The Characterization of Cardiac Explants Reveals Unique Fibrosis Patterns and a Predominance of CD8+ T Cell Subpopulations in Patients with Chronic Chagas Cardiomyopathy

Abstract

Aim: The present study aimed to characterize the histopathological findings and the phenotype of inflammatory cells in the myocardial tissue of patients with end-stage heart failure (ESHF) secondary to CCC in comparison with ESHF secondary to non-Chagas cardiomyopathies (NCC). Methods: A total of 32 explanted hearts were collected from transplanted patients between 2014 and 2017. Of these, 21 were classified as CCC and 11 as other NCC. A macroscopic analysis followed by a microscopic analysis were performed. Finally, the phenotypes of the inflammatory infiltrates were characterized using flow cytometry. Results: Microscopic analysis revealed more extensive fibrotic involvement in patients with CCC, with more frequent foci of fibrosis, collagen deposits, and degeneration of myocardial fibers, in addition to identifying foci of inflammatory infiltrate of greater magnitude. Finally, cell phenotyping identified more memory T cells, mainly CD8+CD45RO+ T cells, and fewer transitioning T cells (CD45RA+/CD45RO+) in patients with CCC compared with the NCC group. Conclusions: CCC represents a unique form of myocardial involvement characterized by abundant inflammatory infiltrates, severe interstitial fibrosis, extensive collagen deposits, and marked cardiomyocyte degeneration. The structural myocardial changes observed in late-stage Chagas cardiomyopathy appear to be closely related to the presence of cardiac fibrosis and the colocalization of collagen fibers and inflammatory cells, a finding that serves as a basis for the generation of new hypotheses aimed at better understanding the role of inflammation and fibrogenesis in the progression of CCC. Finally, the predominance of memory T cells in CCC compared with NCC hearts highlights the critical role of the parasite-specific lymphocytic response in the course of the infection.

Correlation of blood-based immune molecules with cardiac gene expression profiles reveals insights into Chagas cardiomyopathy pathogenesis

“…If, in one hand, CD8+ T cells are essential for the recognition of cells infected by T. cruzi and, consequently, for controlling the infection in the acute phase ( 40 ), on the other hand a massive cytotoxicity mediated by CD8+ T cells may contribute to heart tissue damage and progression of CCC ( 14 , 41 ). Notably, molecules important for T-cell cytotoxicity, such as perforin, granzyme A and the Eomes transcription factor ( 42 ) are upregulated in the cardiac tissue and displays increased expression in circulating T cells of CCC patients ( 12 , 35 ), corroborating previously suggested data of the critical role of these cells in the pathogenesis of CCC ( 12 , 14 , 38 , 39 ). It is noteworthy to mention that the analysis of NK-derived cytotoxic genes displayed an association with CD8+ cells that was stronger than the one observed with NK cells themselves, implicating CD8 cells in disease pathology.…”

“…Of note, the manuscript by Feng Li et al. showed that enrichment analysis revealed that DEGs in heart of patients with dilated cardiomyopathies were also involved in the immune-related pathological process ( 38 ).…”

Immunologic changes are detectable in the peripheral blood transcriptome of clinically asymptomatic Chagas cardiomyopathy patients

“…In line with this, a growing body of evidence has suggested that the host immune system plays a role in CCC pathogenesis[22]. Histologic studies indicate that CCC hearts, compared to other non-Chagas dilated cardiomyopathy hearts, have significantly increased CD8+ T cells, memory T cells[21, 23, 24], B cells[23], macrophages[23, 25], and mast cells[24] infiltrating cardiac tissue, all of which can contribute to tissue damage. In the peripheral blood, proinflammatory cells such as activated CD4+ T cells, NKT cells, cytotoxic NK cells[26], degranulating double-positive T cells[27], inflammatory monocytes[28], and cytokines such as TNF, INF- γ , and IL-6 are also increased[29].…”

“…Despite a dearth of research on the early processes involved in progression to CCC, evidence suggests the immune system plays an important role in the development of the cardiac damage that results in CCC. While T. cruzi is known to cause DNA damage, oxida6ve stress, and cell lysis [16], and thus is capable of directly damaging the heart, parasites can be difficult to detect in blood and 6ssues during the chronic stage of infec6on, thereby calling into ques6on the extent to which the parasite alone is responsible for chronic 6ssue damage [17][18][19][20][21]. In line with this, a growing body of evidence has suggested that the host immune system plays a role in CCC pathogenesis [22].…”

“…While together these data suggest a role for the immune system in the development of CCC, most observations implicating the immune system in CCC have been derived from tissues acquired during late-stage, symptomatic disease [5, 6, 22, 30]. It thus remains unclear what role the immune system may play in the earliest stages of CCC and whether early immunologic changes could mediate and/or signal the development of CCC in a subset of infected patients.…”