The Indeterminate Phase of Chagas' Disease: Ultrastructural Characterization of Cardiac Changes in the Canine Model

Abstract

The indeterminate phase of Chagas' disease is defined as the prolonged period of clinically silent infection that follows the phase of acute primary infection with Trypanosoma cruzi. The dog is the only experimental animal model in which the indeterminate phase progresses to the late phase of severe, chronic myocarditis. This report describes the cardiac histologic and ultrastructural findings in dogs that survived the acute phase of infection with T. cruzi, becoming clinically and electrocardiographically normal for up to 3.5 years, while maintaining positive serologic test results during this period of time. Most of the myocardium appeared morphologically normal; however, small foci of mild, chronic myocarditis were present, with interstitial edema, mild fibrosis, and infiltration by lymphocytes, macrophages, and plasma cells. No microvascular lesions and no areas of close contact between immune effector cells and endothelial cells or cardiac myocytes were present. These findings were in sharp contrast to those observed in the canine model during the acute infection with T. cruzi. In this model, acute myocyte damage and lesions in the microcirculation, including fibrin microthrombi, were associated with close contacts between immune effector cells and myocytes or endothelial cells. Focally inflamed interstitial tissue showed increased deposition of amorphous and collagenous extracellular matrix as well as evidence of breakdown of collagen. The features of the inflammatory cells in the indeterminate phase of Chagas' disease were interpreted as indicating a self-limited cycle of focal inflammatory changes, with modulation and suppression of cell-mediated immune responses. Thus, we consider the indeterminate phase of Chagas' disease to be a stage of host-parasite equilibrium rather than a process of progressive damage.

Cavia porcellus as a Model for Experimental Infection by Trypanosoma cruzi

“…In human patients, the indeterminate form of chronic Chagas disease, which is nearly universal in the early chronic phase, can last for 15 to 30 years or for the life of the host. The early chronic phase may be attributed to a progressive stage in the life of the parasite that ends with chronic disease manifestations 43 or may be the result of host-parasite equilibrium. 44 Understanding the mechanisms involved in maintenance of the indeterminate form may be important in explaining the eventual progression to clinical disease in a portion of infected individuals.…”

“…44 Understanding the mechanisms involved in maintenance of the indeterminate form may be important in explaining the eventual progression to clinical disease in a portion of infected individuals. Dogs 43 and nonhuman primates 44 have been shown to have an early chronic phase with characteristics similar to humans; however, development of the disease in these animals occurs over a long period. The development of the early chronic phase of disease in guinea pigs occurs in a much shorter period, making this animal model practical for laboratory research.…”

Aspectos clínico-laboratoriais da infecção natural por Trypanosoma cruzi em cães de Mato Grosso do Sul

“…Três animais apresentaram aumento na duração da onda P no ECG, que, embora possa indicar aumento de câmara cardíaca, não foi confirmado por meio dos outros métodos de avaliação e pode estar associado à presença de áreas de fibrose intramiocárdica causada pela ação do T. cruzi. Estudos ultra-estruturais em pacientes chagásicos confirmaram a ocorrência de miocardite granulomatosa com necrose e fibrose em cardiomiócitos, células especializadas do sistema de condução átrio ventricular e neurônios do gânglio autônomo cardíaco, que provoca um retardo na condução e no alargamento da onda P (BARR et al, 1989;ANDRADE et al, 1997;LANA et al, 1988;KITTLESON & KIENLE, 1998).…”

I Diretriz Latino-Americana para o Diagnóstico e Tratamento da Cardiopatia Chagásica

“…There is experimental evidence that, after the intense myocarditis of the acute phase of CD, when parasitemia and tissue parasitosis are controlled by immune mechanisms, inflammation subsides and persists focally at low intensity during the indeterminate form of disease 40 . It has been postulated that the balance and relative pathological stability of that the indeterminate form, in which the immune mechanism should be essentially modulated in the protective direction, are disrupted by still obscure factors, when inflammation, necrosis and fibrosis become more intense, diffuse and progressive [24][25][26][27]39,41 .…”