Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-β

doi:10.1016/j.tcm.2016.08.003

Trends in Cardiovascular Medicine

Volume 27, Issue 2, February 2017, Pages 81-91

https://doi.org/10.1016/j.tcm.2016.08.003 Get rights and content

Abstract

Chagas disease is caused by the trypanosomatid Trypanosoma cruzi, which chronically causes heart problems in up to 30% of infected patients. Chagas disease was initially restricted to Latin America. However, due to migratory events, this disease may become a serious worldwide health problem. During Chagas disease, many patients die of cardiac arrhythmia despite the apparent benefits of anti-arrhythmic therapy (e.g., amiodarone). Here, we assimilate the cardiac form of Chagas disease to an inflammatory cardiac disease. Evidence from the literature, mostly provided using experimental models, supports this view and argues in favor of new strategies for treating cardiac arrhythmias in Chagas disease by modulating cytokine production and/or action. But the complex nature of myocardial inflammation underlies the need to better understand the molecular mechanisms of the inflammatory response during Chagas disease. Here, particular attention has been paid to tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGF-β) although other cytokines may be involved in the chagasic cardiomyopathy.

Section snippets

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 I_to 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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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.
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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.
The soluble receptors tumor necrosis factor-alpha (sTNFRs) can lead to an increase in the expression of tumor necrosis factor, increasing its detrimental to systemic inflammatory activation in Chagas cardiomyopathy (ChC). However, the correlation between sTNFRs levels, echocardiographic, and functional levels in patients with ChC remains unknown. This study aimed to verify the correlation between the plasma sTNFRs levels, echocardiographic, and NYHA functional levels in patients with ChC.
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: 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.

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Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-β

Abstract

Section snippets

Clinical aspects of Chagas disease

Macroscopic aspects of heart changes during acute and chronic phases of Chagas disease

Mechanical cardiomyocyte remodeling during the development of Chagas disease

The role of the inflammatory response in the severity of the myocarditis and heart contractility during Chagas disease

Cardiac electrical remodeling during Chagas disease

The inflammatory response in the heart during the chronic phase as a therapeutic target for Chagas disease: The paradigm of TNF

Anti-TNF therapy in Chagasic cardiomyopathy

New possible strategies to treat Chagas disease

Cardiomyocyte death versus survival: A possible evolutionary strategy?

Conclusion

Review on Trypanosoma cruzi: host cell interaction

Int J Cell Biol

Chagas׳ disease

N Engl J Med

Pathogenesis of chronic Chagas heart disease

Circulation

American trypanosomiasis (Chagas disease)

Infect Dis Clin North Am

Mechanisms of Trypanosoma cruzi persistence in Chagas disease

Cell Microbiol

The role of parasite persistence in pathogenesis of Chagas heart disease

Parasite Immunol

Autoimmunity

Adv Parasitol

Autoimmune pathogenesis of Chagas heart disease: looking back, looking ahead

Am J Pathol

Antitrypanosomal therapy for chronic Chagas׳ disease

N Engl J Med

Chagas disease: an overview of clinical and epidemiological aspects

J Am Coll Cardiol

Evaluation and treatment of chagas disease in the United States: a systematic review

J Am Med Assoc

Chagas disease

Lancet

The innate immune response to Trypanosoma cruzi infection

Microbes Infect

Chagas׳ disease: an update on immune mechanisms and therapeutic strategies

J Cell Mol Med

Back to the future in Chagas disease: from animal models to patient cohort studies, progress in immunopathogenesis research

Mem Inst Oswaldo Cruz

Immune system recognition of Trypanosoma cruzi

Curr Opin Immunol

Cardiopatia chagásica crônica em pacientes na faixa de 12 a 15 anos

Arq Bras Cardiol

Immunological relationship between seven strains of Trypanosoma cruzi and its application in the diagnosis of Chagas׳ disease

Am J Trop Med Hyg

Autonomic blockade in chronic chagas׳ heart disease. Heart rate response at rest and during upright exercise. A preliminary report

Arq Bras Cardiol

Alterações do sistema de gênese e condução do estímulo cardíaco na fase aguda da doença de Chagas humana

Arq Bras Cardiol

Role of neurotransmitter autoantibodies in the pathogenesis of chagasic peripheral dysautonomia

Ann N Y Acad Sci

Functional alterations of the autonomic nervous system in Chagas׳ heart disease

Sao Paulo Med J

Doença De Chagas Experimental No Cão. Relação morfológica e eletrocardiográfica na fase aguda da infecção

Arq Bras Cardiol

O eletrocardiograma na doença de chagas crônica. estudo de 100 casos

Arq Bras Cardiol

Kinetoplast DNA signatures of Trypanosoma cruzi strains obtained directly from infected tissues

Am J Pathol

Novel insights into the development of chagasic cardiomyopathy: role of PI3Kinase/NO axis

Int J Cardiol

Avaliação clínica do parassimpático na cardiopatia chagásica crônica

Arq Bras Cardiol

Ultrastructural aspects of acute experimental Chagas׳ heart disease in the guinea-pig

Arq Bras Cardiol

Disruption of myofibrillar proteins in cardiac muscle of Calomys callosus chronically infected with Trypanosoma cruzi and treated with immunosuppressive agent

Parasitol Res

Altered Cardiomyocyte Function and Trypanosoma cruzi Persistence in Chagas Disease

Am J Trop Med Hyg

Ventricular arrhythmia in Chagas disease. Diagnostic, prognostic, and therapeutic features

Arq Bras Cardiol

Pathologic anatomy of the his-tawara system and eletrocardiographic abnormalities in chronic Chagas׳ heart disease

Arq Bras Cardiol

Disfunção sistólica e diastólica nas formas indeterminada, digestiva e cardíaca crônica da moléstia de chagas

Arq Bras Cardiol

Changes of heart conduction system in patients with Chagas' disease subjected to sudden death.