Case Report: A Case of Post-Transplant Chagas Reactivation after Negative Trypanosoma cruzi Testing.

Patients with Chagas cardiomyopathy carry a significant risk of reactivation after heart transplantation. Reactivation of Chagas disease can lead to graft failure or systemic complications such as fulminant central nervous system disease and sepsis. As such, careful screening for Chagas seropositivity prior to transplant is crucial to preventing negative outcomes in the post-transplant setting. One challenge in screening these patients is the variety of laboratory tests available and their differing sensitivities and specificities. In this case report, we present a patient who tested positive by a commercial Trypanosoma cruzi antibody assay and later tested negative by CDC confirmatory serological analysis. After the patient underwent orthotopic heart transplant, he underwent protocol-based polymerase chain reaction surveillance for reactivation as a result of persistent concerns for T. cruzi infection. It was discovered shortly thereafter that the patient had reactivation of Chagas disease, confirming that he did have Chagas cardiomyopathy prior to transplantation, despite negative confirmatory testing. This case illustrates the complexities of serological diagnosis of Chagas disease and the importance of additional testing for T. cruzi when the post-test probability remains high even with a commercial, negative serologic test.

Chronic Chagas Disease-the Potential Role of Reinfections in Cardiomyopathy Pathogenesis.

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.

Revisiting the History of Chagas Disease: "Live to tell"

Abstract In 1907, Carlos Chagas was designated to fight paludism in the Rio das Velhas region along the Central do Brasil railroad. During his field research, Chagas discovered a hematophagous insect ( Panstrongylus megitus ) carrying a new trypanosomatide, which he named Trypanosoma cruzi . On April 14th, 1909, he found the same parasite in the blood of a febrile child, submitting the announcement of his discoveries to the Brasil Médico scientific journal. Here, we discuss the early stages in the establishment of a new human morbid entity during the first decades after its discovery with a definite influence from its discoverer, Carlos Chagas, as well the first collaborators. Moreover, we cover the importance of the Center for the Study and Prophylaxis of Chagas Disease in Bambuí (MG), unraveling the most advanced developments in research within the disease's habitat and the widening perspectives for modern research that have emerged after the 1960s and continue to improve to this day. In this revisitation to the history of Chagas disease, we begin at Manguinhos (RJ ), making our way to Lassance (MG), where the discovery took place. Then, we travel back to Rio de Janeiro in the beginning of the twentieth century and Brazilian republic until the current day, revealing milestone publications that settled Chagas disease both as a source of pride for Brazilian medicine and as a challenge with important aspects that remain to be clarified. Any similarities to our country's politics and economy in the twentieth century are not mere coincidences.

MICA and KIR: Immunogenetic Factors Influencing Left Ventricular Systolic Dysfunction and Digestive Clinical Form of Chronic Chagas Disease.

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.

Autoantibodies against the immunodominant sCha epitope discriminate the risk of sudden death in chronic Chagas cardiomyopathy.

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.

Prevalence of Chagas heart disease in dilated cardiomyopathy / Prevalencia de cardiopatía chagásica en la miocardiopatía dilatada

Abstract 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.

Resumen Objetivo: El objetivo principal del estudio es conocer la prevalencia de tripanosomiasis americana en pacientes con cardiomiopatía dilatada, en un hospital de concentración en el occidente de México. Métodos: Desde enero de 1991 a febrero de 2016 se incluyeron 387 pacientes consecutivos con diagnóstico de cardiomiopatía dilatada, se excluyeron los casos con dilatación ventricular secundaria a cardiopatía isquémica, valvulopatías, hipertensión arterial sistémica, enfermedad pulmonar, enfermedad pericárdica o cardiopatías congénitas. El diagnóstico se realizó mediante la detección de anticuerpos anti-tripanosoma cruzi con 2 métodos positivos diferentes o con la detección del parásito en sangre. Resultados: Se incluyeron 387 paciente con cardiomiopatía dilatada, en el 6.9% se confirmó cardiopatía chagásica; dos pacientes en fase aguda (uno con sospecha de transmisión transfusional). La mayoría de los pacientes provenían de zonas rurales. El 96.2% de los casos presentó insuficiencia cardiaca congestiva, un paciente con aneurisma apical del ventrículo izquierdo solo manifestó palpitaciones. El 66% presentó bloqueo de la rama derecha del haz de His, hemibloqueo anterior izquierdo o la asociación de ambos, en el 14.8% se encontró taquicardia ventricular no sostenida. Conclusiones: La cardiopatía chagásica es frecuente en nuestro medio, principalmente en personas que nacieron o vivieron durante la infancia en áreas rurales. Es causa común de insuficiencia cardiaca. La cardiomiopatía chagásica debe sospecharse en pacientes que reciben transfusión sanguínea, incluso sin otros antecedentes epidemiológicos

Prevalence of Chagas heart disease in dilated cardiomyopathy.

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.

Myocardial Involvement in Chagas Disease and Insulin Resistance: A Non-Metabolic Model of Cardiomyopathy.

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.

Lack of Association of IL6 polymorphism with the susceptibility to Chagas disease in Latin American populations.

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.

A retrospective study on the influence of siblings' relatedness in Bolivian patients with chronic Chagas disease.

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.

Chagas Cardiomyopathy in Latin America Review.

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.

Case Report: High Mannose-Binding Lectin Serum Determined by MBL2 Genotype and Risk for Clinical Progression to Chagasic Cardiomyopathy: A Case Report of Three Patients.

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.

High fat diet aggravates cardiomyopathy in murine chronic Chagas disease.

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.

Pathology and Pathogenesis of Chagas Heart Disease.

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.

Autoimmunity in Chronic Chagas Disease: A Road of Multiple Pathways to Cardiomyopathy?

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.

Heart transplant outcomes in patients with Chagas cardiomyopathy in the United States.

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.

Chronic Chagas Heart Disease Management: From Etiology to Cardiomyopathy Treatment.

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.

Heart Transplantation for Chagas Cardiomyopathy.

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.

Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial

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.