Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-β
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Clinical aspects of Chagas disease
Chagas disease is one of the most important neglected diseases in Latin America. This disease was first discovered and described by the Brazilian physician Carlos Chagas in the early 20th century. Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and insect members of the subfamily Triatominae are intermediate host. They are known in the folk culture as “barbeiro.” According to the World Health Organization, 6–7 million people worldwide, mostly in Latin America, are infected
Macroscopic aspects of heart changes during acute and chronic phases of Chagas disease
The mortality rate during the acute phase of Chagas disease is low (i.e., approximately 5%). At this stage, there is an increase in parasite number in the blood stream. The parasitaemia is controlled by humoral and cellular immune responses as extensively reviewed [14], [15], [16], [17]. The intense inflammatory process during the initial infection is essential to confine the etiologic agent in the intracellular environment and prevent tissue damage. The tissue lesions in the acute phase are
Mechanical cardiomyocyte remodeling during the development of Chagas disease
To date, no studies have been performed using human tissue to identify the molecular pathophysiology of chagasic cardiomyopathy. Most of our knowledge is derived from experimental animal models.
One of the first studies that proposed a molecular mechanism to explain the depressed cardiac function, demonstrated that sera obtained from chagasic patients exerted a positive chronotropic effect on isolated rat atrium [43]. These results indicate that a soluble compound that is likely to exert an
The role of the inflammatory response in the severity of the myocarditis and heart contractility during Chagas disease
More recently, our group demonstrated that cardiomyocyte function is disrupted during the acute and chronic phases of experimental T. cruzi infection in mice, considering the Colombian strain of T. cruzi, which has cardiac tropism. We found that cellular contractility, measured as a fraction of cardiomyocyte shortening, exhibited a complex behavior [56]. Changes in contractile activity were evaluated in ventricular and atrial myocytes during the acute phase [i.e., 30 days post-infection (dpi)]
Cardiac electrical remodeling during Chagas disease
One of the first studies to demonstrate the putative molecular basis for the electrical disturbances observed in Chagas disease was published in 1992 [65]. Cultured rat neonatal cardiomyocytes infected with T. cruzi exhibited reduced junctional conductance when compared to uninfected heart cells. Importantly, immunocytochemical studies demonstrated that parasitic infection significantly reduced connexin 43 expression at junctional membrane regions [65]. It was later demonstrated that human
The inflammatory response in the heart during the chronic phase as a therapeutic target for Chagas disease: The paradigm of TNF
Based on the evidence provided until now, it could be postulated that chronic heart inflammation is the pivotal trigger for heart dysfunction (electrical and mechanical remodeling) during the transition from acute to chronic phase of Chagas disease. As discussed above, TNF may play a crucial role in the reduction of Kv4.3 expression and therefore cause a significant reduction of Ito density and a subsequent delay in action potential repolarization.
Chagasic patients presenting with the cardiac
Anti-TNF therapy in Chagasic cardiomyopathy
It is reasonable to think that anti-TNF therapy would benefit patients presenting chagasic cardiomyopathy. Inhibition of TNF effects can be achieved with a monoclonal antibody against circulating TNF, such as infliximab, or with a soluble TNF receptor fusion protein such as etanercept. Etanercept is a recombinant soluble receptor TNF-R2-IgG1, whereas infliximab is a chimeric monoclonal antibody [105].
Importantly, blockade of TNF activity by infliximab directly or indirectly affects TNF mRNA
New possible strategies to treat Chagas disease
Chagas disease is a complex and multifactorial disease. Thus, other forms of therapy are under investigation. It is important to note that other cytokines have been proven to be important to the overall pathogenesis of chagasic cardiomyopathy and other cardiomyopathies; among them are the members of interleukin 1 family (e.g., IL-1α, IL-1β, and IL-18). For example, in a recent study, it was shown that patients with single nucleotide polymorphism in the gene for IL-18 have more susceptibility to
Cardiomyocyte death versus survival: A possible evolutionary strategy?
T. cruzi internalization into mammalian cells was first demonstrated to occur via the TGF-β receptor [134]. In cardiomyocytes, TGF-β can activate the PI3kinase/AKT pathway [135]. An interesting study performed by Chuenkova and colleagues demonstrated that a parasite-derived molecular mimicry of neurotrophic factors that is present in the membrane of T. cruzi triggers an unknown receptor. This receptor is believed to be present in the membrane of mammalian cells and to trigger the PI3kinase/AKT
Conclusion
Chagas disease is a multifactorial illness that has a complex time course. This disease is strongly influenced by the T. cruzi strain and the host immunological background. The immune system appears to be capable of modulating heart function during the time course of Chagas disease. TNF appears especially capable of modulating the electrical properties of cardiomyocytes by controlling the expression of distinct voltage-dependent K+ channel genes, leading to alterations in action potential
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Chagas disease: Immunology of the disease at a glance
2021, Cytokine and Growth Factor ReviewsCitation Excerpt :It is important to note that IFN-γ and TNF seem to play a dual role according to the course of the disease. In the early phase of the disease, these cytokines are important to combat the parasite, but they can be harmful when produced in excess in the chronic phase [38,39]. Other cytokines may be important in the initial stages of the infection.
Plasma levels of soluble TNF receptors are associated with cardiac function in patients with Chagas heart disease
2020, International Journal of CardiologyCitation Excerpt :Thus, the role of the sTNFRs release on cell injury needs to be clarified. However, the present results are according to literature that the specific immunity, especially related to TNFα, acts by modulating in cardiac function during the course of Chagas disease [16]. There was no significant difference in the sTNFR1 and sTNFR2 levels among the NYHA functional classes I and II.
Thioridazine aggravates skeletal myositis, systemic and liver inflammation in Trypanosoma cruzi-infected and benznidazole-treated mice
2020, International ImmunopharmacologyCitation Excerpt :In addition, Tio co-administration reduced the efficacy of the reference treatment, since the lowest tissue cellularity was obtained from Bz-based monotherapy. Among these Tio-treated groups, connective tissue expansion was identified, which represents a reactive stromal response to parenchymal damage triggered by the upregulation pro-inflammatory molecules, including TNF-α [21,19]. There is evidence that this cytokine is associated with the activation of fibrogenic pathways [31,30].
Diagnostic Pathology: Cardiovascular
2018, Diagnostic Pathology: CardiovascularEditorial commentary: Targeting Chagas disease
2017, Trends in Cardiovascular Medicine
We appreciate financial support of CNPq, Brazil (Grant no. 404353/2012-6), FAPESP, Brazil (Grant no. 2014/09861-1) and FAPEMIG, Brazil (Grant nos APQ-02410-10 and APQ-00460-12). J.S.C., F.S.M., and C.R. are research fellows of CNPq.
The authors disclose no conflicts of interest.