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Purpose of the Review: Chagas disease is a neglected anthropozoonosis of global importance with significant cardiovascular-associated mortality. This review focuses on the Trypanosoma cruzi reinfections' role in chronic Chagas cardiomyopathy pathogenesis. We discuss and summarize the available data related to pathology, pathogenesis, diagnosis, and treatment of reinfections., Recent Findings: Reinfections influence the genetic and regional diversity of T. cruzi, tissue tropism, modulation of the host's immune system response, clinical manifestations, the risk for congenital infections, differences in diagnostics performances, response to antiparasitic therapy, and the natural history of the disease. Animal models suggest that reinfections lead to worse outcomes and increased mortality, while other studies showed an association between reinfections and lower parasitemia levels and subsequent infection protection. In some regions, the human risk of reinfections is 14% at 5 years. Evidence has shown that higher anti-T. cruzi antibodies are correlated with an increased rate of cardiomyopathy and death, suggesting that a higher parasite exposure related to reinfections may lead to worse outcomes. Based on the existing literature, reinfections may play a role in developing and exacerbating chronic Chagas cardiomyopathy and are linked to worse outcomes. Control efforts should be redirected to interventions that address structural poverty for the successful and sustainable prevention of Chagas disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tissue damage observed in the clinical forms of chronic symptomatic Chagas disease seems to have a close relationship with the intensity of the inflammatory process. The objective of this study was to investigate whether the MICA ( MHC class I-related chain A ) and KIR ( killer cell immunoglobulin-like receptors ) polymorphisms are associated with the cardiac and digestive clinical forms of chronic Chagas disease. Possible influence of these genes polymorphisms on the left ventricular systolic dysfunction (LVSD) in patients with chronic Chagas heart disease was also evaluated. This study enrolled 185 patients with positive serology for Trypanosoma cruzi classified according to the clinical form of the disease: cardiac (n=107) and digestive (n=78). Subsequently, patients with the cardiac form of the disease were sub-classified as with LVSD (n=52) and without LVSD (n=55). A control group was formed of 110 healthy individuals. Genotyping was performed by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). Statistical analyzes were carried out using the Chi-square test and odds ratio with 95% confidence interval was also calculated to evaluate the risk association. MICA-129 allele with high affinity for the NKG2D receptor was associated to the LVSD in patients with CCHD. The haplotype MICA*008~HLA-C*06 and the KIR2DS2 - /KIR2DL2 - /KIR2DL3 + /C1 + combination were associated to the digestive clinical form of the disease. Our data showed that the MICA and KIR polymorphisms may exert a role in the LVSD of cardiac patients, and in digestive form of Chagas disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ayo, Bestetti, de Campos Junior, Ronchi, Borim, Brandão and de Matttos.)

In Chagas disease (ChD) caused by Trypanosoma cruzi, new biomarkers to predict chronic cardiac pathology are urgently needed. Previous studies in chagasic patients with mild symptomatology showed that antibodies against the immunodominant R3 epitope of sCha, a fragment of the human basic helix-loop-helix transcription factor like 5, correlated with cardiac pathology. To validate sCha as a biomarker and to understand the origin of anti-sCha antibodies, we conducted a multicenter study with several cohorts of chagasic patients with severe cardiac symptomatology. We found that levels of antibodies against sCha discriminated the high risk of sudden death, indicating they could be useful for ChD prognosis. We investigated the origin of the antibodies and performed an alanine scan of the R3 epitope. We identified a minimal epitope MRQLD, and a BLAST search retrieved several T. cruzi antigens. Five of the hits had known or putative functions, of which phosphonopyruvate decarboxylase showed the highest cross-reactivity with sCha, confirming the role of molecular mimicry in the development of anti-sCha antibodies. Altogether, we demonstrate that the development of antibodies against sCha, which originated by molecular mimicry with T. cruzi antigens, could discriminate electrocardiographic alterations associated with a high risk of sudden death., (© 2021 New York Academy of Sciences.)

Objectives: The main objective is to determine the prevalence of American trypanosomiasis in patients with dilated cardiomyopathy in a tertiary hospital in western Mexico., Methods: From January 1991 to February 2016, 387 consecutive patients with a confirmed diagnosis of dilated cardiomyopathy were included in the study. Cases with ventricular dilatation secondary to ischemic heart disease, valvular heart disease, hypertension, lung disease, pericardial disease, or congenital heart disease were excluded from the study. Diagnosis was made detecting antibodies against Trypanosoma cruzi with two different methods or parasite in blood., Results: Were included 387 patients with dilated cardiomyopathy, Chagas cardiomyopathy was confirmed in 6.9%, two patients in the acute phase (in one, suspected transfusion transmission was detected). Most patients were born in rural areas. About 96.2% showed congestive heart failure, only one patient with apical left ventricular aneurysm manifested palpitations. About 66% with right bundle branch block, left anterior fascicular block, or the association of both, in 14.8%, non-sustained ventricular tachycardia was found., Conclusions: Chagas cardiomyopathy is common in México, mainly in people who were born or lived during childhood in rural areas. It is a common cause of heart failure. Chagas' heart disease should be suspected in patients receiving a blood transfusion, even without another epidemiological history.

The aim of the present study was to analyze IL6 rs1800795 genetic variant in the susceptibility to Trypanosoma cruzi infection and in the development of chronic Chagas cardiomyopathy (CCC), in five independent Latin American cohorts. A total of 3,087 individuals from Latin American countries (Argentina, Bolivia, Peru, and two cohorts from Colombia) were studied. In all cohorts, patients were classified as seropositive for T. cruzi antigens (n= 1,963) and seronegative (n= 1,124). Based on clinical evaluation, the seropositive patients, were classified as CCC (n= 900) and asymptomatic (n= 1,063). No statistically significant differences in the frequency of IL6 rs1800795 between seropositive and seronegative, or between CCC and asymptomatic patients, were found. Furthermore, after the meta-analysis no statistically significant differences were observed. Our results do not support a contribution of IL6 rs1800795 genetic variant in the susceptibility to the infection and the development of chronic Chagas cardiomyopathy in the studied populations., Competing Interests: Declaration of Competing Interest The authors report no conflict of interests, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Heart failure (HF) and type 2 Diabetes Mellitus (T2DM) represent two chronic interrelated conditions accounting for significant morbidity and mortality worldwide. Insulin resistance (IR) has been identified as a risk factor for HF; however, the risk of IR that HF confers has not been well elucidated. The present study aims to analyze the association between myocardial involvement in Chronic Chagas Cardiomyopathy (CCM) and IR, taking advantage of this non-metabolic model of the disease., Methods: Cross-sectional study performed during the period 2015-2016. Adults with a serological diagnosis of Chagas disease were included, being divided into two groups: CCM and non-CCM. IR was determined by HOMA-IR index. Bivariate analysis and multivariate logistic regression were performed to determine the association between IR as an outcome and CCM as primary exposure., Results: 200 patients were included in the study, with a mean age of 54.7 years and a female predominance (53.5%). Seventy-four (37.0%) patients were found to have IR, with a median HOMA-IR index of 3.9 (Q1 = 3.1; Q3 = 5.1). Multiple metabolic variables were significantly associated with IR. In a model analyzing only individuals with an altered HWI, an evident association between CCM and IR was observed (OR 4.08; 95% CI 1.55-10.73, p = 0.004)., Conclusion: CCM was significantly associated with IR in patients with an altered HWI. The presence of this association in a non-metabolic model of HF (in which the myocardial involvement is expected to be mediated mostly by the parasitic infection) may support the evidence of a direct unidirectional correlation between this last and IR., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Background: Chagas disease is a protozoan infection caused by Trypanosoma cruzi. The disease has a chronic course in which 20-30% of the patients would develop progressive damage to the cardiovascular system and the gastrointestinal tube. We are still unable to predict who will develop end-organ damage but there are some acquired and genetic risk factors already known., Results: We reviewed data from 833 patients with serologically confirmed Chagas disease in this retrospective study. Patients were classified as siblings or non-siblings (controls) and the results of pre-treatment blood PCR assay, end-organ damage (cardiac and/or gastrointestinal), and the presence of delayed type hypersensitivity (DTH) skin involvement in patients treated with benznidazole were analyzed. Siblings were grouped by family and we randomly generated groups of 2 or 3 persons with the remaining controls. We classified the results of each variable as concordant or discordant and compared the concordance in these results among the sibling groups with that among control groups. We identified 71 groups of siblings and randomly generated 299 groups of non-related patients. Pre-treatment blood PCR concordance was significantly higher (19%) among siblings compared to controls (P = 0.02), probably due to a higher frequency in pre-treatment positive results. No other statistically significant differences were found., Conclusions: A significant difference was found in the concordance of pre-treatment blood PCR for T. cruzi among siblings compared to non-related controls.

Purpose of Review: Chagas cardiomyopathy is a major public health disease in Latin America and, due to migration, is becoming a worldwide health and economic burden. This review sought to present the clinical and epidemiological aspects of Chagas cardiomyopathy, as well as some specific features and principles of treatment. We also retrospectively assessed our institutional experience with mechanical circulatory support in refractory heart failure due to Chagas cardiomyopathy over a 10-year period., Recent Findings: The role of antiparasitic treatment in patients with heart failure due to Chagas cardiomyopathy is controversial. Heart transplantation, although formerly contraindicated, is currently established as an important therapeutic option. Also, the favorable characteristics of Chagas patients, such as younger age, little comorbidity, and no reoperations or severe pulmonary hypertension, could be an advantage for a mechanical circulatory support indication in advanced heart failure due to Chagas cardiomyopathy. Despite the absence of large evidence-based data, much has been accomplished since Carlos Chagas' discovery one century ago. Our institutional experience shows that mechanical circulatory support in Chagas patients is associated with more successful bridging to heart transplantation when compared to non-Chagas patients.

Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host-parasite equation. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection-Chagas heart disease-and concludes with a discussion of key unanswered questions and a view to the future.

Chagas disease (CD), caused by infection with the parasite Trypanosoma cruzi , leads to severe cardiomyopathy in 20-30% of patients, whereas the remainder may stay asymptomatic and never develop cardiomyopathy or other clinical manifestations. The underlying cause for this variable outcome is not fully characterized, although previous studies have found high levels of circulating mannose-binding lectin (MBL) to be associated with cardiac failure echocardiographic changes. We report three indeterminate (asymptomatic) chronic Chagas patients who were followed up for 10 years. Two of these patients developed chronic chagasic cardiomyopathy (CCC) during this follow-up period and, when genotyped, were found to be carriers of the high MBL producer HYPA / HYPA genotype, suggesting that genetically determined high MBL serum might be associated with the risk of CCC development. These results suggest the use of MBL quantification and MBL2 genotyping as tools for clinical assessment in patients with chronic CD.

Infection with Trypanosoma cruzi, the etiologic agent in Chagas disease, may result in heart disease. Over the last decades, Chagas disease endemic areas in Latin America have seen a dietary transition from the traditional regional diet to a Western style, fat rich diet. Previously, we demonstrated that during acute infection high fat diet (HFD) protects mice from the consequences of infection-induced myocardial damage through effects on adipogenesis in adipose tissue and reduced cardiac lipidopathy. However, the effect of HFD on the subsequent stages of infection - the indeterminate and chronic stages - has not been investigated. To address this gap in knowledge, we studied the effect of HFD during indeterminate and chronic stages of Chagas disease in the mouse model. We report, for the first time, the effect of HFD on myocardial inflammation, vasculopathy, and other types of dysfunction observed during chronic T. cruzi infection. Our results show that HFD perturbs lipid metabolism and induces oxidative stress to exacerbate late chronic Chagas disease cardiac pathology., (Copyright © 2018 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Chagas disease (CD), a neglected tropical disease caused by the protozoan Trypanosoma cruzi , affects around six million individuals in Latin America. Currently, CD occurs worldwide, becoming a significant public health concern due to its silent aspect and high morbimortality rate. T. cruzi presents different escape strategies which allow its evasion from the host immune system, enabling its persistence and the establishment of chronic infection which leads to the development of chronic Chagas cardiomyopathy (CCC). The potent immune stimuli generated by T. cruzi persistence may result in tissue damage and inflammatory response. In addition, molecular mimicry between parasites molecules and host proteins may result in cross-reaction with self-molecules and consequently in autoimmune features including autoantibodies and autoreactive cells. Although controversial, there is evidence demonstrating a role for autoimmunity in the clinical progression of CCC. Nevertheless, the exact mechanism underlying the generation of an autoimmune response in human CD progression is unknown. In this review, we summarize the recent findings and hypotheses related to the autoimmune mechanisms involved in the development and progression of CCC.

Background: Chagas cardiomyopathy (CC) is one of the chronic manifestations of Trypanosoma cruzi (T. cruzi) infection and is among the leading reasons for heart transplantation (HT) in Latin America. Chagas disease is also present in areas with large Hispanic communities in the United States. Our objective is to evaluate the outcomes of cardiac allograft recipients with the diagnosis of CC in the United States., Methods and Results: We identified 25 adult patients with CC and 15 930 with idiopathic dilated cardiomyopathy (IDCMP) who underwent HT between 1987 and 2015. CC patients were mostly Hispanics, had lower mean pulmonary artery pressure (23 vs 29 mm Hg, P = .035) and lower BMI (24 vs 26, P = .007). Patients with CC were more likely to be supported with a total artificial heart (TAH) as bridge to transplant (P = .009). There were no statistical differences for overall mortality and graft survival between CC and IDCMP cardiac allograft recipients. Induction therapy and mycophenolate mofetil (MMF) use were associated with higher rate of infection in Chagas patients., Conclusions: Heart transplantation recipients with CC diagnosis appear to have similar outcomes to IDCMP patients. Induction therapy and MMF use may be associated with higher risk of infection in CC patients who underwent transplantation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Trypanosoma cruzi (T. cruzi) infection is endemic in Latin America and is becoming a worldwide health burden. It may lead to heterogeneous phenotypes. Early diagnosis of T. cruzi infection is crucial. Several biomarkers have been reported in Chagas heart disease (ChHD), but most are nonspecific for T. cruzi infection. Prognosis of ChHD patients is worse compared with other etiologies, with sudden cardiac death as an important mode of death. Most ChHD patients display diffuse myocarditis with fibrosis and hypertrophy. The remodeling process seems to be associated with etiopathogenic mechanisms and neurohormonal activation. Pharmacological treatment and antiarrhythmic therapy for ChHD is mostly based on results for other etiologies. Heart transplantation is an established, valuable therapeutic option in refractory ChHD. Implantable cardioverter-defibrillators are indicated for prevention of secondary sudden cardiac death. Specific etiological treatments should be revisited and reserved for select patients. Understanding and management of ChHD need improvement, including development of randomized trials., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Chagas cardiomyopathy (CC) is one of the chronic manifestations of Trypanosoma cruzi (T. cruzi) infection and is a major public health disease in Latin America. Since it is a chronic systemic infection, Chagas disease was long considered a potential contraindication for transplantation because of the risk of recurrence with immunosuppression. However, early South American experience in the 1980's established the feasibility of heart transplantation (HT) in patients with Chagas disease. Indeed, the first cardiac transplant for a recipient with CC was performed in 1985 in Brazil. Chagas etiology of heart failure has become the third most common indication for HT in South America. T. cruzi reactivation post-transplant is a common issue that requires prophylactic surveillance but responds well to appropriate therapy. Chagas reactivation has been associated with the potency of the immunosuppressive protocol and occurs more frequently after rejection episodes. Yet, many important questions regarding the management of Chagas HT candidates and recipients remain unanswered. For example, biventricular systolic failure is frequent in end-stage CC, but its impact on the modality of mechanical circulatory bridging has not been described. Also, there is no consensus regarding the most adequate immunosuppressive regimen that balances the risk of graft rejection and disease reactivation. The real efficacy and safety of HT for end-stage CC will only be appreciated when a Latin American transplant registry is established. This review covers the current state of the art of HT for CC., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chagas cardiomyopathy is the most frequent and most severe manifestation of chronic Chagas disease, and is one of the leading causes of morbidity and death in Latin America. Although the pathogenesis of Chagas cardiomyopathy is incompletely understood, it may involve several mechanisms, including parasite-dependent myocardial damage, immune-mediated myocardial injury (induced by the parasite itself and by self-antigens), and microvascular and neurogenic disturbances. In the past three decades, a consensus has emerged that parasite persistence is crucial to the development and progression of Chagas cardiomyopathy. In this context, antiparasitic treatment in the chronic phase of Chagas disease could prevent complications related to the disease. However, according to the results of the BENEFIT trial, benznidazole seems to have no benefit for arresting disease progression in patients with chronic Chagas cardiomyopathy. In this review, we give an update on the main pathogenic mechanisms of Chagas disease, and re-examine and discuss the results of the BENEFIT trial, together with its limitations and implications.

Chagas disease is caused by a protozoan named Trypanosoma cruzi transmitted to humans by reduviid bugs. Severe dilated cardiomyopathy from chronic T cruzi infection is the most common finding, leading to end-stage heart failure. Heart transplant is an effective treatment for Chagas heart disease. However, T cruzi reactivation is of great concern, predisposing patients to episodes of myocarditis and rejection. A 56-year-old woman with a history of Chagas disease and elevated calculated panel reactive antibodies (CPRAs) underwent induction therapy and desensitization strategies aimed at lowering CPRAs, as elevated CPRAs have been implicated in the development of antibody-mediated rejection and reduced allograft survival. Clinical phases and signs and symptoms of Chagas disease are briefly described in an attempt to promote awareness of the disease among clinicians. In addition, serology assays approved in the United States as well as recommendations of experts on Chagas disease to assess tissues and blood specimens from endemic areas are outlined. Ultimately, the importance of ongoing surveillance is emphasized, as the future of heart transplant recipients with Chagas disease is unpredictable and the presence or reactivation of the disease requires prompt attention in an effort to prevent graft failure and death.

There is ample experimental and clinical evidence of functional and structural microvascular abnormalities occurring in patients with Chagas cardiomyopathy, possibly due to the inflammatory process and/or autonomic disturbances caused by Trypanosoma cruzi infection. Those microvascular derangements are likely to constitute at least an ancillary factor that potentiates and amplifies the chronic inflammation in myocardial tissue. It is possible to devise appropriate therapeutic interventions aimed at reverting or slowing the progression of the microvascular abnormalities to positively affect the natural history of Chagas cardiomyopathy.

Rationale: Cardiomyocytes express neurotrophin receptor TrkA that promotes survival following nerve growth factor (NGF) ligation. Whether TrkA also resides in cardiac fibroblasts (CFs) and underlies cardioprotection is unknown., Objective: To test whether CFs express TrkA that conveys paracrine signals to neighbor cardiomyocytes using, as probe, the Chagas disease parasite Trypanosoma cruzi, which expresses a TrkA-binding neurotrophin mimetic, named PDNF. T. cruzi targets the heart, causing chronic debilitating cardiomyopathy in ∼30% patients., Methods and Results: Basal levels of TrkA and TrkC in primary CFs are comparable to those in cardiomyocytes. However, in the myocardium, TrkA expression is significantly lower in fibroblasts than myocytes, and vice versa for TrkC. Yet T. cruzi recognition of TrkA on fibroblasts, preferentially over cardiomyocytes, triggers a sharp and sustained increase in NGF, including in the heart of infected mice or of mice administered PDNF intravenously, as early as 3-h post-administration. Further, NGF-containing T. cruzi- or PDNF-induced fibroblast-conditioned medium averts cardiomyocyte damage by H(2)O(2), in agreement with the previously recognized cardioprotective role of NGF., Conclusions: TrkA residing in CFs induces an exuberant NGF production in response to T. cruzi infection, enabling, in a paracrine fashion, myocytes to resist oxidative stress, a leading Chagas cardiomyopathy trigger. Thus, PDNF-TrkA interaction on CFs may be a mechanism orchestrated by T. cruzi to protect its heart habitat, in concert with the long-term (decades) asymptomatic heart parasitism that characterizes Chagas disease. Moreover, as a potent booster of cardioprotective NGF in vivo, PDNF may offer a novel therapeutic opportunity against cardiomyopathies.

Chagas' disease, caused by Trypanosoma cruzi infection, is ranked as the most serious parasitic disease in Latin America. Nearly 30% of infected patients develop life-threatening complications, and with a latency of 10-30 years, mostly Chagas' heart disease which is currently the major cause of morbidity and mortality in Latin America, enormously burdening economic resources and dramatically affecting patients' social and labor situations. Because of increasing migration, international tourism and parasite transfer by blood contact, intrauterine transfer and organ transplantation, Chagas' heart disease could potentially become a worldwide problem. To raise awareness of this problem, we reflect on the epidemiology and etiopathology of Chagas' disease, particularly Chagas' heart disease. To counteract Chagas' heart disease, in addition to the general interruption of the infection cycle and chemotherapeutic elimination of the infection agent, early and effective causal or symptomatic therapies would be indispensable. Prerequisites for this are improved knowledge of the pathogenesis and optimized patient management. From economic and logistics viewpoints, this last prerequisite should be performed using laboratory medicine tools. Consequently, we first summarize the mechanisms that have been suggested as driving Chagas' heart disease, mainly those associated with the presence of autoantibodies against G-protein-coupled receptors; secondly, we indicate new treatment strategies involving autoantibody apheresis and in vivo autoantibody neutralization; thirdly, we present laboratory medicine tools such as autoantibody estimation and heart marker measurement, proposed for diagnosis, risk assessment and patient guidance and lastly, we critically reflect upon the increase in inflammation and oxidative stress markers in Chagas' heart disease.

Trypanosoma cruzi elicits reactive oxygen species (ROS) of inflammatory and mitochondrial origin in infected hosts. In this study, we examined ROS-induced oxidative modifications in the heart and determined whether the resultant oxidized cardiac proteins are targets of immune response and of pathological significance in Chagas disease. Heart biopsies from chagasic mice, rats and human patients exhibited, when compared to those from normal controls, a substantial increase in protein 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), carbonyl, and 3-nitrotyrosine (3-NT) adducts. To evaluate whether oxidized proteins gain antigenic properties, heart homogenates or isolated cardiomyocytes were oxidized in vitro and one- or two-dimensional gel electrophoresis (2D-GE)/Western blotting (WB) was performed to investigate the proteomic oxidative changes and recognition of oxidized proteins by sera antibodies in chagasic rodents (mice, rats) and human patients. Human cardiomyocytes exhibited LD(50) sensitivity to 30 µM 4-HNE and 100 µM H(2)O(2) at 6 h and 12 h, respectively. In vitro oxidation with 4-HNE or H(2)O(2) resulted in a substantial increase in 4-HNE- and carbonyl-modified proteins that correlated with increased recognition of cardiac (cardiomyocytes) proteins by sera antibodies of chagasic rodents and human patients. 2D-GE/Western blotting followed by MALDI-TOF-MS/MS analysis to identify cardiac proteins that were oxidized and recognized by human chagasic sera yielded 82 unique proteins. We validated the 2D-GE results by enzyme-linked immunosorbent assay (ELISA) and WB and demonstrated that oxidation of recombinant titin enhanced its immunogenicity and recognition by sera antibodies from chagasic hosts (rats and humans). Treatment of infected rats with phenyl-α-tert-butyl nitrone (PBN, antioxidant) resulted in normalized immune detection of cardiac proteins associated with control of cardiac pathology and preservation of heart contractile function in chagasic rats. We conclude that ROS-induced, cardiac-oxidized antigens are targets of immune recognition by antibodies and molecular determinants for pathogenesis during Chagas disease.

Background: Chagas disease is endemic in South and Central America, where 18 million individuals are infected by Trypanosoma cruzi, causing congestive heart failure (CHF) and cardioembolic stroke. Transcranial Doppler (TCD) is able to detect real-time microembolic signals (MES) to the brain vessels and may represent a surrogate marker of stroke risk. We aimed to determine predictors of MES in a population of patients with CHF., Methods: Consecutive CHF patients from a university-based cardiomyopathy clinic underwent TCD recording of the middle cerebral artery for 60 min by a single investigator who was blinded to all clinical data including cardiomyopathy etiology. Predictors of MES were sought by multivariable logistic regression analysis., Results: From April 2004 to February 2009, 144 patients were studied, including 62 (44.6%) patients with Chagas disease. MES were detected in 9 (6.2%) patients and were more frequent in patients with Chagas disease than in patients with other causes of CHF (12.9 vs. 1.2%, p = 0.005). In multivariate analysis corrected for age and left-ventricular ejection fraction, predictors of MES were Chagas disease (odds ratio = 1.15, 95% confidence interval = 1.05-1.26, p = 0.004) and stroke history (odds ratio = 1.27, 95% confidence interval = 1.08-1.50, p = 0.005)., Conclusions: Chagas disease and stroke history are risk factors for MES independent of cardiac disease severity. Other mechanisms besides structural cardiac disease may be operative, increasing embolic risk in Chagas disease., (Copyright © 2010 S. Karger AG, Basel.)

Since serial studies of patients are limited, researchers interested in Chagas disease have relied on animal models of Trypanosoma cruzi infection to explore many aspects of this important human disease. These studies have been important for evaluation of the immunology, pathology, physiology and other aspects of pathogenesis. While larger animals have been employed, mice have remained the most favoured animal model, as they recapitulate many aspects of the human disease, are easy to manipulate genetically and are amenable to study by small animal imaging technologies. Further, developments in non-invasive imaging technologies have permitted the study of the same animal over an extended period of time by multiple imaging modalities, thus permitting the study of the transition from acute infection through the chronic stage and during therapeutic regimens., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A total of 8-10 million persons are infected worldwide with Trypanosoma cruzi, the causative parasite of Chagas disease, most of whom are inhabitants of Latin America. Due to the increased migration of peoples, Chagas disease has been on the uprise outside Latin America, including in Europe. The course of Chagas, also called American trypanosomiasis, runs in 2 phases: an acute phase lasting approximately 2 months, and a chronic phase in which symptoms may appear years after infection. Without treatment, the patient will remain infected for life. The acute phase is usually asymptomatic; in the chronic phase of American trypanosomiasis, severe gastro-intestinal and cardiac abnormalities may develop, finally with fatal course. In the Netherlands, the number of immigrants who would serologically test positive for American trypanosomiasis is estimated to be between 726 and 2929. Healthcare providers in the Netherlands may encounter patients who have Chagas disease more and more frequently. The screening of pregnant women and blood donors at risk for American trypanosomiasis should be considered.

The cardiac involvement of five patients from the Amazon region with Acute Chagas' Disease (ACD) is described. Four of these patients presented probable oral transmission. All of them presented some degree of cardiac involvement, but there were no deaths.

Objectives: The purpose of this study was to determine the pathological importance of oxidative stress-induced injurious processes in chagasic heart dysfunction., Background: Trypanosoma cruzi-induced inflammatory pathology and a feedback cycle of mitochondrial dysfunction and oxidative stress may contribute to Chagas disease., Methods: Sprague-Dawley rats were infected with T. cruzi and treated with phenyl-alpha-tert-butylnitrone (PBN), an antioxidant, and/or benzonidazole (BZ), an antiparasitic agent. We monitored myocardial parasite burden, oxidative adducts, mitochondrial complex activities, respiration, and adenosine triphosphate synthesis rates, and inflammatory and cardiac remodeling responses during disease development. The cardiac hemodynamics was determined for all rats., Results: Benzonidazole (not PBN) decreased the parasite persistence and immune adverse events (proinflammatory cytokine expression, beta-nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase activities, and inflammatory infiltrate) in chronically infected hearts. PBN +/- BZ (not BZ alone) decreased the mitochondrial reactive oxygen species level, oxidative adducts (malonyldialdehyde, 4-hydroxynonenal, carbonyls), hypertrophic gene expression (atrial natriuretic peptide, B-type natriuretic peptide, alpha-skeletal actin), and collagen deposition and preserved the respiratory chain efficiency and energy status in chronically infected hearts. Subsequently, LV dysfunction was prevented in PBN +/- BZ-treated chagasic rats., Conclusions: BZ treatment after the acute stage decreased the parasite persistence and inflammatory pathology. Yet, oxidative adducts, mitochondrial dysfunction, and remodeling responses persisted and contributed to declining cardiac function in chagasic rats. Combination treatment (PBN + BZ) was beneficial in arresting the T. cruzi-induced inflammatory and oxidative pathology and chronic heart failure in chagasic rats.

A better understanding of Chagas' disease is important because the knowledge about the progression and the participation of the different types of cells in this disease are still lacking. To clarify this system, the kinetics of inflammatory cells and parasite nests was shown in an experiment. Using this experimental data, we have developed a three-dimensional multi-agent-based computational model for the evolution of Chagas' disease. Our model includes five different types of agents: inflammatory cell, fibrosis, cardiomyocyte, fibroblast, and Trypanosoma cruzi. Fibrosis is fixed and the other types of agents can move through the empty space. They move randomly by using the Moore neighborhood. This model reproduces the acute and chronic phases of Chagas' disease and the volume occupied by all different types of cells in the cardiac tissue.

Chagas disease is a neglected parasitic disease endemic in the Americas. It mainly affects impoverished populations and the acute phase of the infection mostly affects children. Many cases have also been detected in nonendemic countries as a result of recent migratory trends. The chronic phase is relatively asymptomatic, but 30% of patients with chronic infection eventually develop cardiac and digestive complications that commonly lead to death or disability. Only two drugs are available for the treatment of Chagas disease, benznidazole and nifurtimox. These drugs have been shown to be effective in the treatment of both acute and early chronic phases in children, but the pharmacokinetics of these drugs have never been studied in this population. We have set out to conduct a pharmacokinetics study of benznidazole in a pediatric population with Chagas disease. The results of this study are expected to allow better estimation of the optimal doses and schedule of pharmacotherapy for Chagas disease in children.

This paper summarizes recent data from the literature suggesting that transforming growth factor-beta (TGF-beta) participates at least in four different processes influencing development of myocardiopathy in Chagas disease, a major parasitic illness caused by Trypanosoma cruzi infection: (a) invasion of cardiac fibroblasts and myocytes; (b) intracellular parasite cycle; (c) regulation of inflammation and immune response; (d) fibrosis and heart remodeling during acute and chronic disease. All these effects point to an important role of TGF-beta in Chagas disease myocardiopathy and suggest that monitoring the circulating levels of this cytokine could be of help in clinical prognosis and management of patients. Moreover, TGF-beta-interfering therapies appear as interesting adjuvant interventions during acute and chronic phases of T. cruzi infection.

Chagas heart disease (CHD), caused by the protozoan parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis in the world. The etiology of CHD is unclear and multiple mechanisms have been proposed to explain the pathogenesis of the disease. This review describes the proposed mechanisms of CHD pathogenesis and evaluates the historical significance and evidence supporting each. Although the majority of CHD-related pathologies are currently attributed to parasite persistence in the myocardium and autoimmunity, there is strong evidence that CHD develops as a result of additive and even synergistic effects of several distinct mechanisms rather than one factor.

Background: Benznidazole is effective for treating acute and chronic (recently acquired) Trypanosoma cruzi infection (Chagas' disease). Recent data indicate that parasite persistence plays a pivotal role in the pathogenesis of chronic Chagas' cardiomyopathy. However, the efficacy of trypanocidal therapy in preventing clinical complications in patients with preexisting cardiac disease is unknown., Study Design: BENEFIT is a multicenter, randomized, double-blind, placebo-controlled clinical trial of 3,000 patients with Chagas' cardiomyopathy in Latin America. Patients are randomized to receive benznidazole (5 mg/kg per day) or matched placebo, for 60 days. The primary outcome is the composite of death; resuscitated cardiac arrest; sustained ventricular tachycardia; insertion of pacemaker or cardiac defibrillator; cardiac transplantation; and development of new heart failure, stroke, or systemic or pulmonary thromboembolic events. The average follow-up time will be 5 years, and the trial has a 90% power to detect a 25% relative risk reduction. The BENEFIT program also comprises a substudy evaluating the effects of benznidazole on parasite clearance and an echo substudy exploring the impact of etiologic treatment on left ventricular function. Recruitment started in November 2004, and >1,000 patients have been enrolled in 35 centers from Argentina, Brazil, and Colombia to date., Conclusion: This is the largest trial yet conducted in Chagas' disease. BENEFIT will clarify the role of trypanocidal therapy in preventing cardiac disease progression and death.

Chagas disease continues to be a significant public health problem, as ca. 10 million people are still infected with T. cruzi in Latin America. Decades after primary infection, 30% of individuals can develop a form of chronic inflammatory cardiomyopathy known as Chagas disease cardiomyopathy (CCC). Data from both murine models and human studies support the view that an autoimmune response as well as a parasite-driven immune response involving inflammatory cytokines and chemokines may both play a role in generating the heart lesions leading to CCC. This review aims to summarize recent advances in the understanding of the immunopathogenesis of Chagas disease cardiomyopathy.

A case-control study on chronic Chagas heart disease (CCHD) was carried out between 1997 and 2005. Ninety patients over 50 years of age were examined for factors related to (CCHD). Fourty-six patients (51.1%) with Chagas heart disease (anomalous ECG) were assigned to the case group and 44 (48.9%) were included in the control group as carriers of undetermined forms of chronic disease. Social, demographic (age, gender, skin color, area of origin), epidemiological (permanence within an endemic zone, family history of Chagas heart disease or sudden death, physical strain, alcoholism, and smoking), and clinical (systemic hypertension) variables were analyzed. The data set was assessed through single-variable and multivariate analysis. The two factors independently associated with heart disease were age--presence of heart disease being three times higher in patients over 60 years of age (odds ratio, OR: 2.89; confidence interval of 95%: 1.09-7.61)--and family history of Chagas heart disease (OR: 2.833, CI 95%: 1.11-7.23). Systemic hypertension and gender did not prove to hold any association with heart disease, as neither did skin color, but this variable showed low statistical power due to reduced sample size.

Background: Chagas disease remains a significant public health issue and a major cause of morbidity and mortality in Latin America. Despite nearly 1 century of research, the pathogenesis of chronic Chagas cardiomyopathy is incompletely understood, the most intriguing challenge of which is the complex host-parasite interaction., Methods and Results: A systematic review of the literature found in MEDLINE, EMBASE, BIREME, LILACS, and SCIELO was performed to search for relevant references on pathogenesis and pathophysiology of Chagas disease. Evidence from studies in animal models and in anima nobile points to 4 main pathogenetic mechanisms to explain the development of chronic Chagas heart disease: autonomic nervous system derangements, microvascular disturbances, parasite-dependent myocardial aggression, and immune-mediated myocardial injury. Despite its prominent peculiarities, the role of autonomic derangements and microcirculatory disturbances is probably ancillary among causes of chronic myocardial damage. The pathogenesis of chronic Chagas heart disease is dependent on a low-grade but incessant systemic infection with documented immune-adverse reaction. Parasite persistence and immunological mechanisms are inextricably related in the myocardial aggression in the chronic phase of Chagas heart disease., Conclusions: Most clinical studies have been performed in very small number of patients. Future research should explore the clinical potential implications and therapeutic opportunities of these 2 fundamental underlying pathogenetic mechanisms.

Background: Benznidazole is effective for treating acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain., Objective: To compare long-term outcomes of patients with nonacute Chagas disease treated with benznidazole versus outcomes of those who did not receive treatment., Design: Clinical trial with unblinded, nonrandom assignment of patients to intervention or control groups., Setting: Chagas disease center in Buenos Aires, Argentina., Patients: 566 patients 30 to 50 years of age with 3 positive results on serologic tests and without heart failure., Measurements: The primary outcome was disease progression, defined as a change to a more advanced Kuschnir group or death. Secondary outcomes included new abnormalities on electrocardiography and serologic reactivity., Intervention: Oral benznidazole, 5 mg/kg of body weight per day for 30 days (283 patients), or no treatment (283 patients)., Results: Fewer treated patients had progression of disease (12 of 283 [4%] vs. 40 of 283 [14%]; adjusted hazard ratio, 0.24 [95% CI, 0.10 to 0.59]; P = 0.002) or developed abnormalities on electrocardiography (15 of 283 [5%] vs. 45 of 283 [16%]; adjusted hazard ratio, 0.27 [CI, 0.13 to 0.57]; P = 0.001) compared with untreated patients. Left ventricular ejection fraction (hazard ratio, 0.97 [CI, 0.94 to 0.99]; P < 0.002) and left ventricular diastolic diameter (hazard ratio, 2.45 [CI, 1.53 to 3.95]; P < 0.001) were also associated with disease progression. Conversion to negative results on serologic testing was more frequent in treated patients than in untreated patients (32 of 218 [15%] vs. 12 of 212 [6%]; adjusted hazard ratio, 2.1 [CI, 1.06 to 4.06]; P = 0.034)., Limitations: Nonrandom, unblinded treatment assignment was used, and follow-up data were missing for 20% of patients. Loss to follow-up was more common among patients who were less sick. Two uncontrolled interim analyses were conducted., Conclusions: Compared with no treatment, benznidazole treatment was associated with reduced progression of Chagas disease and increased negative seroconversion for patients presenting with nonacute disease and no heart failure. These observations indicate that a randomized, controlled trial should now be conducted.

Introduction and Objectives: Chagas disease is the most common cause of myocarditis in Latin America, including Venezuela. Some 25% of patients progress to chronic chagasic cardiomyopathy, which is characterized by heart failure and arrhythmias. The serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) have prognostic value in non-chagasic cardiopathy. The goal of this study was to investigate the relationship between the serum levels of CRP and IL-6 and the developmental stage of Chagas disease., Patients and Method: The study included 64 Chagas disease patients (34 female and 30 male; age 62.2 [1.7] years) and 20 healthy individuals (10 of each sex; age 50.4 [2.7] years). Clinical investigations included echocardiography and measurement of CRP and IL-6 serum levels using ELISAs. Chagas disease patients were graded according to Carrasco et al 1994 classification. Patients with ischemic cardiopathy, liver disease, autoimmune disease, a systemic inflammatory condition, immunosuppression, cancer, pericarditis, or endocarditis were excluded., Results: Multiple regression analysis demonstrated an association between Chagas disease developmental stage and the serum IL-6 level. The serum CRP level increased during only the most advanced phase of the disease. In addition, a high left ventricular mass index was associated with a high IL-6 level and male sex., Conclusions: IL-6 and CRP serum levels could be of prognostic value in assessing Chagas disease progression because there are significant correlations between elevated levels and the deterioration of cardiac function.

There is growing evidence to suggest that chagasic myocardia are exposed to sustained oxidative stress-induced injuries that may contribute to disease progression. Pathogen invasion- and replication-mediated cellular injuries and immune-mediated cytotoxic reactions are the common source of reactive oxygen species (ROS) in infectious etiologies. However, our understanding of the source and role of oxidative stress in chagasic cardiomyopathy (CCM) remains incomplete. In this review, we discuss the evidence for increased oxidative stress in chagasic disease, with emphasis on mitochondrial abnormalities, electron transport chain dysfunction and its role in sustaining oxidative stress in myocardium. We discuss the literature reporting the consequences of sustained oxidative stress in CCM pathogenesis.

Heart transplantation (HT) remains the treatment of choice for advanced chagasic cardiomyopathy. New immunosuppression protocols have provided better control of rejection (RJ) and cardiac allograft vasculopathy. However, their influence on infection and Chagas disease reactivation (CDR) is not well established. The aim of this study was to compare the CDR rate in patients under two different immunosuppression protocols. We studied 39 chagasic patients who had undergone orthotopic HT between April, 1987 and June, 2004. They were divided into two groups, one taking azathioprine (group 1=24 patients) and the other taking mycophenolate mofetil (group 2=15 patients), in the standard doses (2 mg/kg/day and 2 g/day, respectively), beside prednisone and cyclosporine, in equivalent doses. The number of CDR and RJ episodes were analyzed in the first and second years after HT. CDR rates were 8%+/-5% at 1 year and 12%+/-6% at 2 years of follow-up in group 1. Otherwise, patients in group 2 presented CDR rates of 75%+/-10% and 81%+/-9% at the same periods, respectively (p<0.0001, hazard ratio=6.06). When comparing RJ rates in the first year after HT, both groups had similar behavior under both immunosuppression protocols (p=0.88). These data show that current prescribed doses of mycophenolate mofetil increase the early risk of CDR without changing RJ incidence in this period.

On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1flox/flox;alpha-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1flox/flox;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with Trypanosoma cruzi. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1flox/flox;alpha-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1flox/flox;alpha-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1flox/flox;alpha-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1flox/flox;alpha-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.

Chagas' disease, caused by Trypanosoma cruzi, has been considered a paradigm of infection-induced autoimmune disease. Thus, the scarcity of parasites in the chronic phase of the disease contrasts with the severe cardiac pathology observed in approximately 30% of chronic patients and suggested a role for autoimmunity as the origin of the pathology. Antigen-specific and antigen-non-specific mechanisms have been described by which T. cruzi infection might activate T and B cells, leading to autoimmunity. Among the first mechanisms, molecular mimicry has been claimed as the most important mechanism leading to autoimmunity and pathology in the chronic phase of this disease. In this regard, various T. cruzi antigens, such as B13, cruzipain and Cha, cross-react with host antigens at the B or T cell level and their role in pathogenesis has been widely studied. Immunization with those antigens and/or passive transfer of autoreactive T lymphocytes in mice lead to clinical disturbances similar to those found in Chagas' disease patients. On the other hand, the parasite is becoming increasingly detected in chronically infected hosts and may also be the cause of pathology either directly or through parasite-specific mediated inflammatory responses. Thus, the issue of autoimmunity versus parasite persistence as the cause of Chagas' disease pathology is hotly debated among many researchers in the field. We critically review here the evidence in favor of and against autoimmunity through molecular mimicry as responsible for Chagas' disease pathology from clinical, pathological and immunological perspectives.

In this study, we evaluated the oxidant status and antioxidant defense capabilities of the heart during the course of Trypanosoma cruzi infection and disease development in a murine model system. Our data show that the extent of protein carbonylation and lipid peroxidation is increased in the heart, but not the skeletal muscle, of infected mice. The level of oxidative injury biomarkers in the myocardium consistently increased with chronic disease severity. The antioxidant defense constituted by catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GSR), and reduced glutathione was increased in murine heart and skeletal tissue in response to the stress of T. cruzi infection. After the initial burst, CAT, GPx, and GSR remained unresponsive to the severity of chronic tissue damage in chagasic hearts. The cardiac level of Mn(2+) superoxide dismutase (MnSOD) was diminished in chagasic mice. Our data suggest that the host responds to acute injuries by activating antioxidant defenses that are of sufficient magnitude to scavenge the reactive oxidants in skeletal tissue. The myocardia of infected mice, however, sustain increased oxidative injuries with disease progression. We surmise that MnSOD deficiencies, resulting in the increased release of mitochondrial free radicals, lead to sustained oxidative stress that exceeds the cardiac antioxidant defense capacity and contribute to persistent oxidative damage in chagasic myocardium.

A progressive destruction of the myocardium occurs in approximately 30% of Trypanosoma cruzi-infected individuals, causing chronic chagasic cardiomyopathy, a disease so far without effective treatment. Syngeneic bone marrow cell transplantation has been shown to cause repair and improvement of heart function in a number of studies in patients and animal models of ischemic cardiopathy. The effects of bone marrow transplant in a mouse model of chronic chagasic cardiomyopathy, in the presence of the disease causal agent, ie, the T. cruzi, are described herein. Bone marrow cells injected intravenously into chronic chagasic mice migrated to the heart and caused a significant reduction in the inflammatory infiltrates and in the interstitial fibrosis characteristics of chronic chagasic cardiomyopathy. The beneficial effects were observed up to 6 months after bone marrow cell transplantation. A massive apoptosis of myocardial inflammatory cells was observed after the therapy with bone marrow cells. Transplanted bone marrow cells obtained from chagasic mice and from normal mice had similar effects in terms of mediating chagasic heart repair. These results show that bone marrow cell transplantation is effective for treatment of chronic chagasic myocarditis and indicate that autologous bone marrow transplant may be used as an efficient therapy for patients with chronic chagasic cardiomyopathy.