phase, followed by an indeterminate or transitional stage and a terminal arrhythmic-congestive phase. This disease appears to evolve from localized myocardial damage to a clinical form of congestive cardiomyopathy, with diffuse myocardial damage [1–4]. Several hypotheses have been postulated in order to explain the mechanisms responsible for the progression of myocardial damage. The proposed mechanisms are (1) microvascular disturbances, (2) immune-mediated myocardial injury, (3) parasite-dependent myocardial aggression, and (4) primary abnormalities of the parasympathetic and sympathetic divisions of the autonomic nervous system. Microcirculatory disturbances and immune-mediated myocardial injury are prominent peculiarities of Chagas cardiomyopathy. However, the roles of these two proposed mechanisms of myocardial damage are very likely ancillary rather than fundamental to the pathogenesis of disease progression. Concerning parasite-dependent myocardial damage, due to the diversity of Trypanosoma cruzi populations isolated from patients presenting the same clinical form of the disease an association between the parasite’s genotype and the clinical manifestations of the disease is still not definitively established. Moreover, the available data are considered insufficient to justify trypanocidal therapy as a therapeutical alternative aimed at modifing clinical outcomes. Nonetheless, the BENEFIT trial (Benefit Evaluation for Interrupting Trypanosomiasis), currently in progress, will undoubtedly provide definitive answers for this crucial therapeutic dilemma [1–4]. The parasympathetic abnormalities were initially attributed to a direct action of the parasite on the postganglionic cardiac parasympathetic neurons. This hypothesis was postulated by Koberle in the 1950s [5, 6]. A cardiac autoimmune response, aimed at the sympathetic postganglionic fibers and
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