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Arq. Bras. Cardiol. vol.97 no.2 supl.3 São Paulo 2011
Sociedade Brasileira de Cardiologia
COORDINATOR OF REGULATIONS AND GUIDELINES OF SBC
Jadelson Pinheiro de Andrade
COMMISSION OF WORDING AND SYNTHESIS
Angelo Amato Vincenzo de Paola, Fábio Vilas-Boas, Gláucia Maria Moraes Oliveira, Jadelson Pinheiro de Andrade and José Antônio Marin Neto
NATIONAL ORGANIZING COMMITTEE
Antônio Carlos Palandri Chagas, Fábio Vilas-Boas, Eduardo Augusto Victor Rocha, Gláucia Maria Moraes Oliveira, Jadelson Pinheiro de Andrade, Leandro Ioschpe Zimerman, Luiz Antonio de Almeida Campos, Marcelo Westerlund Montera, Márcia de Melo Barbosa and Jorge Ilha Guimarães
INTERNACIONAL ORGANIZING COMMITTEE
Carlos Morillo (Canada), Harry Acquatella (Venezuela), Jorge Mitelman (Argentina), Juan Bautista Gonzalez Moreno (Uruguay), Luisa Gimenez (Argentina) and Wistremundo Dones (Puerto Rico)
Abílio Augusto Fragata Filho, Angelo Amato Vincenzo de Paola, Dirceu Rodrigues Almeida, Edimar Alcides Bocchi, Fábio Vilas-Boas, Fernando Bacal, João Carlos Pinto Dias, José Antônio Marin Neto, Maria da Consolação Vieira Moreira, Sérgio Salles Xavier, Wilson Alves de Oliveira Junior
Group 1 - Introduction and Epidemiology
Coordinator: Fernando Bacal
Participants: Armênio Costa Guimarães, Felix Jose Alvarez Ramires and João Manoel Rossi Neto
Group 2 - Pathogenesis and Pathophysiology of Chronic Chagas' Heart Disease
Coordinator: Jose Antonio Marin Neto
Participants: Andréa Silvestre de Sousa, Antonio Luiz P. Ribeiro, Edécio Cunha Neto, Roberto Coury Pedrosa and Zilton A. Andrade
Group 3 - Clinical Presentation and Classification
Coordinator: Fabio Vilas-Boas Pinto
Participants: Antonio Carlos Pereira Barretto, Barbara Maria Ianni, Salvador Rassi and Sergio Perrrone (Argentina)
Group 4 - Clinical Diagnosis, Differential Diagnosis and Prognosis of Chronic Chagas' Heart Disease
Coordinator: Dirceu Rodrigues Almeida
Participants: Alejandro Luquetti Ostermayer, Antonio Carlos Pereira Barretto, Carlos Eduardo Rochitte, Renato Barroso Pereira de Castro
Group 5 - Etiological Treatment of Chagas' Heart Disease
Coordinator: Abilio Augusto Fragata Filho
Participants: Alejandro Luquetti Ostermayer, Maria de Lourdes Higuchi and Salvador Rassi
Group 6 - Treatment of Heart Failure in Chagas' Heart Disease
Coordinator: Maria da Consolação Vieira Moreira
Participants: Barbara Maria Ianni, Carlos Morillo (Canada), Faustino Torrico (Bolivia), Felix José Alvarez Ramires, Luciana Armaganijan (Canada) and Reinaldo Bestetti
Group 7 - Treatment of Arrhythmias and Conduction Disturbances in Chagas' Heart Disease
Coordinator: Angelo Amato Vincenzo de Paola
Participants: Adalberto Menezes Lorga Filho, Diego Vanegas (Colombia), Eduardo Argentino Sosa, Guilherme Drummond Fenelon Costa, Luiz Roberto Leite da Silva, Martino Martinelli Filho and Silas dos Santos Galvão Filho
Group 8 - Heart and Cell Transplantation and Other Surgical Therapies in Chronic Chagas' Heart Disease
Coordinator: Edimar Alcides Bocchi
Participants: João David de Souza Neto, Jose Henrique Andrade Vila, Maria de Lourdes Higuhi, Mirta Diez (Argentina), Reinaldo Bulgarelli Bestetti, Ricardo Ribeiro dos Santos and Victor Sarli Issa
Group 9 - Special Subgroups in Chagas' Heart Disease: Co-infection (HIV), Immunosuppressive Therapy and Non-heart Transplant, Pregnant; Newborn; Children and adolescents; Seropositive and Blood Banks
Coordinator: Sergio Salles Xavier
Participants: Alejandro Marcel Hasslocher Moreno, Ana Marli C. Sartori, Andréa Silvestre de Sousa, Christina Gallafrio Novaes, Jaime Altcheh and Pedro Emmanuel Alvarenga Americano do Brasil
Group 10 - Recommendations for the Establishment of Structured Monitoring Services to Patients with Chronic Chagas' Heart Disease
Coordinator: Wilson Alves de Oliveira Junior
Participants: Alejandro Marcel Hasslocher Moreno, Dayse Elizabeth Campos, Divina Seila de Oliveira Marques, Maria da Glória Aureliano de Melo Cavalcanti, Jorge Mitelman (Argentina) and Silvia Marinho Martins
Group 11 - Recommendations for Public Health Strategies, Transmission Control and Eradication of Chagas' Disease; Identification of Seropositive; Vector Control and Legal Medicine Aspects
Coordinator: João Carlos Pinto Dias
Participants: Alejandro Luquetti Ostermayer, Antônio Carlos Silveira, Hélio de Souza and Roberto Salvatella (Uruguay)
The guideline should be cited as:
Andrade J.P., Marin-Neto J.A., Paola A.A.V., Vilas-Boas F., Oliveira G.M.M., Bacal F., Bocchi E.A, Almeida D.R., Fragata Filho A.A., Moreira M.C.V., Xavier S.S., Oliveira Junior W. A., Dias J.C.P. et al. Sociedade Brasileira de Cardiologia. I Diretriz Latino Americana para o Diagnóstico e Tratamento da Cardiopatia Chagásica. Arq Bras Cardiol 2011; 97(2 supl.3): 1-48.
We used the following definitions for degree of recommendation and level of evidence:
Class of recommendation
Class I: Conditions for which there is conclusive evidence, or, if not, there is consensus that the procedure is safe and useful/effective.
Class II: Conditions for which there is conflicting evidence and/or divergent opinions about the procedure's safety and usefulness/effectiveness.
Class IIa: Weight or evidence/opinion in favor of the procedure. Approved by most professionals.
Class IIb: Safety and usefulness/effectiveness less well established, with no predominance of opinions in favor of the procedure.
Class III: Conditions for which there is evidence and/or consensus that the procedure is not useful/effective and, in some cases, that it may be detrimental.
Level of Evidence
Level A: Data derived from multiple significantly sized randomized trials, consistent and/or robust meta-analysis of randomized clinical trials.
Level B: Data derived from less robust meta-analysis, grounded on a single randomized trial or nonrandomized (observational) trials.
Level C: Data derived from consensual opinions of experts.
Note that the levels of evidence classified as B or C may not be interpreted as weak recommendations. There are many consensual recommendations; thus having class of recommendation I, level of evidence C (expert opinions). On the other hand, some indications considered controversial (class of recommendation II) may be grounded on randomized controlled trials (level of evidence A).
The description of the life cycle of Chagas' Heart Disease by the Brazilian scientist Carlos Chagas, published in "Memórias do Instituto Osvaldo Cruz", entitled "Nova tripanosomiaze humana. Estudos sobre a morfolojia e o ciclo evolutivo Schizotrypanum cruzi n. gen. n SP., agente etiológica de nova entidade mórbida no homem" has celebrated its 100-year anniversary in 2009.
Given the relevance and significance of this fact for the Brazilian and international Medicine, the Executive Board of Sociedade Brasileira de Cardiologia (SBC) proposed that this date be celebrated producing a guideline on the diagnosis and treatment of the Chagas' Heart Disease.
Looking at the overall current scenario for the Chagas' Heart Disease, a relevant pidemiological issue in several South American and North American countries, including countries in Europe and other continents, SBC chose to invite the South American and Inter-American Societies of Cardiology to prepare together this document and, on account of that, the I Latin American Guideline for the Diagnosis and Treatment of Chagas' Heart Disease was outlined.
The guideline was prepared with an editorial board made up of Brazilian and Latin American cardiologists. The cardiologists participating in the joint effort have recognized expertise and qualifications in the subject, which is substantiated by a number of papers published in reference scientific journals nationally and internationally. Furthermore, they were supported by a large group of cardiologists, having similar qualifications, and integrating and forming working groups.
SBC intends that the scope of this objective be widened, in concert with the Latin American Cardiology Societies, so as to reflect the international scientific knowledge and thereby gain acceptance, recognition and application by cardiologists of the countries involved.
The Brazilian, South American and Inter-American Societies of Cardiology, in addition to the editors and the entire group of professionals cooperating in the drafting of this guideline expect that its development and disclosure contribute to an enhanced coping and regulating of the behavior towards prevention, diagnosis and treatment of all forms of Chagas' Heart Disease.
1. Introduction and epidemiology
The 100th anniversary of the discovery of Chagas disease (CD) is celebrated with the publication of the first Latin American Guideline for the Management and Treatment of CD, and with homage paid to Carlos Chagas (Figure 1). With his geniality, he described the disease, from its etiology to its clinical findings, including its major mode of transmission and epidemiology. Differently from what Carlos Chagas did, the clinical-epidemiological presentation of an infectious disease usually motivates the search for its causative agent and mode of transmission, such as happened with Mycobacterium tuberculosis, discovered by Robert Koch in 1882.
At the end of 1907, already a physician at Instituto Oswaldo Cruz, where he entered in 1906, three years after graduating at the Rio de Janeiro Medical School, currently known as Medical School of the Rio de Janeiro Federal University, Carlos Chagas and Belisário Penna were designated by Oswaldo Cruz to control the outbreak of malaria in Lassance, a village in the state of Minas Gerais, close to the margins of the São Francisco river, where malaria hindered the work at the camping site of the Central do Brasil Railroad. Right after arriving at Lassance, the railroad engineer Cantarino Mota made Carlos Chagas aware of an insect that lived in the crevices of the mud walls of the thatched-roof houses. The insects emerge at night, when the inhabitants are sleeping, and tend to feed on blood on people's faces, being known as "barbers"1. Carlos Chagas initiated then an investigation that showed his brilliant innate talent as a researcher. He found protozoa in the intestine of those hematophagous insects, which he sent to the Instituto Oswaldo Cruz. There those insects infected experimental animals, which became ill, and, in their blood, a new species of parasite was identified, being named Trypanosoma cruzi (T. cruzi) after Oswaldo Cruz. The human disease was characterized on April 23rd, 1909, when the T. cruzi was identified in the blood of a 2-year-old girl with an acute febrile disease, called Berenice. That was the first case of acute CD described, whose patient survived. In that same year, Carlos Chagas disseminated his discovery, describing the disease cycle in brief notes in the Brasil Médico and in the Archiv fur Schiffs-und Tropen Hygiene, followed by an extensive article, in Portuguese and German, published in the Memórias do Instituto Oswaldo Cruz, entitled "Nova tripanosomiaze humana. Estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n sp., ajente etiolojico de nova entidade morbida do homem2".
From the identification of the new disease in 1909 until Carlos Chagas' death in 1934, he dedicated himself to widen the knowledge on the American trypanosomiasis. The village of Lassance became a permanent site for the study of that and other rural endemic diseases. In 1912, Oswaldo Cruz received federal government funding to map the geographic distribution of the disease, to equip a small hospital in that railroad station, and to begin simultaneously at Manguinhos the construction of a hospital aimed at studying the cases referred from that site. The continuation of the research in Lassance and at the Instituto Oswaldo Cruz allowed Chagas to develop a complete study on the essential features of the new trypanosomiasis. Chagas counted on several researchers from Manguinhos to help him with that task, mainly Gaspar Vianna, Arthur Neiva, Eurico Villela, Magarinos Torres, César Guerreiro, Astrogildo Machado, Evandro Chagas and Emmanuel Dias.
Finishing his cycle of direct contribution on CD, Carlos Chagas has published a review article3 approaching the epidemiology and etiopathogenesis of the disease, with emphasis on its congenital transmission, then described by Gaspar Vianna, one of his collaborators. It is worth noting the description of clinical forms with a rare lethal outcome or remission in the acute phase, as well as the progression to heart failure (HF) and/or sudden death (SD) in the chronic forms. Sudden death, as a primary event in that disease progression, was frequently registered in endemic areas, affecting apparently healthy individuals; HF, however, characterized the clinical form that served as a base for the clinical and pathological recognition of that disease. In addition, atrial, ventricular and atrioventricular arrhythmias, common in that condition, were described in details, the latter as variable bundle-branch block. That review article carefully recorded arterial and venous pulse by use of direct technique, and later by use of electrocardiogram (ECG), a then incipient technique, better mastered by the cardiologist Eurico Villela.
Of the speculations about not granting the Nobel Prize to Carlos Chagas, two aspects are worth noting: first, the lack of massive support of the Brazilian scientific and academic community to the indications; and, second, the fact that the disease was is restricted to Latin American countries, which are not within the colonial interests of European nations and the United States of America. Nevertheless, History has paid homage to the scientific contribution of Carlos Chagas, who should remain as a paradigm of scientist, physician and sanitarian for Brazilians and the rest of the world4.
1.1. Epidemiological aspects in Brazil
Since its description, the attempt to control CD transmission in Brazil has proved to be a challenge. In the 1970's, there were intense efforts and political and social pressures as organized acts of campaigns to control the disease. However, it was only in 1991 that the development of the Subregional Initiative for CD Control by the Southern Cone Countries boosted that control5.
Organized and coordinated campaigns to control the triatomine vector and the transmission via transfusion, with greater strictness in blood banks, have provided a significant reduction in new cases. In June 2006, the World Health Organization (WHO) issued the certificate of elimination of CD transmission via the wild vector Triatoma infestans (T. infestans) to Brazil 6. This, somehow, represents the disease eradication, because isolated outbreaks in different Brazilian states and registration of sporadic acute cases continue to occur. The reduction in transmission is confirmed by comparing 1975-1985 data, approximately 4,500,000 infected individuals, with data from 30 years later, estimated 1,900,000, in 20057. A survey conducted by the Brazilian Ministry of Health, assessing the result of the Southern Cone program for that disease control, evidenced that, from 1975 to 1995, 89% of the potential transmissions were prevented, thus avoiding approximately 2,339,000 new cases and 337,000 deaths. That assessment has also shown the cost-effectiveness of the CD control program, evidencing that, for each US$ 1.00 spent, US$ 17.00 were saved8,9. With better control of the vectorial and transfusional modes of transmission, the oral mode has gained relative importance, as seen in the following outbreaks: 2005, in the states of Santa Catarina and Pará; 2006, in the states of Ceará and Pará; and 2007, in the states of Pará and Amazonas. In the Amazon region, the number of acute cases has increased, from less than 10 in 1968 to almost 100 in 2007. This has mainly occurred as isolated outbreaks usually with oral transmission, or, less frequently, via isolated nondomiciliary vectors, or still via human exposure to vectors in the wild10,11. Because of that increase in the number of cases in the Amazon region, a specific program (AMCHA) was created in 2004 to map and detect the disease transmission12.
A serological inquiry performed with schoolchildren from 7 to 14 years of age, in 1994-1997, revealed a 0.05% seroprevalence13. In 1999, for that same age group, the prevalence of T. cruzi-infected individuals was 0.04%. In 2005, the screening of Brazilian blood banks showed 100% assessment of the samples regarding a possible T. cruzi infection, with only 0.21% seropositivity14.
Thus, in Brazil, permanent surveillance is required, as well as the continuity of control programs for other modes of transmission, whose results will be assessed in the medium and long run.
1.2. Epidemiology of Chagas disease in Latin America and the rest of the world
Chagas disease is crossing the borders of countries historically known as its major sources.
The exodus of millions of Latin Americans to more developed countries has been decisive to the fact that over 100,000 chronically infected individuals are now living in the United States. In addition, other cases of T. cruzi infection were associated with blood transfusion and transplantations in the United States of America, Canada and several European countries, where screening for CD in donors was not performed until recently15.
In the United States of America, the concern about CD has increased to a point that it is now considered a prevalent disease and an important differential diagnosis in several clinical settings16. A recent analysis with immigrants (data from the PEW Hispanic Center and US Department of Homeland Security) estimates that 300,000 individuals have T. cruzi infection, and between 30,000 and 45,000 have clinical disease. Similarly to classically endemic countries, in the United States of America, most individuals with T. cruzi infection have neither signs nor symptoms of chronic CD, being considered as having the indeterminate form17. Since 2007, comprehensive screening of blood and organ donors have been federally enforced in the United States of America, contributing to increase the visibility of CD18.
In Spain, where most immigrants come from Bolivia, whose CD prevalence is between 20% and 40%, a recent communication has revealed that, in the past two years, the CD prevalence among Bolivian pregnant women at a Spanish hospital was 17.7%, with a vertical transmission rate of 1.4%19.
Thus, new epidemiological, socioeconomic and political problems have been recently arisen created, resulting from CD globalization, due to legal and illegal migration from endemic to non-endemic countries, mainly the United States of America, Canada, Spain, France, Switzerland, Italy, Japan, Asian emerging countries and Australia (Figure 2)20. Compounding those problems, the following issues are worth noting: the risk for transfusional and congenital transmission; the need for medical care; difficulties in CD diagnosis due to the lack of experience of physicians in recognizing the disease pathology; and need for additional control at blood banks in countries with little experience in the topic. Such epidemiological aspects differ from those in endemic countries. In the Americas, the CD epidemiological characteristics can be distributed in the following groups of countries according to the transmission cycle and the transfusion and vector control programs (Figure 3)21:
Group I - Argentina, Bolivia, Brazil, Chile, Ecuador, Honduras, Paraguay, Peru, Uruguay and Venezuela have domestic, peridomiciliary and wild transmission cycles, with a high prevalence of human infection and predominance of chronic Chagas cardiopathy (CCC).
Group II - Colombia, Costa Rica and Mexico have domestic and peridomiciliary transmission cycles, and CCC.
Group III - El Salvador, Guatemala, Nicaragua and Panama have domestic, peridomiciliary and wild transmission cycles, with deficient clinical information.
Group IV - Antilles, Bahamas, Belize, Cuba, United States of America, Guyana, French Guiana, Haiti, Jamaica and Suriname have wild transmission cycles and scarce clinical information21.
1.3. Control measures for disease transmission
An overview of CD allowing the definition of comprehensive preventive strategies has been provided by a cross-sectional epidemiological survey individually conducted in 15 Latin American countries since the 1980s. The results have shown that the original endemic areas with domiciliary vectorial transmission to humans comprised 18 countries with the highest T. cruzi-infection rates, infested with T. infestans (Southern Cone countries) and Rhodnius prolixus (Andean and Central American countries), which are the best adapted triatomine species to the human household22.
The most effective means to interrupt the transmission of T. cruzi infection have also been indicated: 1) implementation of vector control activities in the household aimed first at reducing, and, then, at eliminating the T. cruzi vectorial transmission; and 2) development and implementation of policy for blood screening for human use to prevent CD transfusional transmission.
In 1975, the program to control CD vectorial transmission was initiated in Brazil. This consisted of insecticide spraying in the houses and around them, aiming at interrupting the domestic and peridomiciliary transmission cycles involving vectors, and animal and human reservoirs. In addition, sanitary educational measures have been adopted and a monitoring system involving the local community members has been established. In Brazil, those programs proved effective to eliminate the T. infestans domiciliary vector, the most important vector from the epidemiological viewpoint23. At the beginning of the program, 711 municipalities had T. infestans-infested houses. A significant reduction in the number of T. infestans-infested houses was observed: from 166,000 insects collected in the control program in 1975 to only 6,111 insects collected in 1999. The mean infestation rate dropped to 1 insect to every 10,000 houses investigated, a figure significantly lower than the minimum required for disease transmission21,22. The prevalence of human T. cruzi infection at young age groups can also be considered a control index of disease transmission. As previously reported, for in the age group of 7-14 years, in 1999, a 0.04% positivity rate was observed, representing a 99.8% reduction as compared with 18.5% observed in 198014. In 2007, the results of 94,000 serological tests in samples of 0 to 5 years indicated 0% positivity rate.
2. Pathogenesis and pathophysiology of chronic Chagas cardiopathy
Chronic Chagas cardiopathy is essentially a dilated cardiomyopathy, in which chronic inflammation, usually mild and continuous, causes progressive tissue destruction and extensive heart fibrosis. Several mechanisms contribute to the pathogenesis of the cardiac lesions and consequent installation of the pathophysiological disorders, according to recent reviews24-28.
2.1. Cardiac dysautonomia
Several independent postmortem studies with chagasic patients and experimental models of T. cruzi infection have evidenced neuronal depopulation, predominantly of the cardiac parasympathetic system29. Such pathological changes are accompanied by cardiac dysautonomia, confirmed by several researchers with varied methods of functional assessment. They precede the appearance of ventricular dysfunction, being found even in the indeterminate and digestive forms of the disease24,30,31. As a consequence of those functional disorders of the cardiac autonomic regulation, chronic chagasic patients can be deprived of the vagal inhibitory control normally exerted on the sinus node and other cardiac structures. In addition, they can become incapable of rapid chronotropic adjustments in response to physiological stimuli, such as posture changes and physical exercise, mediated by the vagal system24,30. Furthermore, the implication of loss of cardiac parasympathetic control in mechanisms of SD in CCC would be a plausible pathophysiological hypothesis. Although to a lesser extent, structural and functional changes of the cardiac sympathetic system, such as at the ventricular level, also occur in association with myocardial contractility and perfusion disorders32. Circulating antibodies, capable of interfering with receptors of both sympathetic and vagal systems, are likely to affect pathophysiologically the cardiac autonomic behavior and to modulate electrophysiological properties involved in the mechanisms of malignant arrhythmias33. However, the role played by those antibodies in the genesis of myocardial changes is still unclear, and not correlated with ventricular contractility dysfunction34.
Briefly, although morphological and functional changes of the cardiac autonomic system are detected in some chronic chagasic patients, they vary in intensity and do not correlate directly with the degree of ventricular depression. Thus, the "neurogenic theory", as understood on pioneer studies29, does not convince to explain myocardial destruction in CCC24.
2.2. Microcirculatory disorders
Experimental models of T. cruzi infection have evidenced microvascular changes, such as the formation of microthrombi associated with microcirculatory spasm, endothelial dysfunction and increased platelet activity35. Such microcirculatory disorders might result from the inflammation directly related to T. cruzi or mediated by immune injury36. Those microcirculatory changes are considered to amplify the inflammatory effects and to cause myocardial ischemia24. Several patients with CCC manifest angina-like symptoms, have electrocardiographic changes suggestive of ischemia and various myocardial perfusion defects32,37. Their epicardial coronary arteries are usually angiographically normal, but can react abnormally to vasodilating or vasoconstricting stimuli37,38. It has been postulated that such microcirculatory changes cause hypoperfusion in myocardial areas relatively devoid of coronary branches (zones of marginal perfusion or "watersheds"), being associated with the formation of aneurysms in the apical and posterior basal left ventricular (LV) walls39.
Similarly to the "neurogenic theory", the "microvascular hypothesis" still requires more convincing clinical support, but, despite not being an independent pathogenic mechanism of CCC, it can potentiate chronic myocardial inflammation.
2.3. Immunopathological mechanisms
There is experimental evidence that, after the intense myocarditis of the acute phase of CD, when parasitemia and tissue parasitosis are controlled by immune mechanisms, inflammation subsides and persists focally at low intensity during the indeterminate form of disease40. It has been postulated that the balance and relative pathological stability of that the indeterminate form, in which the immune mechanism should be essentially modulated in the protective direction, are disrupted by still obscure factors, when inflammation, necrosis and fibrosis become more intense, diffuse and progressive24-27,39,41. Several factors can determine the stability or instability of the process: parasite load, parasite strain or tissue tropism, duration of infection, and genetic components of the host. The existence of proper immunoregulatory mechanisms are believed to be crucial in differentiating individuals who control their infection without developing important tissue damage (through limited inflammatory response) from those progressing to severe disease, with intense inflammation, necrosis and reactive fibrosis.
There is unequivocal evidence that autoimmune pathogenic reactions occur in CCC, through molecular mimicry, polyclonal activation and other mechanisms24-27,42.. It is not clear whether the autoimmunity-dependent injury to cardiac structures is decisive for the installation of the characteristic lesions of CCC. Despite the current knowledge limitation, the theory that the immune system reaction to T. cruzi infection is actually a "two-edged sword" and plays as fundamental role in the chronic phase of chagasic myocarditis is supported by an extensive body of experimental and clinical evidence24-27,39-41.
2.4. Inflammation and tissue injury dependent on the parasite presence
In the chronic phase of CD, the classical histologic methods used to emphasize the absence or paucity of parasites in the hearts of T. cruzi-infected experimental animals or humans29. With more sensitive techniques [immunohistochemistry or polymerase chain reaction (PCR)], the persistence of parasites in myocardial inflammatory foci has been evidenced43,44. In addition, a reduction in the parasite load due to trypanocidal treatment in experimental animals and humans has been observed to attenuate or halt the progression of chronic myocarditis45,46. In contrast, T. cruzi reinfections or its multiplication during immunodepression exacerbate the inflammatory manifestations and CCC course47,48.
Based on that evidence, there is an emerging consensus that the essence of CCC pathogenesis resides on the inflammation directly dependent on the parasite persistence and consequent adverse immune reaction elicited by it24-28,49. This rescues the notion that, even in its chronic phase, the cardiopathy is essentially an infectious inflammatory process, requiring testing whether in that phase the trypanocidal treatment alters the natural history of CCC.
There is substantial evidence that the cytokines produced by T. cruzi-infected patients and animals can modulate the gene and proteomic expression of myocardial cells and other cardiac tissuecomponents50. Polymorphism of genes related to innate immune response and to cytokine production can influence the course of the pathogenetic process of CCC.
2.5. Pathophysiology of chronic Chagas cardiopathy
The cardiac injury in CD results from fundamental changes (inflammation, necrosis and fibrosis) caused directly or indirectly by T. cruzi in the specialized conducting tissue, contractile myocardium and intramural nervous system.
The frequent impairment of the sinus node, atrioventricular node and bundle of His due to inflammatory, degenerative and fibrotic changes can cause sinus node dysfunction and various types of varied atrioventricular and intraventricular blocks. The right bundle branch and the left anterior superior fascicle are more vulnerable and frequently affected because they are more individualized structures. Inflammatory foci and areas of fibrosis in the ventricular myocardium, especially in the posterior-lateral and inferior-basal regions, can produce electrophysiological changes, favoring the appearance of reentry. That is the major electrophysiological mechanism of malignant ventricular tachyarrhythmias, which cause SD even in patients with neither HF nor severe LV dysfunction.
Another consequence of the myocardial lesions is the biventricular dysfunction characteristic of CCC. Initially, there is regional impairment, similar to that which occurs in cardiopathy due to coronary obstruction, but, gradually, generalized dilation and hypokinesia develop, conferring the hemodynamic pattern of dilated cardiomyopathy on CCC.
Since the earliest phases, dyssynergia or ventricular aneurysms predispose to thromboembolic complications. In advanced stages, global dilation, venous stasis and atrial fibrillation are additional factors that propitiate the formation of thrombi and consequent pulmonary and systemic embolism, such as in the central nervous system51. That aspect confers on CCC, in addition to the predominant characteristic of causing malignant arrhythmias and refractory HF, the characteristic of essentially causing embolic complicationssm.
3. Clinical presentation and classification
According to its course, CD should be classified into two phases: acute and chronic. The acute phase can be due to primary infection or reactivation of the chronic phase. The chronic phase can have four clinical forms: indeterminate; cardiac; digestive; and mixed (cardiac and digestive impairment in the same patient). The cardiac form can occur with or without global ventricular dysfunction (usually called arrhythmogenic form). The chronic phase can also be classified into stages of cardiac impairment (A, B, C and D), according to international recommendations adapted to the chagasic etiology52.
Stage A comprises patients with the indeterminate form, with neither current nor previous HF symptoms and with normal ECG and chest radiography (XR) findings.
Stage B comprises patients with structural cardiopathy, who never had HF signs or symptoms. This stage contemplates two clinical situations: B1 and B2. Stage B1 comprises patients with electrocardiographic changes (conduction disorders or arrhythmias) and no ventricular dysfunction, who can have mild echocardiographic changes (regional contractility abnormalities), but normal global ventricular function. Stage B2 comprises patients with global ventricular dysfunction and reduced LV ejection fraction (LVEF).
Stage C comprises patients with current or previous HF symptoms and ventricular dysfunction [NYHA functional class (FC) I, II, III and IV].
Stage D comprises patients with HF symptoms at rest, refractory to maximized clinical treatment (NYHA FC IV), requiring specialized and intensive interventions.
That classification is simple, operational and consistent, allowing international understanding and comparison with other etiologies (Chart 1).
3.1. Acute phase
After the initial infection, the acute phase of CD lasts 6-8 weeks. The clinical findings are similar to those of other types of myocarditis, with systemic manifestations of fever, disproportional tachycardia, splenomegaly and edema. Inflammation can be observed at the site the parasites penetrate the skin. If the entrance site is the ocular region, conjunctivitis can occur accompanied by unilateral eyelid swelling and preauricular satellite adenopathy (Romaña's sign). The ECG can reveal sinus tachycardia, low-voltage QRS complexes, prolonged PR and/or QT interval, and alteration of ventricular repolarization. Ventricular arrhythmias, atrial fibrillation and right bundle-branch block can be observed, indicating worse prognosis53. When the disease transmission is congenital, hepatosplenomegaly, jaundice, cutaneous hemorrhage and neurological signs can supervene associate, especially in premature neonates. Other rarer conditions, such as oral contamination and laboratory accident, can lead to the acute form of disease54,55.
The acute phase is most frequently detected in children. If untreated, 5% to 10% of symptomatic patients die during that phase, due to acute HF or meningitis, SD being rare.
The acute phase can also result from the reactivation of a previously established infection in its chronic phase. Immunosuppressive conditions can cause parasite proliferation, necrotic or tumoral lesions in the brain and esophagus, and myocarditis aggravation56. This has been frequently observed in HIV coinfection, particularly with CD4 counts lower than 200/mL, and in organ transplantation57. Acute myocarditis and/or esophagitis have been observed with exacerbation of previous cardiopathy and congestive HF (CHF). After cardiac transplantation and in the presence of fever, myocarditis and cutaneous lesions, differentiating reactivation from rejection can be difficult58.
3.2. Chronic phase
After the initial acute phase, three clinical conditions can occur: indeterminate form; cardiac form without ventricular dysfunction; and cardiac form with ventricular dysfunction. This new classification should be preferred rather than the one previously used, which defined independent congestive and arrhythmic forms. Ventricular dysfunction, the major prognostic marker, is worth noting. Those clinical forms usually occur after the latency period of several decades that characterizes the indeterminate form59.
Given the current wide availability of echocardiography (ECHO), its performance should be considered as part of the initial assessment of patients with positive serology and whenever there are changes in the clinical or electrocardiographic findings. For patients with electrocardiographic changes, ambulatory ECG (Holter monitoring) should be considered at the initial assessment and later whenever warranted by the symptoms require (Table 1).
3.2.1. Indeterminate form
By definition, patients with the indeterminate form of CD have positive T. cruzi serology and/or parasitological tests, but neither symptoms, nor physical signs; in addition, they have no evidence of organic lesion (cardiac and extracardiac) on ECG and chest XR, and on any other radiological imaging study (esophageal and colon)60-62. However, more strict and sophisticated tests (ECHO, autonomic assessment, exercise testing, Holter monitoring, myocardial scintigraphy, magnetic resonance imaging, cardiac catheterization, and endomyocardial biopsy) can evidence some changes, usually mild and with no prognostic value established in any study61,63-66. Because such patients have chagasic infection, they are believed to be at an increased risk for developing HF and regional contractility abnormalities, and, thus, for progressing to the cardiac form of the disease.
The indeterminate form can last 30-40 years, and 30%-40% of the patients will eventually develop the cardiac form of CD62,67. The other patients will remain asymptomatic during their entire life, maintaining the immune balance between the parasite and the host68. The gradual appearance of electrocardiographic or echocardiographic changes marks the beginning of the chronic cardiac form69.
3.2.2. Cardiac form without ventricular dysfunction
Most commonly, arrhythmic manifestations coexist with congestive findings. Some patients, however, can have a form of chagasic cardiopathy characterized only by arrhythmias and intraventricular and atrioventricular conduction disorders, with normal ventricular function. Although malignant ventricular arrhythmia is more common among patients with concomitant ventricular dysfunction, it can also occur among those with preserved ventricular function, being an important prognostic marker70.
Arrhythmia-related symptoms include palpitations, dizziness, lipothymia and syncope. Syncope in chagasic cardiopathy can be due to both episodes of ventricular tachyarrhythmias and to sinus node dysfunction and atrioventricular blocks (AVB) with asystole71. Sudden death is the major cause of death, has a proteiform multiple mechanism (ventricular tachycardia or fibrillation and asystole) and is associated with multiple scar areas in the myocardium59,70.
Chronotropic incompetence can result from degeneration of the conduction system and autonomic dysfunction, causing symptoms related to intolerance to physical exercise, even in the presence of normal ventricular function30,72.
3.2.3. Cardiac form with ventricular dysfunction
Chronic HF usually installs at least 20 years after the original infection. At that stage, the clinical findings depend on the expression of three frequently coexisting disorders: HF, arrhythmias and thromboembolism. The most frequent clinical presentation is biventricular HF, with predominance of symptoms related to serious higher impairment of the right ventricle function (jugular venous stasis, hepatomegaly, ascitis and lower limb edema), associated with ventricular and atrial arrhythmias and atrioventricular and intraventricular conduction disorders73,74.
Patients usually complain of weakness rather than of dyspnea, which can be partially explained by their lower blood pressure levels as compared with those of other HF etiologies and by the concomitance or preponderance, in some cases, of right ventricular (RV) dysfunction. Several patients complain of chest pain, usually as like atypical angina, possibly due to microcirculation abnormalities caused by the inflammatoryprocess75. The clinical exam reveals significant cardiomegaly with impulsive and diffuse ictus cordis, murmurs of mitral and tricuspid regurgitation and split of the second cardiac sound.
Dilated ventricles with apical aneurysms, in addition to the high prevalence of atrial fibrillation at more advanced stages, are important sources of mural thrombi, causing systemic and pulmonary thromboembolic phenomena76. Cerebral vascular accidents (CVA) are more common in chagasic HF than in HF of other etiologies, being CD a risk factor for CVA77. The prognosis worsens as congestion progresses and arrhythmias become more difficult to control78-80.
4. Clinical diagnosis, differential diagnosis and prognosis of chronic chagasic cardiopathy
4.1. Clinical diagnosis of CCC
As previously mentioned, CCC can manifest as HF, thromboembolic events, ventricular arrhythmias and SD80. Its diagnosis is based on positive epidemiology, anamnesis, physical exam, electrocardiographic and radiological changes and serological tests81-83. The major symptomatology is HF with progressive dyspnea, fatigue and asthenia. Symptoms of right HF, such as edema, increased abdominal volume and epigastric discomfort, can appear early, but are more frequent at advanced stages of disease, accompanied by low cardiac output symptoms, such as intolerance to exertion. Suggestive history of arrhythmic events (bradyarrhythmia or tachyarrhythmia) with palpitations, presyncope and syncope is frequent79,84,85. Thromboembolic events, mainly CVA, can be the first manifestation of CCC, and originates mainly from intracavitary thrombi84. Angina of atypical character is frequent, results from ischemia in the absence of angiographically detectable coronary obstruction, and is explained by inflammatory changes, thrombosis and other coronary microcirculation disorders32,37,75. The physical exam can evidence global cardiomegaly, murmurs of mitral and tricuspid regurgitation and presence of the third cardiac sound. Low cardiac output signs, such as hypotension and filiform pulse, are detectable in some individuals, unlike signs of the less conspicuous pulmonary congestion, due to the important RV dysfunction73,86,87.
4.1.1. Serological tests (Table 2)
Because of the low parasitemia in the chronic phase of CD, parasitological tests are not used, and the serological tests based on the detection of antibodies against T. cruzi should be routinely used to establish the etiology of the cardiopathy81.
The serological diagnosis of T. cruzi infection is confirmed, or excluded, by using at least two serological tests of different principles, which should confirm the existence of anti-T. cruzi antibodies81. Quantifying the concentration of antibodies is desirable. The most commonly used and useful serological tests are the conventional ones: enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) and indirect hemagglutination (IHA). When those three tests are performed, concordance between them is obtained in more than 98% of the sera88,89. Each test has different characteristics regarding sensitivity and specificity: ELISA and IIF have sensitivity greater than 99.5%, but lower specificity (97%-98%), while the IHA tests have lower sensitivity (97%-98%) and higher specificity (99%)90-93. The use of two serological tests prevent false-positive or false-negative results, with ethical and legal connotations81,89-94.
4.1.2. Complementary tests (Table 3)
Electrocardiographic changes are frequently the first indicators of CCC. Initially, the changes are characterized by transient or fixed atrioventricular conduction delays, right bundle-branch conduction delays, ventricular repolarization changes and ventricular ectopies95,96. With disease progression, mainly when global or regional contractility disorders appear, the changes on ECG become outstanding, with relevant prognosticimplications69,97.
In CCC, complete right bundle-branch block associated with left anterior hemiblock is the most frequently found abnormality change (> 50% of the patients)69,95,96. Impairment of the left bundle branch or of the left posterior fascicle is rare. Variable grades of AVB are commonly described in several studies69,95-98. More advanced AVBs result from extensive lesions of the atrioventricular node and bundle of His, and can be the first manifestation of the disease. Dysfunction of the sinus node can cause episodes of sinoatrial block, with bradycardia or ectopic atrial tachycardia. Atrial flutter and fibrillation occur late and usually after the installation of severe ventricular dysfunction, as in other cardiopathies99,100.
Polymorphic ventricular extrasystoles are common in the presence of ventricular dysfunction. Complex ventricular arrhythmias, such as non-sustained or sustained ventricular tachycardia (NSVT and SVT, respectively), can even occur in patients with no HF; however, they usually occur in more advanced cases, and their coexistence indicates worse prognosis69,79,85,97.
22.214.171.124. Chest radiography
In advanced phases, severe global cardiomegaly usually contrasts with mild or absent pulmonary congestion. It is worth noting that, due to the frequent and intense RV impairment and tricuspid regurgitation, the enlarged right cavities can stand out on chest XR. Systemic venous congestion, and pleural and pericardial effusion frequently accompany the signs of cardiomegaly.
Echocardiography allows assessing regional and global LV contractility, RV impairment, presence of apical or submitral aneurysms, intracavitary thrombi and diastolic functionchanges74,101. In large case series, even in the indeterminate phase of the disease, ECHO can show segmentary contractility changes in the inferior or apical LV wall in 10%-15% of the patients, and apical aneurysm can be detected in 40%-60% of the patients with CCC74,101,102. Systolic dysfunction has also been detected by using tissue Doppler imaging. The systolic shortening and diastolic stretching velocities, even in patients with normal ECG, can show prolonged isovolumetric contraction times in both ventricles103-106. Thus, a normal ECG reading does not exclude the presence of functional damage to the myocardium103,105-107. Studies with pharmacological stress have reported a reduction in the inotropic and chronotropic response to dobutamine infusion, including biphasic contractile response72. Finally, stress ECHO can induce complex ventricular arrhythmias even in patients at the early phases of cardiopathy108.
It is worth noting that, although some patients with the indeterminate form can have diastolic or systolic function changes, usually mild, on ECHO, several case series have documented the usually excellent prognosis of patients with that form of CD14,62,68,82,109.
The classical echocardiographic aspect of advanced CCC is that of large dilation of the atrial and ventricular cavities, with diffuse biventricular hypokinesia, which is more not so marked than in ischemic cardiomyopathy or in those of other etiologies63,74.In addition, atrioventricular valve regurgitation secondary to the dilation of valvar rings is observed. Despite the predominance of diffuse contractile deficit, ventricular aneurysms detected on ECHO in 47%-67% of the patients are characteristic of CCC, being associated with a higher thromboembolic risk (apical position) and with malignant ventricular arrhythmias (basal inferior or posterior lateral wall)102. Intramural thrombi can be visualized on ECHO also in atria, especially in the presence of atrial fibrillation. All those echocardiographic aspects are relevant to the prognosis of patients with CCC74,101,109.
126.96.36.199. Cardiac magnetic resonance
In CCC, myocardial fibrosis is a constant and intense substrate associated with disease progression and poor prognosis due to the high risk of SD and ventricular arrhythmias39,70. Cardiac magnetic resonance imaging can identify early cardiac involvement, by detecting delayed enhancement areas that indicate fibrosis, thus allowing a more accurate stratification of the stages of disease severity110. The extent of fibrosis correlates directly with the stage of disease and functional class FC, and inversely with the LVEF, contributing to the prognostic stratification of CCC110.
188.8.131.52. Nuclear medicine
Assessing the biventricular function on nuclear angiocardiography with 99mTc is an alternative to ECHO, mainly to assess RV ejection fraction and the conditions of contractile synchronization of both ventricles, which have prognostic value63,86. Myocardial perfusion scintigraphy shows segmental perfusion deficits in as much as 30% of patients with CCC and angina, but with normal coronary angiography, indicating coronary microcirculation changes, and myocardial fibrosis, disorders that correlate with the progressive deterioration of ventricular function75,111.
184.108.40.206. Dynamic electrocardiography (Holter)
Dynamic electrocardiography is indicated to assess the chagasic patient with syncope, which can be due to ventricular bradyarrhythmia or tachyarrhythmia112,113. Both can coexist in the same patient, the most severe being SVT and advanced AVB. In retrospective and prospective series, as well as in a systematic review, NSVT has also been proved to predict worse prognosis79,85,112,113.
220.127.116.11. Exercise test and cardiopulmonary test
Exercise and cardiopulmonary tests, although of limited usefulness to clarify chest pain in chagasic patients, are useful to detect exertion-induced arrhythmias in CCC and to establish their prognosis108,112. The cardiopulmonary test with direct measurement of oxygen consumption (VO2) shows high mortality in one year for patients with VO2 lower than 12 mL/kg/min, being also used as an auxiliary method to indicate cardiac transplantation (CT).
18.104.22.168. Electrophysiological study
The electrophysiological study (EPS) allows the investigation of sinus function and AV conduction, being also indicated to clarify syncope of undetermined origin after noninvasive assessment, in patients with resuscitated SD112,113. It is not indicated for risk assessment in patients with preserved systolic function or with NSVT. It is also indicated to map refractory ventricular tachycardia for possible ablation of arrhythmogenic foci113.
22.214.171.124. Cardiac catheterization
Cardiac catheterization in CCC should only be indicated in special situations, such as some patients with typical angina and classical risk factors for coronary disease, or with a large ischemic area evidenced on noninvasive tests. It should not be indicated in chagasic patients with atypical pain and no coronary risk factors37. The recommendation for cardiac catheterization in patients requiring CT is discussed further ahead in this document.
4.2. Differential diagnosis of CCC
There are no pathognomonic manifestations for CCC by either clinical or complementary tests. In most cases, the serological confirmation of the disease in a patient with HF clinical syndrome is diagnostic68,79,81. On ECG, right bundle-branch block associated with left anterior hemiblock is highly suggestive of CCC in patients from endemic areas95,98, while left bundle-branch block makes the chagasic etiology less likely. According to some researchers, LV apical aneurysm, sparing the septum, would be a "marker of the disease"74,102. In addition to changes in LV segmentary mobility, finding prominent RV impairment, which is less frequent in ischemic and hypertensive cardiopathies, contributes to the diagnosis of CCC63,86,87. The presence of precordial pain, usually similar to atypical angina, in patients with suggestive epidemiology, even in the presence of perfusion defects on myocardial scintigraphy, supports the chagasic etiology in the differential diagnosis24,75,111. Under such circumstances, the positive serology should be confirmed rather than referring patients to coronary cineangiography, which usually reveals no angiographically detectable coronary obstruction.
4.3. Prognosis of chronic chagasic cardiopathy
Chronic chagasic cardiopathy is almost always progressive, its prognosis depending on the phase and clinical form of disease79,80,85. In the acute phase, 90% of the cases have cardiac impairment, which is usually benign in more than 90% of the cases. The prognosis is usually inversely proportional to the patient's age, being more severe in children with myocarditis or severe encephalitis114.
In the indeterminate form, electrocardiographic changes appear in 2.0% of the patients every year61,82,101. Although several researchers have described mild changes in the LV systolic and diastolic function of patients with the indeterminate form72,74,105-108, and despite the speculation whether those disorders might identify patients who will later progress to the cardiac form of disease, two observations should be considered: usually those studies have not met the strict criteria for including only patients with the indeterminate form (for example, a barium enema has not been performed to rule out the presence of colopathy)115; although preliminary research has suggested that early changes in regional LV contractility of chagasic patients with normal ECG indicate further deterioration of global LV function116, no study has proved the importance of any abnormality for prognostic stratification in that phase of the disease61. Thus, a benign prognosis and survival similar to that of individuals without CD should be considered for the indeterminate form of CD61,62,81,82,100,117.
Several observational case series have shown a worse outcome for patients with CCC as compared to those with other cardiomyopathies118,119. Several pathophysiological factors contribute to that difference, but several studies have reported LV contractility dysfunction as an independent prognostic predictor when assessed via both cardiomegaly on chest XR and LVEF or ventricular diameter79,85,109,118-120.
In 2006, for patients with CCC assessed with different noninvasive methods, a risk score was described using six prognostic factors identified via multivariate analysis and long-term follow-up79. The following variables showed independent prognostic value: NYHA FC III or IV (5 points); cardiomegaly on XR (5 points); left ventricular dysfunction on ECHO (3 points); NSVT on Holter (3 points); low-voltage QRS complex (2 points); and male gender (2 points). Based on the Rassi score79, weighted on the prognostic significance of the variables, patients at low risk (score 0 to 6 points) showed 10% mortality, while those at intermediate risk (score 7 to 11 points) showed 44% mortality, and those at high risk (score 12 to 20 points) showed 84% mortality in a 10-year follow-up79.
A systematic review of studies on prognosis comprising 3,928 patients has identified the following independent prognostic variables: LV systolic dysfunction; NYHA FC III/IV; and cardiomegaly on chest XR85. The combination of ventricular dysfunction with the presence of NSVT on Holter monitoring increases the risk for death during follow-up on average 2.14 times79,85. The presence of ventricular arrhythmia in patients with HF increases their chance of SD79, 85,119,120. Those algorithms can stratify prognosis in a simplified and logical way by using clinical parameters and methods available at most cardiology services in Brazil79,85. In CCC, as in other cardiopathies, other variables, such as FC, RV dysfunction, ventricular diameter, LVEF, VO2, duration of exercise, and brain natriuretic peptide (BNP) level, can affect the prognosis78,86,119-122 (Figure 4).
5. Etiological treatment of Chagas disease
The etiological treatment of CD is controversial, especially regarding its indication in the late chronic phase. Currently, only two confirmed trypanocidal drugs are available (only one in Brazil), confirming the lack of interest of the pharmaceutical industry in developing new drugs over several decades. No definitive studies assessing the parasiticide treatment effect on the natural history of the disease have been conducted, and the context of uncertainty is compounded by the lack of tests that assure the complete eradication of the parasite and confirm the cure of the disease. The following items are intended to reinforce concepts approached in previous chapters of this guideline.
5.1. Parasite participation
5.1.1. Acute phase
The presence and amount of parasites bear a direct relationship to the severity of myocarditis. However, even with no parasiticide treatment, more than 90% of acute cases recover from the infection with no apparent immediate sequelae.
5.1.2. Chronic phase
The importance of lymphocytic myocarditis in the progression to HF could be identified by use of endomyocardial biopsy in patients with different clinical forms. Studies have shown the topographic association of T. cruzi antigens and DNA with myocarditis foci, suggesting that the presence of the parasite is fundamental to the perpetuation of the inflammatory process. However, inflammation severity is disproportionally intense as compared to the paucity of T. cruzi elements123.
5.2. Trypanocidal drugs
5.2.1. Nifurtimox (nitrofuran)
Nifurtimox was described in 1965 (Lampit, by Bayer, no longer available in Brazil), but its mechanism of action has not been completely clarified. The tablet contains 120 mg of active substance. The recommended dose is 15 mg/kg/day for children and acute cases, and 8-10 mg/kg/day for adults, for 60 days, the daily dose being divided into three. The drug has gastrointestinal absorption, is metabolized in the liver (cytochrome P450) and excreted preferentially by the kidneys. Its side effects comprise anorexia (the most severe and frequent), abdominal pain, nauseas, vomiting and weight loss.
5.2.2. Benznidazole (nitroimidazole)
Benznidazole was developed by Roche in 1971 under the commercial name of Rochagan, being currently produced by the Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE). The tablets have 100 mg of active substance. It has gastrointestinal absorption, preferentially renal excretion, and half-life of 12 hours. Its recommended dose is 10 mg/kg/day for children and acute cases, and 5 mg/kg/day for chronic cases, for 60 days, the daily dose being divided into three or two administrations. The recommended maximum dose is 300 mg/day. For adults weighing more than 60 kg, the total dose should be calculated, and the duration of treatment prolonged beyond the 60 days to complete the total dose required. Thus, a 65-kg patient will receive 300 mg/day for 65 days; a 70-kg patient will receive that daily dose for 70 days; and a 80-kg patient will receive the maximum dose of 300 mg/day for 80 days. For patients over that weight, the daily dose of 300 mg for the maximum period of 80 days should be used. The most frequent side effect is exantemous urticarial dermatitis, which occur in up to 30% of the patients, usually already at the end of the first week of treatment. They respond well to anti-histamines or, more effectively, to small oral doses of corticosteroids. In the presence of fever and lymph node enlargement, the drug should be interrupted suspended. Other side effects include polyneuropathy (usually at the end of the 60-day treatment), with pain and/or tingling in the lower limbs, and anorexia (much less intense than that of Nifurtimox). Significant leukopenia and agranulocytosis are rare, but, in their presence, the treatment should be interrupted. Lymphomas have been reported in rabbits and rats treated with benznidazole, but not in thousands of patients treated by several authors for several decades.
Those drugs are contraindicated during pregnancy and for patients with kidney or liver failure124-127.
5.3. Indication for etiological treatment in CD (Table 4)
A WHO bulletin127 has authorized the trypanocidal treatment to all chagasic patients as long as prescribed by a physician with experience in managing the drug, and who can diagnose and treat possible side effects, as well as ensure post-treatment follow-up128. There are two types of indication for the trypanocidal treatment81,129,130.
5.3.1. Consensual indications
126.96.36.199. Acute phase for all patients, regardless of the mode of transmission
In most acutely infected patients, the disease is not diagnosed due to the unspecificity of symptoms and signs in that phase; nevertheless, treatment should be performed in all cases and as soon as possible, regardless of the mode of transmission, except for the presence of pregnancy, which contraindicates the etiological treatment81,114,131,132.
188.8.131.52. Chronic phase in children
A Brazilian randomized, placebo-controlled study, assessing 130 chagasic children, aged between 7 and 12 years, receiving either benznidazole (7.5 mg/kg/day for 60 days) or placebo, has reported that, after a three-year follow-up, the IIF reactions of 37 out of the 64 children treated (58%) and only three out of the 66 on placebo (5%) were negative (p < 0.001). That favorable effect on the host-parasite ratio was maintained after a six-year follow-up133,134. In another independent case series in Argentina, 106 chagasic children, aged between 6 and 12 years, have been randomized for benznidazole or placebo for four years. The authors have reported that the serology (ELISA) for T. cruzi of 62% of the children treated and none of those on placebo were negative (p < 0.01)134. Based on those results, and even with no evidence that the treatment changes the prognosis in a clinically relevant way, all chagasic children should be treated early.
184.108.40.206. Accidental contamination
Treatment should be initiated as soon as the accident is characterized as bearing a high risk for infection transmission. The following are characterized as bearing high risk: accidents caused by cutting and piercing instruments and objects or by mucosal contact, during the manipulation of material containing live parasites, such as samples for culture, vectors and infected laboratory animals, samples from patients suspected of having high parasitemia and autopsy specimen. Benznidazole, at the dose of 7-10 mg/kg, should be maintained for at least ten days. In the presence of high parasite load, the treatment should extend for at least 30 days. When contact with blood of a chronic patient (low risk) is involved, drug prophylaxis is not routinely indicated, serological monitoring being recommended81,128.
Reactivation of CD (disease exacerbation in a chronic patient) can occur in pharmacologically immunosuppressed patients or those with HIV coinfection. The specific conventional treatment for 60-80 days is indicated in such situations, depending on the patient's clinical condition. When there is no symptom, but the parasitemia is persistently high, trypanocidal treatment has been indicated, although long follow-up periods are required to better assess the efficacy of that approach81,128.
5.3.2. Nonconsensual indications
220.127.116.11. Late chronic phase and indeterminate form in young individuals
The WHO and the Pan American Health Organization (PAHO)127 have disclosed concepts about the etiological treatment, and have recommended its implementation in countries with poor CD control. Treatment in the late chronic phase is aimed at reducing the parasitemia, preventing the appearance or progression of visceral lesions and interrupting the chain of transmission. Treatment in that phase is indicated to patients with the indeterminate form and mild cardiac and digestive forms81,132. The indication of trypanocidal treatment for chronic chagasic patients with the indeterminate form is a public health policy in some South American countries, and has been a primordial recommendation based on seminars conducted by the North American Centers for Disease Control and Prevention as soon as serological tests have become mandatory for blood and organ donors, through federal decision, in the USA133. Despite the lack of proof that the etiological treatment of the indeterminate form changes the natural history of disease (randomized studies with that outcome have not been published), it is worth noting that the results of observational and randomized studies in children (favorably changing surrogate outcomes) have been considered sufficient to support the recommendation, aimed at preventing the installation of cardiopathy134-141.
The indication for trypanocidal treatment in patients with established CCC remains controversial. Several researchers support that treatment based on the following: a) experimental evidence by several researchers that the etiological treatment attenuates the progression of cardiomyopathy45,418; b) observational studies in humans, although not "definitive", but with clinically relevant outcomes, have reported a possible positive impact on the natural history of the disease, even in the non-advanced phase of CCC46,81,126,132,133,141; and c) the relative paucity and low severity of the side effects, as compared with the potential benefit of short-term treatment (usually two months). In an attempt to solve the dilemma, and considering the opposite risks of alpha or beta errors, an ongoing international, multicenter, randomized, double-blind, placebo-controlled investigation, the BENEFIT study, assesses the six-year clinical outcome of patients with CCC treated with benznidazole or placebo49.
The results of the BENEFIT study will be strategic for the management of chagasic patients with manifest cardiopathy. The editors of this guideline have not reached a consensus regarding the recommendation class and level of evidence of the indication of treatment for those patients. While some editors have suggested that treatment of the non-advanced cardiac form receives recommendation class IIa with level of evidence B, and that the indeterminate form in young adults receives recommendation class IIa with level of evidence C, other editors have suggested recommendation class IIb, and are waiting for the results of the investigations to yield a definitive recommendation.
5.4. Criteria for infection cure
Laboratory follow-up of treated patients in both the acute and recent or late chronic phases is aimed at assessing the presence of parasites and antitrypanosoma antibobies142. Parasitological tests (xenodiagnosis, blood culture, PCR) are useful only when T. cruzi is found, which means therapeutic failure. Negative parasitological results are insufficient to assure infection cure. The antibody tests involve serological tests. Positive results (presence of antibodies) do not necessarily mean unsuccessful trypanocidal treatment; however, persistently negative results (over many years) mean cure143,144. With therapeutic success, there is progressive decline of antibody titers, until the serological tests become negative. Those titers decline, reaching values observed in the non-infected population in various time frames, which depend on the time the treatment is performed. In cases treated during the acute phase (regardless of age), antibody titers decline in the first year, becoming negative in less than five years. In children (12-14 years) or adults treated within the first years following infection, antibody titers decline in the first five years, becoming negative usually in ten years from treatment. In adults treated later, the curve of antibody titers shows inflexions after 10-20 years, and those titers become negative after 30 years or more132. Although not yet totally accepted, the proposed conceptual advance is to consider significant decreases in anti-T. cruzi antibody titers to have the same meaning as their absence. The serological tests should be repeated annually until persistently negative results are obtained88,145,146 (Table 5).
Control with parasitological tests after treatment is unnecessary, because they will be valid only when showing therapeutic failure. If available, they can be indicated annually147.
5.5. Clinical managements for patients with the indeterminate form
As already mentioned, the indeterminate form is characterized by seropositivity for anti-T. cruzi antibodies, absence of symptoms and physical signs, no changes on ECG and chest, esophageal and colon radiological tests (normal barium enema required to characterize the patient as having that disease form, even with normal bowel habits)115. Because the prognosis of those patients compares to those of the non-chagasic population, neither restrictions to normal life nor indication for absence from work should exist131. Restriction to activities that threaten the patient's or a third party's life is arguable82. Chagasic pregnant women and those breast-feeding should receive the same instructions as non-chagasic women under the same conditions; however, special attention should be paid to newborns, aiming at the early diagnosis of congenital transmission. Whenever possible, parasitological tests with blood samples of the newborns should be performed. When positive, the trypanocidal treatment should be initiated; when negative or when the parasitological test is unavailable, the serological test (IgG) should be performed from the 6th to the 9th month of life (when maternal antibodies are no longer present). When the serological test is positive, the trypanocidal treatment should be initiated, and, when negative, the child should be considered not infected81. For patients with the indeterminate form, clinical assessment and annual or biannual ECG are recommended129.
Redefinition of the indeterminate form has been proposed, excluding the barium enema for asymptomatic chagasic patients (or replacing it with abdominal ultrasound) and requiring normal ECHO and no ECG changes; however, the proposal has not been well received115.
6. Treatment of ventricular dysfunction and heart failure
In addition to parasite infection control, as seen in the etiological treatment chapter, CCC management consists of treating the different clinical manifestations of the disease, i.e. ventricular dysfunction and HF, thromboembolic phenomena and rhythm disorders (Table 5).
6.1. Ventricular dysfunction and heart failure
Similarly to other cardiopathies, the treatment of chagasic HF is based on the routine combination of three types of drugs: diuretics; angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB); and adrenergic beta-blockers (BB)148.
However, although CD is an important cause of HF in Latin America, patients with CD and HF have not been included in large studies assessing those drugs to treat HF. Thus, their real efficacy and tolerability in patients with CCC have not been scientifically established, and their use have been extrapolated empirically from the results obtained for HF of other etiologies.
6.1.1. Renin-angiotensin-aldosterone system blockade
The renin-angiotensin-aldosterone system blockade plays a fundamental role in adverse cardiac remodeling and ventricular dysfunction progression of HF149. Several studies have shown the benefit of the chronic administration of ACEI150,151 or ARB152 to the treatment of patients with HF, in both LV remodeling and morbidity and mortality reduction. However, almost none of those studies, except for some small ones, have enrolled patients with CCC153.
In an experimental study with mice, the use of captopril has reduced myocarditis and fibrosis in the acute phase of CCC154. A clinical study including 17% of patients with CCC and assessing the action of captopril on the FC of 115 patients with HF has shown the benefit of that blockade, but has not separated the effects according to the etiologies155. Another study with 42 patients with HF and CD has shown that the increase in enalapril dose up to the maximum recommended was well tolerated and improved the quality of life, in addition to reducing BNP levels and the radiological cardiothoracic index156.
The use of ACEIs in CCC is recommended to all patients with ventricular dysfunction, from NYHA FC I up to FC IV. When ACEIs are not tolerated, the use of ARBs is recommended, supported by extrapolation from studies on HF of other etiologies157.
Regarding the aldosterone blockade, the use of spironolactone and eplerenone after myocardial infarction has proved beneficial in terms of morbidity and mortality of patients with HF158,159. The largest randomized, double-blind and placebo-controlled study assessing spironolactone in the chronic phase of HF has included etiologies other than ischemia, such as CD (some patients with CCC)159. That study has evidenced the benefit of that drug to patients in NYHA FC III-IV. However, the analysis of a subgroup of chagasic patients has not been conducted and would not have practical value, because it was not prespecified and the sample size was very small. An experimental study with spironolactone has suggested some benefit to survival and myocardial fibrosis reduction in T. cruzi-infected hamsters160. That drug is indicated to patients with LV systolic dysfunction, LVEF < 35%, and NYHA FC III/IV HF.
6.1.2. Beta-adrenergic blockade
Several studies have shown that, in ischemic cardiopathy and dilated cardiomyopathy with systolic dysfunction, HF treatment with adrenergic BBs, in addition to renin-angiotensin-aldosterone system blockers, is effective in improving the quality of life, reducing symptoms and the need for hospitalizations, and in increasing survival161-166.
As exposed in the chapter on pathogenesis, there are peculiar aspects of the pathophysiology of CCC involving the autonomous nervous system29-34,167,168. There is evidence that CCC has the characteristic of being a cardioneuropathy model because of its important parasympathetic denervation, which precedes the installation of LV systolic dysfunction. In addition, the circulation of antibodies against β-1 adrenergic and M-2 muscarinic receptors, which can be implicated in the perpetuation of the HF process, has been demonstrated. The characteristic adrenergic activation installed with ventricular dysfunction and intensified with HF progression can be more exacerbated in chagasic patients than in patients with other cardiopathies. This can contribute to accelerate the harmful process of ventricular remodeling, to induce arrhythmias and to increase the risk for SD.
Thus, extrapolating the indication of BB to treat chagasic patients with ventricular dysfunction, based on studies of other HF causes, seems logical. Considering the high frequency of bradycardia in CCC (due to sinus node dysfunction, sinus node denervation and several AV blocks), it is worth noting that physicians are considerably afraid of aggravating that condition by using BB. Thus, in the BENEFIT study, which has enrolled approximately 1,800 patients with CCC (80% in NYHA FC I and II), only 32% were treated with BB49.
However, although scarce, there is direct evidence that the use of BBs is beneficial to treat HF, specifically that of chagasic etiology. A randomized, double-masked, place-controlled study with 42 patients with CCC and LVEF < 45% has reported that the use of carvedilol, added to enalapril and spironolactone, has caused the following: significant improvement in the Framingham score and quality of life; significant reduction in the cardiothoracic index and BNP circulating levels; and a 2.8% increase in LVEF156. In the randomized, double-masked CHARITY study, in its final phase, the use of bisoprolol in chagasic patients with HF is being compared with the use of placebo (ClinicalTrials.gov, NCT00323973)169. Extrapolating the recommendations regarding the treatment of patients with HF of other etiologies148, carvedilol, bisoprolol or metoprolol succinate should be used to treat chagasic patients with previous or current HF symptoms and/or signs, and LVEF < 45%. The daily dose should be slowly titrated, aiming at avoiding heart rate < 50/min at rest. Those drugs can also be indicated even in the absence of HF symptoms and signs, when there is LV dysfunction or remodeling. Those drugs are contraindicated to patients with bradycardia < 50 bpm or AV conduction disorders (PR > 280 ms).
6.1.3. Hydralazine and nitrate
Extrapolating from the V-HeFT-II and A-HeFT studies, the combination of hydralazine and nitrate is recommended to treat chagasic patients of any ethnicity in NYHA FC II-III with contraindication to ACEI or ARB (progressive renal failure or hyperkalemia). In addition, extrapolating from the A-HeFT study, those drugs are recommended to Afro-descendants in NYHA FC III-IV already on optimized therapy based on ACEI or ARB170,171.
Digitalis has been used in HF treatment for the longest time. Of all drugs with a positive inotropic action and tested for prolonged use, it was the only that did not increase mortality as compared with placebo (digitalis was even with placebo, but reduced the number of hospitalizations due to HF)172. Despite the lack of evidence in chagasic patients, and recognizing that its inhibitory action on the sinus node and the atrioventricular junction can be potentiated by the association with other drugs, such as BB and amiodarone, the use of digoxin can be justified in chagasic patients with symptomatic LVEF < 45% (NYHA FC II-IV HF), mainly when the ventricular frequency is elevated in the presence of atrial fibrillation173.
As in other etiologies of HF, diuretics should be used in chagasic patients to relieve congestive symptoms and signs. In a meta-analysis of several studies, those drugs have evidenced a mild effect of mortality reduction, being also useful to modulate the beneficial responses to other drugs, such as neuro-hormonal antagonists, whose effects depend on sodium balance174. The association of thiazides with loop diuretics is more effective in more advanced HF stages. Thiazides inhibit sodium resorption mainly in the distal convoluted tubule and are mild diuretics, but are not effective when creatinine clearance is lower than 30 mL/min. Loop diuretics, of which furosemide is the most used in Brazil, inhibit sodium, potassium and chlorine resorption in the ascending limb of Henle's loop, have a rapid action, short period of action (4-6 hours) and cause abundant diuresis, and can be intravenously administered. There is no reason to consider that the effect of diuretics in patients with CCC differs from that in cardiomyopathies of other etiologies81,175.
6.2. Prevention of thromboembolic events
Some series have reported an annual incidence of thromboembolic phenomena of 1%-2% in patients with CCC176,177, higher (60%) in the subgroup with chronic HF. In those series, apical LV aneurysm and LV mural thrombosis have been observed in 23% and 37% of the patients, respectively. In postmortem studies, thrombosis of the apical LV aneurysm has been described in up to 99% of the cases178. Among patients with HF, the prevalence of thrombosis of the right cardiac chambers (53%) exceeds that of the left chambers (43%)178. Pulmonary thromboembolism is rarely seen in patients without manifest HF, but can affect 37% of those with HF. In 85% of the cases, it associates with mural thrombosis of the right chambers179.
Systemic thromboembolism affects mainly the brain, can be the first clinical manifestation of the disease, and associates with mural thrombosis and apical LV aneurysm176. A case-control study has reported the following independent risk factors of cerebral thromboembolism: HF; arrhythmias on ECG; female sex; and apical LV aneurysm77. Table 6 shows the indications for anticoagulation.
In 2008, the Arquivos Brazileiros de Cardiologia published an article on the development of a score derived from a prospective cohort of 1,043 patients to assess the risk of cardioembolic CVA in CCC and to implement its prevention. The reported incidence of that event was 3.0% or 0.56%/year. The presence of LV systolic dysfunction contributed with 2 points, whereas apical aneurysm, primary change of ventricular repolarization on ECG and age > 48 years contributed with 1 point each. By use of risk-benefit analysis, warfarin would be indicated for patients scoring 4-5 points (in this subgroup, the incidence of CVA is 4.4% versus 2.0% of severe bleeding per year). In the subgroup scoring 3 points, the event and bleeding rates with oral anticoagulation are equivalent, and either acetylsalicylic acid or warfarin could be indicated. For patients scoring 2 points, with low incidence of CVA (1.22% per year), either acetylsalicylic acid or no prophylaxis would be recommended. Patients scoring 0-1 point, with event incidence close to zero, do not require prophylaxis51.
6.3. Treatment of the acute phase cardiopathy
Mortality in the acute phase is lower than 10% of the cases with established diagnosis, and usually results from meningoencephalitis, severe HF, and, more rarely, SD10,180,181. In most patients, the acute phase passes unnoticed. When signs and symptoms of myocarditis are present, the treatment should be similar to that recommended for myocarditis of other etiologies181,182, and consists of circulatory support and conservative measures. After In the presence of hemodynamic stabilization, the treatment should meet the recommendations for the chronic management of ventricular systolic dysfunction and HF (Table 6).
6.4. Treatment of decompensated chronic heart failure
Decompensated HF secondary to CD causes 3% of the hospitalizations in the Brazilian Unified Health Care System (SUS), accounting for 33,684 hospitalizations in 2007, at the approximate cost of R$ 2,300,000.00175.
The hemodynamic profile of chagasic patients with decompensated HF is that of HF due to LV systolic dysfunction. It is characterized by an increase in atrial pressures and in ventricular filling pressures, and a reduction in cardiac output, with an increase in systemic and pulmonary vascular resistances81. There is no evidence of cardiac decompensation caused by isolated LVdiastolic dysfunction in chagasic cardiomyopathy. Patients with decompensated HF experience an improvement in symptomatology with the use of furosemide at conventional doses183. Spironolactone has a beneficial effect on the neurohormonal profile of patients with mild to moderate HF, mainly when associated with ACEI155. Thus, that drug might also be useful to treat chagasic patients with decompensated HF.
The intravenous use of sodium nitroprusside considerably relieves the symptoms of chagasic patients with decompensated HF, reducing pulmonary capillary pressure, ventricular filling pressures and atrial pressures, making the treatment of the most severe cases of decompensated HF more effective attractive184.
The use of ACEI has a favorable impact on the neurohormonal profile of chagasic patients with decompensated HF, particularly when used after digitalization, which, acutely, has a clear hemodynamic effect185,186.
In extreme cases of decompensated HF (cardiogenic shock or pre-shock), intravenous noradrenaline seems to improve the short-term prognosis of patients184. Recently, the usefulness of levosimendan has been suggested188 in chagasic patients who developed cardiogenic shock due to chagasic acute myocarditis.
6.5. Chagasic cardiopathy and co-morbidities
6.5.1. Diabetes mellitus
The risk factors for atherosclerosis should be properly controlled, regardless of the positivity of CD serological tests, because the patients are at the same risk of those with negative serology189,190. In addition, diabetes mellitus is by itself a risk factor for the development of HF191. Diabetes mellitus can lead to the impairment of the epicardial coronary arteries and of the microcirculation, which, in patients with CD, have already been previously affected. Recent studies have shown that T. cruzi-infected diabetic rats die at a higher rate, and have a change in the metabolism of adipose cells, suggesting that, although very initially, inflammation in that tissue could be related to the development of cardiopathy192.
Two particularities of the treatment of diabetic patients with CCC and HF are worth noting: the use of thiazolidinediones and of metformin. Regarding the former, rosiglitazone, when used to FC I/II patients, caused fluid retention, although there was no change in LVEF, requiring drug adjustment for compensation193. Thus, it is contraindicated to FC III and IV patients. Regarding metformin, it should be carefully used in the more advanced phases of HF of chagasic etiology, in which the renal function impairment is more frequent and intense, because of the higher likelihood of developing metabolic acidosis.
6.5.2. Thyroid disorders
Approximately 30% of the patients with HF have some thyroid dysfunction, with reduced T3 levels, which can be related to the severity of that syndrome. A complicating factor in HF of chagasic etiology is the high prevalence of supraventricular and mainly complex ventricular arrhythmias. One of the few drugs studied and with somehow favorable results in that population of patients is amiodarone, which is known to cause thyroid dysfunction (both hyperthyroidism and hypothyroidism) and can affect up to 64% of the patients194. However, the benefits of amiodarone should be opposed to the risk of thyroid dysfunction. Periodical monitoring of the thyroid function in chagasic patients on amiodarone is recommended. In patients on amiodarone and with symptomatic thyroid hypofunction, such as bradycardia aggravation, hormone replacement should be carefully performed.
6.5.3. Systemic arterial hypertension
Some studies have shown that patients with CD and systemic arterial hypertension are older and have cardiopathy more often than hypertensives with negative serology195, although the clinical-laboratory characteristics are similar in both groups. In the follow-up of patients with in the indeterminate form, systemic arterial hypertension was the most frequently found comorbidity, contributing to ventricular dysfunction196. Arterial hypertension control in patients with positive serology has to be as effective and careful as that in patients with negative serology, and the combination and choice of drugs are similar.
6.5.4. CCC and coronary artery disease
Until a few decades ago, chagasic patients were mainly rural workers, at low risk for obstructive coronary artery disease. With the increasing urbanization of the chagasic population, mainly from 1980 onwards, they have been exposed to the same risks of non-infected individuals. Thus, the prevalence of atherosclerotic disease as a cause of acute myocardial infarction is similar in chagasic and non-chagasic patients197. The notion that the prevalence of non-obstructive atherosclerotic disease (minimal lesions), or even apparently normal epicardial coronary arteries, is higher in chagasic patients who already had acute myocardial infarction is controversial37,189.
It is worth noting the difficulty of establishing the differential diagnosis in chagasic patients with precordial pain, which can be intense and disabling. The ECG can evidence changes compatible with coronary artery disease (repolarization anomalies, Q waves, and fibrosis) or that hinder its correct interpretation (AVBs). In addition, those patients often have perfusion disorders. Thus, many several chagasic patients are referred for coronary angiography, which, most of the time, evidences angiographically normal coronary arteries37.
As a general rule, chagasic patients with obstructive coronary artery disease should receive the same treatment of patients without T. cruzi infection.
7. Treatment of arrhythmias and conduction disorders in chagasic cardiopathy
7.1. Mechanisms and substrate of arrhythmias and conduction disorders in chagasic cardiopathy
Arrhythmias and conduction disorders can occur in both the acute phase and CCC28,198. The acute phase is usually asymptomatic, but, similarly to other types of myocarditis, arrhythmias and AVB can occur during the acute infection, being markers of poor prognosis28. Most arrhythmias and conduction disorders occur during the chronic phase, being direct consequences of the chronic fibrosing myocarditis triggered by T. cruzi28,198, with formation of scars and aneurysms24,28,198. Those myocardial scars, focal or scattered spread across the ventricles, contribute to the genesis of reentry ventricular arrhythmias199-201. In addition, the cardiac excito-conduction tissue is frequently damaged, leading to sinus node dysfunction and disorders of the atrioventricular and intraventricular conduction28,198. In addition to the repairing and reacting fibrosis, damage to the cardiac nervous endings, especially the parasympathetic ones, occurs, a phenomenon that has been associated with an increase in the number of ventricular ectopies, myocardial electrical instability and SD in patients with CCC24,28,198. Changes in the density and function of connexins could also contribute to the genesis of arrhythmias and conduction disorders present in the disease202.
Arrhythmias in chagasic patients can cause disabling symptoms and SD70,203-205. Ventricular arrhythmias are the most frequent and can manifest as isolated ectopies or repetitive forms206. The SVT is the most common potentially fatal reentry arrhythmia in patients with CCC and segmentary contractile changes, even when the global systolic function is preserved24,28,198-200. The arrhythmogenic substrate of that disease is complex, with LV subendocardial, transmural and epicardial scars, which can also affect the right ventricle200,201-207. Because of that anatomical complexity, the subendocardium or subepicardium (approximately 55% of ventricular tachycardias), or both (transmural circuits), can participate in the reentry circuits of CCC, explaining the presence of episodes of SVT with multiple morphologies200,201,207.
7.1.1. Mechanisms of rhythm changes in chagasic cardiopathy
1. Acute phase - myocarditis (rare)
2. Chronic phase - the invariably present substrate comprises:
Subendocardial, subepicardial or transmural fibrotic scar;
Aneurysms (predominantly posterior-basal and apical);
Destruction of the autonomous nervous system.
7.2. Laboratory investigation for diagnostic and therapeutic definition of arrhythmias in CCC
The initial assessment of patients with CD should consider the presence or absence of symptoms and of ventricular dysfunction. Rest ECG, ambulatory ECG (Holter monitoring), exercise testing and ECHO are extremely important and have precise indications.
Patients with the indeterminate form of CD have normal ECG findings, even in the presence of myocardial lesion. With progression to the cardiac form, the most frequently found changes include right bundle-branch block, often associated with left anterior hemiblock, presence of electrically inactive zones, ST-T abnormalities, ventricular extrasystoles and AVB. The ECG also allows risk stratification. According to the Rassi score79,85, low QRS voltage is assigned 2 points, probably associated with diffuse myocardium fibrosis.
The exercise test can induce or worsen complex ventricular arrhythmias and guide the treatment and clinical follow-up108,208, in addition to objectively establishing the patients' FC and tolerance to exercise.
7.2.1. Ambulatory electrocardiography (Holter monitoring)
Patients with CCC, mainly those with electrocardiographic changes, regional or global ventricular dysfunction and HF, usually have a high density of ventricular arrhythmias209,210. In those patients, Holter monitoring should be performed independently of symptoms, because it can identify complex arrhythmias, impacting on the treatment and prognosis79,85. According to the Rassi score, the presence of NSVT on Holter is a marker of worse prognosis, being assigned 3 points79. Periodical Holter monitoring is not required for asymptomatic patients in the indeterminate form209.
In CCC, autonomous nervous system impairment is evidenced on several physiological and pharmacological tests30-32,211. However, RR variability, the most clinically available autonomic function index is inconsistent for prognostic assessment or therapeutic guidance in CCC.
Ventricular function assessment on ECHO allows therapeutic and prognostic guidance198,201. Chagasic patients with ventricular arrhythmias can have ventricular aneurysms as follows: in the left ventricle, 80%; in the right ventricle, 10%; and in both ventricles, 10%. The presence of aneurysm is associated with the occurrence of ventricular tachycardia and ischemic CVA212. Transesophageal ECHO is indicated for patients with CVA, and lack of visible thrombi in the left cavities on transthoracic ECHO.
7.2.2. Electrophysiological study
The ideal anatomical substrate for reentry is present in CCC, justifying the programmed ventricular stimulation protocol to assess the possibility of inducing reentrant arrhythmias209,210. Being an invasive exam, the EPS can cause more risks than benefits in patients with the indeterminate form of disease.
The EPS has proved to be useful for risk stratification of patients with CCC. Some authors have shown that patients with NSVT undergoing programmed ventricular stimulation and who had SVT induction had worse prognosis, with a higher event rate during clinical follow-up209,213-215. A study has shown that, in patients with previous SVT or NSVT treated with amiodarone, programmed ventricular stimulation was useful in identifying those with the worst prognosis214. In addition, the EPS has a significant role in the assessment of syncope in CCC, especially when non-invasive exams are inconclusive. In those cases, syncope can be caused by both bradyarrhythmia (sinus node dysfunction, atrioventricular blocks, asystole) and ventricular tachyarrhythmia (Table 7).
7.3. Pharmacological treatment of the arrhythmias of chagasic cardiopathy
The pharmacological treatment of arrhythmias in CCC is aimed at controlling symptoms, with no clear evident effectiveness in SD prevention. Although ventricular arrhythmias in CD are associated with a higher risk of SD and increased total mortality70,205,206,208,216, there is no conclusive evidence that antiarrhythmic drugs have clinically relevant benefits. The most frequent ventricular arrhythmias in chagasic patients are isolated or repetitive ventricular ectopies. The presence of those arrhythmias in asymptomatic patients with preserved ventricular function requires no antiarrhythmic treatment. When symptomatic in patients with ventricular dysfunction, the antiarrhythmic treatment can be individualized217. Amiodarone, despite being the most efficient antiarrhythmic drug, has a high incidence of side effects. Beta-blockers, sotalol and group I drugs, such as propafenone, mexiletine, disopyramide and procainamide, have been considered for the treatment of those patients. However, currently those group I drugs should be avoided in patients with structural cardiopathy (LV dysfunction) because of their higher risk of proarrhythmias.
When ventricular ectopies and NSVT are present in patients with LV dysfunction, amiodarone is the only safe drug. Although there is no evidence that it changes the long-term prognosis of those patients, its power to reduce the density of arrhythmias and to control symptoms is well known218-223. At the usual doses of 200-400 mg/day, amiodarone can be associated with beta-blockers to reduce severe arrhythmic events79. Sustained ventricular tachycardia in CD should be carefully assessed, because it can result in SD as at its first manifestation, even in the absence of left ventricular dysfunction199,224.
When approaching SVT at the emergency room, electrical cardioversion should be used for hemodynamically unstable patients. For stable patients, cardioversion reversal with injectable amiodarone, at the dose of 150 mg in 10 minutes, can be attempted, and can be repeated in case of no reversal. After reversal, amiodarone infusion should be continued at the dose of 1 mg/minute in the first 6 hours, and later, 0.5 mg/minute in the following 18 hours. Antiarrhythmic drugs should be used for patients with SVT and severe important LV dysfunction (LVEF < 35%) only as an auxiliary treatment to implantable cardioverter defibrillator (ICD) implantation. Amiodarone, at the dose of 200-400 mg/day, remains the drug of choice under such circumstances. For patients with well-tolerated SVT and preserved ventricular function, amiodarone use and catheter ablation can be considered, although ICD is the safest option (Table 8).
7.4. Surgical and catheter ablation of ventricular tachycardia in CCC
The occurrence of SVT in patients with CCC is an important risk factor for SD199, mainly in the presence of severe LV dysfunction (LVEF < 30%)216. Ablation has improved the patients' quality of life, preventing the discomfort of shocks in those with ICD and reducing the number of hospitalizations for SVT reversion during the antiarrhythmic treatment225.
7.4.1. Surgical ablation
The use of SVT ablation in CCC has been initiated and developed with cardiac surgery225,226. Pre- and intraoperative electrophysiological mapping has allowed the identification of the site of origin and its relationship to akinesia and dyskinesia areas usually located in the left ventricle227. The analysis of biopsy specimens obtained during surgical treatment guided by electrophysiological mapping has confirmed the presence of the scar substrate228, showing that the inferior, lateral and basal LV walls were the most frequent sites of origin of SVT, independently of the presence of apical aneurysm225. With technological development, the surgical treatment of SVT in CCC has been gradually replaced by the treatment via catheter, being currently rarely recommended, except for highly selected patients (Table 9).
7.4.2. Catheter ablation of SVT in CCC
The origin of SVT in CCC is usually topographically related to the endocardial, epicardial or intramyocardial segmentary scar. In addition, SVT can have multiple sites of origin, making the task of eliminating all circuits a challenge201,207,213,229,230. In general, the site of origin of well-tolerated recurring SVT can be identified and the SVT interrupted in 60%-80% of the patients, but rapid and poorly tolerated SVT are frequently induced in the final assessment of the procedure201,213,227-229. During long-term follow-up, at least 50% of the patients undergoing conventional ablation have clinical relapse, justifying the maintenance of antiarrhythmic drugs or ICD implantation230. Clinical results have been more consistent in patients with incessant SVT or receiving ICD shocks, undergoing simultaneous endocardial and epicardial mapping, with the help of electroanatomical mapping207. The procedure can bear high risk in the presence of clinically unfavorable conditions and severe ventricular dysfunction. Although rare, the major complications are as follows: ventricular dysfunction worsening, cardiogenic shock, electromechanical dissociation, cardiac tamponade, complete AVB, CVA, coronary artery occlusion and death (Table 10).
7.5. Bradyarrhythmia and pacemaker indication in CCC
Bradyarrhythmia in CCC can result from sinus node dysfunction or AVB. The disease causes damage to the entire cardiac excito-conduction tissue, which is mainly evidenced at the sinus node and His-Purkinje system, with inflammatory infiltrate, replacement of the normal tissue with fibrosis, and possiblly autonomic denervation caused by substances released from the interaction with live or dead parasites231. Intraventricular blocks are also frequent in CCC, especially right bundle-branch block associated with left anterior hemiblock232. Several observational studies have suggested that cardiac pacemakers are beneficial in CCC233-235, which, in some Latin American regions, where CD is endemic, is the most frequent indication for pacemaker implantation. The indications for cardiac pacemakers in CCC are approached in the Brazilian Guidelines for Implantable ElectronicCardiacDevices236 (Table 11).
7.6. Indications for CDI
The scientific evidence regarding indications for ICD in CCC is limited to publications of case series, retrospective cohorts or registries, involving only secondary prevention of cardiac SD237-249. So far, no large-scale randomized clinical trial, comparing the efficacy of ICD with active drug or placebo in CCC, has been published (Table 12).
There is no scientific evidence supporting the indication for ICD in primary prevention of cardiac SD, and, thus, there is currently no recommendation about it.
7.7. Cardiac resynchronization therapy (CRT)
Cardiac resynchronization therapy is the defined therapeutic alternative for advanced HF in patients with dilated cardiomyopathy and dyssynchrony of ventricular activation244. Cardiac resynchronization therapy is based on the concept that QRS prolongation can cause intra-and interventricular dyssynchrony, impairing ventricular systolic function245,246. The global results of clinical trials have shown that CRT causes a significant reduction in FC, improves the quality of life, and increases the distance covered in 6 minutes and peak VO2; in addition, they have suggested a reduction in total mortality247,248. Those trials have mainly included patients with ischemic cardiopathy and idiopathic dilated cardiomyopathy. Although those results may be reproduced in CCC, there is no report of cohort, registry or randomized study including exclusively chagasic patients. It is worth noting that complete left bundle-branch block, the major electrocardiographic indication for that procedure, is rare in CCC249.
Conversely, it is worth noting that the conventional pacemaker, frequently indicated in CCC, causes a morphology pattern of left bundle-branch block (delayed LV activation), mainly for leads positioned at the RV apical site250 leading to There is evidence of significant hemodynamic impairment, mainly in the presence of preexisting ventricular dysfunction.
In clinical practice, despite the lack of consistent scientific evidence, the criteria for CRT indication in CCC are extrapolated from those used for ischemia and idiopathic dilated cardiomyopathy, whose results, despite restrictions, are well known236,251,252 (Table 13).
8. Cardiac and cellular transplantation and other surgical therapies in CCC
Brazilian researchers have pioneered the performance and development of orthotopic CT to treat CCC253-256. Heterotopic CT is not usually indicated because chagasic patients have neither pulmonary hypertension nor hyper-resistance; in addition, it is associated with a higher number of complications257. Orthotopic CT can be used with bicaval anastomosis and prophylactic tricuspid annuloplasty258,259. In Brazil, CCC chagasic cardiomyopathy is the third most common indication for CT260,261.
8.1. Etiopathogenic and pathophysiological peculiarities to consider for CT in patients with CCC
Regular tests have shown that parasitemia can be persistent in chronic chagasic patients262. Several techniques have shown parasite DNA or antigens in myocardial inflammation foci263-265. T. cruzi can induce changes in the host's immune system, such as no interleukin receptor (IL)-2 expression and lower expression of CD3+, CD4+ and CD8+ surface molecules of lymphocytes265. Local production of IL-7 and IL-15 can be associated with CD8+ cells264. T. cruzi coinfections, by such as archaea, have been recently suggested, and they have potential repercussion after transplantation, because of the immunosuppression induced266.
Although the criteria defined for other etiologies apply, the indications for CT in CCC have peculiarities81. Patients with CCC usually tend to have lower pulmonary vascular resistance, pulmonary artery pressures and transpulmonary gradient, minimizing the chance of RV dysfunction, frequent after CT267. Thus, some centers of CT have not even performed invasive tests in patients with pulmonary artery systolic pressure indirectly estimated by use of Doppler ECHO below 50 mm Hg. When invasive tests are indicated, the pulmonary reactivity test should be performed with vasodilators, such as sodium nitroprusside, nitric oxide, prostaglandins, phosphodiesterase-5 inhibitors, if pulmonary artery systolic pressure > 50 mm Hg, if transpulmonary gradient > 15 mm Hg or if pulmonary vascular resistance > 3 Wood units268. Nitric oxide bears the risk of acute pulmonary edema269,270. Determining BNP level may be useful in that population66.
Usually patients with CD have a less favorable social and cultural status, the indication for CT constituting an additional challenge for them. However, no relationship between socioeconomic level and outcome after CT has been reported271. Nevertheless, special attention should be given to the identification and improvement of social conditions, acceptability, access to the transplantation center, adherence to recommendations, educational level and family dynamics.
Considering the worse prognosis of CCC as compared to other HF etiologies, the use of inotropes/vasopressors and mechanical assistance devices (intraaortic balloon, ventricular assistance, mechanical ventilation) should be valued in that etiology. In addition, ascitis and RV dysfunction can be associated with liver dysfunction and higher risk of bleeding (Table 14).
In CCC, the contraindications to CT should be assessed individually, because the patients are usually younger and have a low rate of co-morbidities272 (Table 15). It is worth noting the possibility of megaesophagus and megacolon, which, according to their severity, can contraindicate CT.
8.1.2. Organ acceptance criteria
The diagnosis of CD is important for organ donation because of its high prevalence in Latin America and developed countries due to immigration16,21. As a rule, T. cruzi-infected individuals should not donate organs, because disease transmission and death have been reported in cases of chagasic donors to non-chagasic recipients273,274. In selected situations and emphasizing the marginal recipient in countries with no regulation, donors with positive serology for CD and no heart impairment could be considered for recipients with CCC. In a case report, a recipient of a donor with positive serology for CD underwent prophylaxis with benznidazole and there was no manifestation of CD275. However, chagasic myocarditis has been reported in recipients of organs from donors with negative serology for CD276.
Several regimens combining immunosuppressive drugs, with or without graft tolerance induction, have been used for CT in CCC, with a good outcome277-279. Of the drugs that can be used to prevent rejection, the following stand out: corticosteroids, cyclosporine, tacrolimus, azathioprine, mycophenolate, rapamycin and everolimus. In maintenance immunosuppression, the most used regimen is the association of cyclosporine and azathioprine, and corticosteroid withdrawal as soon as possible. There are studies comparing the various immunosuppression regimens; however, more reactivations have been diagnosed with the use of mycophenolate mofetil280. Experience with the use of tacrolimus, rapamycin, methotrexate and everolimus has not been published, despite their potential benefit281. The following can be used to induce tolerance or to treat a rejection episode: corticosteroids; cyclophosphamide; methotrexate282,283; interleukin-2 receptor antagonists; polyclonal antibodies; monoclonal antibodies; and apheresis. The use of drugs for induction is controversial and reserved for selected cases and centers284.
The preponderant concept is that, having the T. cruzi infection, a chagasic patient should receive the lowest intensity of immunosuppression possible, provided there is no rejection (Figure 5).
8.1.4. T. cruzi-infection monitoring before and after CT (Table 16)
Monitoring T. cruzi-infection reactivation, before and after CT, by use of clinical, laboratory or histological findings, is fundamental, because of its inherent risk, including infection transmission285-287.
8.1.5. Follow-up chronology of seropositive recipients after CT
Monitoring of T. cruzi-infection reactivation after CT should be performed routinely and during suspected reactivation episodes. However, there is no scientific data defining exactly when that should be routinely done. Some centers perform it during the same period of biopsies, but others recommend it weekly up to two months after CT, then, fortnightly up to the sixth month, and, finally, monthly until the end of the first year of CT.
Serological tests are useful only for seronegative patients receiving organs from seropositive donors. Hematoxylin-eosin and giemsa staining, in addition to specific agent screening, should be used in the histological analysis of endomyocardial and other tissue biopsies. Patients suspected of clinical reactivation based on symptoms should undergo the following exams: skin biopsy, in the presence of skin lesions; endomyocardial biopsy, if myocarditis is suspected; cerebrospinal fluid analysis, in the presence of neurological manifestations; and myelogram or bone marrow biopsy, if bone marrow involvement is suspected. Polymerase chain reaction has been tested to assess T. cruzi infection with promising preliminary results288-290.
8.1.7. Methods to detect T. cruzi in tissues (Table 17)
The histological diagnosis is made in the presence of T. cruzi amastigote nests or antigens. The major differential diagnosis is with toxoplasmosis; therefore, immunohistochemistry is fundamental, and can reveal parasite antigens even in the absence of the characteristic nests. Nodules of disease reactivation usually present as panniculitis foci in the subcutaneous tissue, with accumulation of lymphocytes and histiocytes, and intense proliferation of T. cruzi amastigotes inside macrophages and endothelial cells291,292.
8.1.8. Differential diagnosis between rejection and T. cruzi myocarditis after CT (Table 18)
Differentiating between acute cellular rejection and chagasic myocarditis is particularly difficult, because those processes have histopathological similarities represented by foci of lymphocytes attacking non-parasitized cardiac fibers, although they differ regarding some characteristics of the infiltrate292-294.Parasitic nests should be routinely sought in histological sequential sections, and immunohistochemistry against T. cruzi antigens should be performed. Polymerase chain reaction has been used for that purpose, but the sensitivity and relationship with reactivation are yet to be confirmed288,295.
8.2. Results of CT in CCC treatment
A registry of patients undergoing CT has suggested that the prognosis of chagasic recipients is better than that of non-chagasic recipients. The survival probability of those patients is 76%, 62% and 46% in one year, two years and six years after the cardiac procedure, respectively296. Other centers have reported survival similar to that of non-chagasic individuals. That might be due to the following factors: younger patients with less co-morbidities; less severe rejections; low incidence of graft vascular disease; lower prevalence of pulmonary hyper-resistance; and no previous surgery296. Reactivation of CD and neoplasms have already been important problems, but that has been overcome with higher experience and with the use of low doses of immunosuppressive drugs or of alternative immunosuppressive regimens119.
Currently, infection is the major cause of death (21%) of chagasic recipients of CT in the mid- and long-term297. Rejection is the second cause of death, affecting 10%-14% of chagasic recipients260,297.Surprisingly, in a limited experience38, chronic pericarditis was the cause of death of 14% of the patients. Currently, graft coronary artery disease and neoplasms are not frequent causes of death.
8.3.1. Immediate postoperative period
In the perioperative period, the clinical outcome, as well as morbidity and mortality, of chagasic patients receiving CT is similar to that of non-chagasic patients. This might be related to the fact that, in the perioperative period, the complications are related to the conditions of the donor, the cardiac procedure and general conditions of the recipient, rather than to the etiology of the recipient terminal chronic HF.
The major complications observed in those patients during that period are as follows: graft dysfunction (20%); grade 3A rejection or more intense (10%-20%); acute renal failure; bleeding (10%), mainly in patients using an artificial ventricle; and bacterial infection (20%-30%)269. Infection and rejection are the most frequent complications, affecting up to 30% and 20% of the patients, respectively270. It is worth noting that clinical reactivation of CD, frequently found in chagasic patients receiving CT, is exceptional in the immediate postoperative period. The major causes of early death are acute graft failure (right or left HF) and infection, mainly those located in the respiratory tree293. The RV dysfunction usually normalizes afterwards298.
8.3.2. T. cruzi-infection reactivation
18.104.22.168. Clinical presentation
The frequency of T. cruzi-infection reactivation in cardiac transplanted patients ranges from 0% to 50%, being a rare cause of death260,279,289,294,296, 297,299-301. It manifests as fever, skin lesion, bone marrow impairment, myocarditis, and neurological symptoms and signs. The parasite is frequently detected on direct smear inspection, xenodiagnosis or blood culture, in addition to serological tests302,303. The most frequent presentation form is myocarditis, which can be asymptomatic, but can manifest as HF or even cardiogenic shock293. Patients can have several reactivation episodes during follow-up, with different manifestations, even if the initial episode was treated or the patient received preventive treatment. So far, CCC in the recipient has not been reported277.
22.214.171.124. Reactivation diagnosis
Infection reactivation is confirmed when, in addition to symptoms and signs of infection, the parasite is detected in the blood, cerebrospinal fluid, or tissue samples. However, infection reactivation is also considered in asymptomatic individuals, in whose tissues or blood the parasite is persistently detected. The following factors are associated with T. cruzi-infection reactivation: number of rejection episodes; neoplasms; and immunosuppression grade (use of mycophenolate)304,305. The decrease in immunosuppression reduces the chance of reactivation. It is still controversial whether the T. cruzi characteristics would have a preponderant role in infection reactivation306.
126.96.36.199. Routine etiological treatment before (waiting list) or after transplantation (Table 19)
During the treatment of a rejection episode, the dose of immunosuppressive drugs increases, consequently increasing the risk of T. cruzi-infection reactivation. Although the prophylactic use of anti-T. cruzi drugs might be simple, no study has shown their efficacy in this context. Thus, follow-up and strict monitoring of the reactivation possibility is the ideal management (Table 12). Treatment with benznidazole has been indicated as carcinogenic in an experimental model, but that has not been confirmed in human beings307.
188.8.131.52. Drugs used in the treatment (Table 19)
The therapeutic regimen was reported in the chapter about etiological treatment. Benznidazole is the preferred drug, nifurtimox being the second option, including for parasite strains resistant to the former308,309. Although experience with a small number of patients has reported the effectiveness of allopurinol, that treatment is not recommended310-312.
Infections are the most important mid- and long-term morbidities of chagasic patients undergoing CT, affecting approximately 30% of the patients in the first year, and 50% of them after two years293,298,303. Infections can occur in the surgical site or other organs313-315. However, the current incidence of infection in chagasic recipients seems to be lower than that observed in the past294, and also lower as compared with that of non-chagasic individuals303. Infection is the cause of death in 10%-21% of chagasic recipients of CT297.
Humoral rejection, although theoretically possible, has not been reported in chagasic patients undergoing CT315. However, cellular rejection is frequently found in those patients - approximately 70% of them have that complication in the first year after CT305. The great problem of finding an inflammatory mononuclear infiltrate in the myocardial biopsy is that it can actually be due to CD reactivation, because the parasite is not always seen with the routine staining techniques, and the inflammatory infiltrate of CD reactivation is similar to that observed in grade 3A or 3B rejection. Actually, up to 43% of the patients can have myocardial inflammation consistent with the diagnosis of 3A rejection or more severe, which does not respond to pulse corticosteroid therapy, but subsides with the specific treatment for CD316. Cellular rejection usually responds properly to pulse corticosteroid therapy. Exceptionally, rescue therapy can be required to overcome rejection. Invasive and noninvasive methods are used to detect rejection317,318.
At the beginning, chagasic recipients of CT had shown an apparent increase in the incidence of neoplasms275,319. A recent re-analysis has shown that such higher incidence of neoplasms was more likely related to the use of a more elevated dose of cyclosporine296. Currently, with the use of lower doses of immunosuppressive agents, the incidence of neoplasms in chagasic recipients of CT is extremely low, accounting for the death of 2% of those patients296.
8.3.6. Graft coronary artery disease
The incidence of graft coronary artery disease in chagasic recipients of CT is little known. However, it seems to be low, less than 10% of the patients undergoing CT280,297,320. For the purpose of diagnosis and prevention, the same methods used for other etiologies are recommended321-324.
8.4. Cellular transplantation and other special therapies
8.4.1. Experimental results of cellular transplantation
Bone marrow cells have been obtained from healthy mice and intravenously injected in mice in the chronic phase of chagasic infection. A significant reduction in myocarditis has been observed two months after transplantation as compared with controls325. A study with nuclear magnetic resonance imaging has shown, in mice treated with bone marrow mononuclear cells, a regression in RV dilation326. The potential mechanisms of those beneficial effects include: a reduction in apoptosis, in fibrosis, and in the inflammatory process; stimulation of local resident cells and transplanted cells that acquired the morphology of cardiomyocytes and myosin expression, indicating possible differentiation of transplanted cells into that cell type or fusion with cardiomyocytes of the recipient animal327,328.
8.4.2. Clinical results
Phase I-II studies have reported favorable initial results of the treatment with stem cells in CCC69,329-332. However, the results of an unpublished phase II-III randomized study have shown no benefit, even when assessing only surrogate endpoints and not clinically relevant events333. Nevertheless, the research with stem cells is still considered to be promising. It is worth noting that the following remain to should be determined: the best cell type; doses to be used; time and form of application; and the adequate patient. In addition, it is worth noting the potential of mesenchymal cells, and the use of cellular hormones capable of recruiting, inducing proliferation and differentiation of stem cells, such as G-CSF328,329, which seems to significantly reduce both inflammation and fibrosis in the heart of chronic chagasic mice334.
8.4.3. Others and new novel surgical therapies in the treatment of HF due to CD
Because of the limitations in the number of donors335 and contraindications to CT, several other procedures have already been or are currently tested for the treatment of CCC336. Of those procedures, the following stand out: cardiomyoplasty337-342; isolated mitral valve surgery to repair mitral regurgitation with reconstruction or prosthesis343-345, or associated with other procedures345,346; and reduction ventriculectomy (Randas procedure)347-354. In addition to Despite the small number of patients included, from the clinical viewpoint, none of those procedures proved to be effective in the long run, although some hemodynamic or functional class benefits have been observed274,275. Those surgical procedures were aimed at repairing the remodeling or its consequences, such as mitral regurgitation and excessive ventricular diameter enlargement355-360. Thus, no surgical procedure other than CT is indicated for the treatment of CCC, except for the use of temporary mechanical support.
Mechanical circulatory support, such as bridge to transplant, bridge to bridge, or bridge to recovery, has a high potential for future use in CCC, as in other etiologies and observing the same criteria of indication361. The first mechanical circulatory support as bridge to transplant for CCC was performed in 1994, and the patient remains well up to the present time361. However, the major limitation to its applicability is its high cost.
9. Special subgroups in Chagas disease: coinfection (HIV); immunosuppressive therapy and non-cardiac transplantation; pregnant women; newborns; children and adolescents; seropositive individuals and blood banks
9.1. HIV coinfection
T. cruzi/HIV coinfection is important because of the risk of trypanosomiasis reactivation in patients with chronic CD in the presence of immunosuppression caused by HIV, particularly in patients with CD4+ T lymphocyte count < 200 cells/mm3 362-367. In addition, high frequency of congenital T. cruzi transmission with severe meningoencephalitis and/or myocarditis was observed, as was high mortality in offsprings of coinfected mothers364,368.
Conversely, CD can negatively interfere with HIV outcome, because it activates the immune system5, which favors HIV replication, and can lead to faster disease progression. Transient increase in HIV viral load concomitantly with CD reactivation has been reported369.
The prevalence of CD/HIV coinfection is not well known. In an outpatient clinic specialized in the treatment of HIV/AIDS infection in São Paulo, an investigation on trypanosomiasis has been conducted in 52.8% of the patients assessed, coinfection being diagnosed in 2.3% of them370. In a health care service in Buenos Aires, serological tests for CD have been performed in 51.3% of the HIV+ patients, coinfection being identified in 4.2% of them371.
The diagnosis of T. cruzi/HIV coinfection is based on serological tests. Serological tests for CD should be indicated for all HIV+ patients coming from an endemic area or exposed to the risk of T. cruzi infection (blood transfusions, mother with CD)363,369.
The follow-up of coinfected patients should be performed preferentially at reference centers363. In addition to the diagnosis and treatment of the various manifestations associated with HIV infection and chronic CD, the initial assessment and follow-up of those patients are aimed at the early detection of reactivation.
The frequency of trypanosomiasis reactivation in HIV coinfected patients is not well known. In a prospective study with long-term follow-up, approximately 20% of coinfected patients had reactivation364. In addition to reduced levels of CD4+ T lymphocytes (< 200 cells/mm3), high parasitemia (observed with quantitative methods) has been identified as a predictive factor of reactivation (50% of the cases).
The most common clinical manifestation of reactivation is meningoencephalitis363-365,367,369. Myocarditis has been reported in 30%-40% of the cases363-365,372. Other manifestations, such as pericarditis, peritonitis, erythema nodosum and colpitis, have been occasionally described. Oligosymptomatic and asymptomatic forms can also occur364.
Chagas disease reactivation in HIV+ patients has high lethality363,364,367, which can reach 100% in untreated patients or those treated late. Early treatment is associated with better prognosis and a 20% reduction in lethality for patients completing 30 days of specific treatment.
Preemptive etiological treatment of T. cruzi infection can be considered for HIV+ patients with high parasitemia detected on semiquantitative xenodiagnosis or quantitative PCR363,364.
Secondary prophylaxis with benznidazole (5 mg/kg/day, 3x/week) has been used, mainly for patients with CD4+ T lymphocytes < 200 cells/mm3, similarly to other opportunistic diseases363,369,373, but it still requires validation in prospective studies.
In parallel with the treatment of trypanosomiasis, antiretroviral treatment should be maintained or initiated as early as possible.
Specific treatment should be monitored with clinical and laboratory assessment, which includes hemogram, liver enzymes, urea, creatinine, electrolytes and parasitemia control (direct parasitological tests twice a week to control the therapeutic response, until they become negative). In addition, after treatment suspension, periodical parasitological tests should be performed because therapeutic effectiveness has not been well established in those patients363 (Table 20).
9.2. Noncardiac transplantation and immunosuppressive therapy
The following three mechanisms can account for CD in recipients of solid organs and bone marrow374,375:
Transmission via contaminated blood derivatives given to a recipient negative for CD. This pathway is easily controlled in endemic countries, where serology for CD in blood derivatives is mandatory;
Acquisition of de novo infection via infected grafts, which would also be easily controlled in endemic regions, where serology for CD is mandatory in the donation process;
Reactivation of latent disease in a previously infected recipient, with acute invasion of the disease-free graft via dissemination of the parasitemia associated with immunosuppression.
The CD reactivation rate has been reported to range from 9% to 16% with renal transplantation58 and from 17% to 40% with bone marrow transplantation376, being more common in the first year, when immunosuppression is more intense. In general, the response to treatment is good, but there are reports of graft dysfunction and loss or even death, regardless of the appropriate use of benznidazole377.
When infected renal grafts are given to used for negative recipients, the estimated transmission rate is 35%378; however, cases originating from infected renal or liver grafts are usually reported as mild, some with undetected parasitemia and excellent response to trypanocidal therapy378,379. It is worth noting that CD in a potential recipient is no contraindication to any type of transplantation, because, as already mentioned, the specific treatment can rapidly suppress the clinical manifestations of reactivation.
Cases of CD reactivation clinically manifested as meningoencephalitis and/or myocarditis and skin lesions have also been reported in immunosuppressed patients with hematological malignancy (leukemia and lymphoma). In such cases, the parasite is easily found in peripheral blood, and mortality can be high, mainly when the diagnosis is established late. Treatment with nifurtimox or benznidazole can lead to remission and significantly reduce mortality380.
Corticotherapy, frequently used chronically in patients with autoimmune diseases, is associated with an increase in parasitemia, but its role in the clinical reactivation of the disease has not been entirely proved. The cases reported involve cell immunity impairment by the underlying disease or by the concomitant use of other immunosuppressive drugs. Thus, the prophylaxis with trypanocidal drugs in chagasic patients on chronic corticosteroids is still controversial, with some authors reporting possible benefits of primary prophylaxis380, while others point to the lack of controlled clinical trials and the risk for side effects of that medication381.
9.3. Pregnant women
CCC is the second most common cardiopathy of the pregnancy/puerperium period, rheumatic cardiopathy being the first. A study carried out in the state of Minas Gerais in 2009 identified a 0.5% prevalence of CD in puerperal women, the most elevated rates being observed in the Northern region of the state, ranging from 2.3% to 23%382.
The risk of vertical transmission is substantially higher in the acute phase (62%) than in the chronic phase (1.6%)383. The vertical transmission mechanisms are not entirely known. The production of immunoregulatory cytokines and parasite load seem to play a relevant role in the context384. Chagasic mothers not transmitting their infection to the fetus have no higher frequency of abortion, prematurity or perinatal mortality; however, those transmitting their infection have higher natimortality. Successive pregnancies seem to increase the risk for transmission385.
The impact of CD on the course of a pregnancy is controversial. Some studies have pointed to the benignity of the association386, while others have reported higher incidence of gestational complications, perinatal mortality, and neonatal hypotrophy, considering chagasic pregnant women at high obstetric risk387.
The prognosis of pregnant women with chagasic cardiopathy is closely related to the severity of ventricular dysfunction and FC at the beginning of gestation. Those beginning pregnancy in FC I and II usually have an uneventful pregnancy. Conversely, those beginning pregnancy in FC III or IV have a 25% to 50% likelihood of maternal death388.
The presence of cardiopathy, when as long as followed up and not severe, does not contraindicate pregnancy, but patients should be closely followed. In such situation, CCC does not limit the number of gestations, does not predispose to prematurity, does not accelerate the birth date and does not significantly affect the newborn weight. Patients with high FC and/or severe arrhythmias should be discouraged from becoming pregnant. Because of the likelihood of aggravation during gestation, pregnant women under those conditions require special follow-up and care.
The etiological treatment with trypanocidal drugs should not be instituted in pregnant women or those at childbearing age who are not on contraceptives. Cardioactive drugs should only be used in chagasic pregnant women in accordance with absolute medical indication, because of their potential effects on the fetus (Table 21).
In the current stage of vectorial and transfusional control, vertical transmission has become an important mode of CD transmission in Brazil and other Southern Cone countries81,389. The T. cruzi vertical transmission rate has regional differences, ranging from 1% in Brazil to 4%-12% in other Southern Cone countries, and seems to depend on parasite- and host-related factors. The high likelihood of cure of congenital CD makes its early diagnosis imperative.
Studies carried out in Brazil, Argentina, Chile and Paraguay have shown that 60%-90% of the newborns with congenital infection are asymptomatic. In symptomatic newborns, the most frequent clinical findings are prematurity, low weight, fever and hepatosplenomegaly390.
In the first weeks of life, the diagnosis of congenital infection is based on finding T. cruzi by using the direct parasitological test, which should be performed in children with clinical manifestations suggestive of congenital infection. The micro-hematocrit technique is easy to perform and has good sensitivity, especially in the first month of life. If the result is positive, etiological treatment should be initiated immediately. Congenital CD is considered acute, its notification being, thus, mandatory.
If the result is negative, diagnostic investigation should be completed with serological tests (with two distinct techniques) after the seventh month of life. Serological study before the sixth month is not useful because of the passive passage of maternal antibodies. Between the sixth and ninth months, such antibodies disappear, and the diagnosis of congenital CD can be made. Seropositivity implies initiating specific treatment. Negative serology after that period permits allows excluding the diagnosis of chagasic infection.
The use of PCR for the diagnosis of chagasic infection is a recent advance391, but, some centers have had problems with specificity, thus it should not be used in clinical practice.
Chagasic infection treatment in newborns can be performed with benznidazole or nifurtimox for 30 to 60 days, with similar results and high cure rates392.
After the end of treatment, serological control should be performed every six months, until two consecutive negative results are obtained. If the treatment of the newborn is initiated with positive micro-hematocrit, this parasitological test should be repeated 15 days after initiating the medication389.
The current criterion for cure is a persistent negative serology after the treatment. The time required for that depends on the age the treatment is initiated. Infants diagnosed in the first months of life will have a negative serology between the second and twelfth months, after initiating treatment. Polymerase chain reaction, which has been proposed as a marker of therapeutic response, still awaits higher standardization to be used in clinical practice (Table 22).
9.5. Seropositive individuals and blood banks
Routine CD screening in blood banks is part of a preventive strategy for T. cruzi transmission established by Southern Cone countries in the 1990s, and should be performed in all candidates for donation in endemic countries283.
In non-endemic countries, two strategies have been used to prevent transmission via blood transfusion: routine exclusion of donors with a positive epidemiological history or acceptance of donation after a negative serological test. The second strategy has been introduced in countries with a huge population of Latin American emigrants, such as the United States of America, Spain and France.
Several tests using the ELISA technique are considered sensitive enough to be recommended as a single tool to screen CD in blood donors393. The practical technique to screen CD in blood banks will have to abide by local legislations. Reacting or positive results of the tests performed in blood banks should be considered as only preliminary screening, that is, a non-definitive result, and further confirmatory diagnostic investigation being thus performed indicated at reference centers.
10. Recommendations for constituting structured follow-up services for patients with CCC
Considering the importance of the impact of social, economic and cultural factors involved in the CCC genesis and progression, its approach requires the adoption of a health care model that transcends the purely biological aspect, offering integral care to the patient, and considering a set of biological, psychological and social determinants. That initiative requires the creation of a multiprofessional team, technically well prepared and in tune with the caring ideology.
Considering those peculiarities, the experience has shown that the health system has been challenged, because there are innumerous gaps in patients' management, regarding follow-up at clinics with no appropriate structure. An appropriate structure implies an outpatient clinic linked to a hospital, preferentially a teaching hospital, with availability of invasive and non-invasive diagnostic methods, clinical and surgical treatment, and high complexity beds. Such service is aimed at improving adherence to treatment, reducing morbidity and mortality, and at having a positive impact on the patients' quality of life394.
10.1. Attributions of a structured service
1 To make the etiological diagnosis by use of clinical and epidemiological data and serological tests (two tests of different methodologies);
2. To stage the cardiac impairment, that will determine the periodicity of follow-up;
3 To establish the therapeutic plan (based on etiology and symptoms) and prognosis according to the stage of cardiac impairment;
4 To monitor the patient systematically;
5 To identify associated digestive impairment, when present, and to instruct the patient or refer him/her the patient to a reference center in gastroenterology;
6 To treat the comorbidities identified or refer the patient for interconsultation at a specialized service;
7. To stimulate adherence to pharmacological and non-pharmacological treatment optimizing the cost/effectiveness ratio;
8. To educate the patient, family members and caregivers about the disease and self-control, aiming at the early identification of signs and symptoms of cardiac decompensation;
9. To explain the impossibility of donating blood, organs and tissues;
10. To provide nutritional guidance;
11. To provide psychological support to the patient and family, aiming at reducing the stigma, the self-bias, taboo and improper beliefs related to the disease;
12. To instruct about medical, labor and insurance aspects, gestation, family planning, physical exercise and sexual activity;
13. To inform the patient and family when pacemaker or ICD implantation or CT is required;
14. To instruct about the prevention of aggravating factors (alcohol, smoking, legal and illegal drugs);
15. To provide care to patients under special conditions (e.g. those with pacemakers or ICD);
16. To enable and recycle health professionals focusing on the peculiarities of CCC patients, stimulating learning and research;
17. To identify other family members contaminated with T. cruzi, and to include them in the program for therapeutic management;
18. To stimulate and support the creation of associations of patients with CD, aiming at the best integration of participants (patients and families), establishing a communication channel with the scientific community and a policy of respect to their claims394.
10.2. Multiprofessional team
A multidisciplinary team is currently recognized as the best way system to care for patients with chronic diseases81,395-397. When creating a service destined and devoted to patients with CD, it is important to consider their peculiarities, and to understand them within a biopsychosocial context398-400. In that approach, all each members of the team play a defined role, and should know their limits, possibilities and responsibilities, understanding that it is fundamental that all interact with each other. Each member observes one aspect of the same individual. The team needs to have basic knowledge on CCC, and the routine of its management, so that all speak the same language, avoiding distorted or even iatrogenic information. Considering that multiple knowledge areas need to interact, the great challenge is to maintain a cooperative environment, avoiding predatory competition.
The structured service should ideally count on the following professionals: general physician, cardiologist, nurse, psychologist, nutritionist and social worker. It can be extended according to the adoption of new therapies, with the participation of a physical educator, physical therapist, pharmacist and occupational therapist. The size of the team should be adjusted to the reality and possibilities of each service, patients' demand, and mainly to its purpose394,401.
10.3. Identification of comorbidities and creation of reference and counter-reference mechanisms
As the population with CCC ages and the management of the cardiopathy becomes more demanding appropriate, the prevalence of comorbidities increases and their identification is required, mainly of those that increase the cardiovascular risk and contribute to worsen the cardiopathy, aggravating the prognosis402.
10.4. Education and health
The education of the patient and family starts with the assessment of their knowledge on the disease and its treatment. Individual or collective educational activities should be periodically performed, focusing on information about the disease, its contagion mechanisms, course, need for periodical assessment even in asymptomatic individuals, importance of regular treatment and, usually, impossibility of donating blood, organs or tissues. Nowadays, chagasic individuals can donate blood, organs and tissues under the "expanded donation" circumstance, that is, patients with CD can be donors as long as recipients consent to it and have the same pathology403.
10.5. Management model for a structured service
Health care and promotion to patients with CCC should be based on a health care structure allowing integral actions, permeated with humanization practices and quality management404-406. The health care model to that patient in the public health network integrated with the Brazilian Unified Health Care System (SUS) presupposes the existence of the conditions necessary to its development, via the technical and managerial strengthening of the institutions involved in planning, coordination, execution and assessment of services at all levels, aiming at providing better care and observing the cost/effectiveness of the actions407-409.
10.6. Benefits expected of a structured service for the follow-up of patients with CCC
The structured service for the follow-up of patients with CCC should emulate might confirm that used which has been described for other chronic diseases81,395,397. Although the implantation of a structured service is known to require a higher investment in the number of professionals involved, limited financial resources and managerial aspects, its creation is believed to become cost/effective in the middle and long term21-410. That proposition should not be considered a closed mathematical model, but as based on general guidance principles to aid in the composition of structured services. Briefly, structured services have the major mission to promote care that favors the patient's clinical, psychological and social stability.
11. Preventing transmission and addendum on serological criteria
In 200581, the endemic area at risk for vectorial transmission of CD in Latin America comprised 19 countries, and involved 108,595,000 people. In 1950, actions against the insect vector were initiated in Brazil, Chile, Argentina and Venezuela, concomitantly with the intensification of urbanization, rural exodus and agricultural modernization. Since 1980, the Brazilian program of CD control has been prioritized, and blood banks began to screen donors for CD, which resulted in the current 100% coverage of serological assessment of donors in Brazil. The transmission has been drastically reduced, and the certification of elimination of T. infestans and of transfusional transmission has been achieved in Uruguay, Chile and Brazil81. Thus, there has been a decrease in disease prevalence in childbearing-age women, and in the congenital transmission of the disease. Of the estimated 100,000 new cases per year in Brazil in 1979, currently around 200 cases are detected, most of which in the Amazon region, due to outbreaks of oral transmission81,410. Currently available actions and strategies are sufficient to control the major modes of CD transmission in the most common situations. No safe and effective vaccine against CD exists411. The basic challenges are to maintain blood banks under control and to support and maintain the necessary epidemiological surveillance of the vector88. The present chapter is based on field results, longterm investigation and documents of official consensus81 (Table 23).
11.2. Modes of transmission and factors involved
The following modes of CD transmission are admitted or possible412,413:
B. Alternative (or secondary):
Accidental in the laboratory
Oral (including maternal milk)
Insect bite (triatomines and others)
Contact with feces of infected triatomines
Bizarre (sadomasochist practices, blood oaths for love, criminal).
11.2.2. Briefly description of the major mechanisms
184.108.40.206. Vectorial transmission
Occurs via the contact of a susceptible individual with feces of T. cruzi-infected triatomines. The parasite enters the host through a skin lesion or intact mucous membrane. Out of more than 140 vector species described, the most competent transmitters are those with the greatest power of household colonization, more anthropophilic habits and metacyclogenesis, and shortest feeding-defecation time. Currently there are virtually controlled areas with occasional risk of transmission through secondary or wild vectors (Uruguay, great part of Brazil), and areas with still active transmission and poor or nonexistent control. Because of the presence of wild foci throughout Latin America, transmission will always be possible. However, domiciliary transmission can be virtually eliminated through continuous control and surveillance actions21,283.
220.127.116.11. Transfusional transmission
Occurs between an infected donor (usually chronic) and a susceptible recipient. The parasite maintains its infecting ability for more than two weeks in stored blood. The transmission risk for 500 mL of chronically infected total blood ranges from 12% to 25%, increasing for donors in the acute phase and immunosuppressive situations (donor or recipient). Infected frozen fresh plasma and concentrates (platelets, red blood cells and leukocytes) can also transmit CD414.
18.104.22.168. Congenital transmission
Occurs mainly after the third gestational month. It consists in the colonization of the placenta by with the parasite, but can also occur through the ingestion of contaminated amniotic fluid or fetal contact with maternal blood. Its risk ranges from 1% to 5% in pregnant women with chronic disease (less frequent in Brazil than in Bolivia), being higher among pregnant women with acute disease or immunosuppressed. An infected woman can transmit the parasite in one or several pregnancies. Most commonly, the newborns are full term and asymptomatic, but fetal death and prematurity can occur. Symptomatic newborns have fever, low weight, tachycardia and hepatosplenomegaly414,415.
22.214.171.124. Accidents in the laboratory
Are due to contamination with different infected materials, management of triatomine bugs and manipulation of infected mammals, cultures, and blood of acute cases. Sporadic contamination during surgeries of chagasic patients and aerosol aspiration has been reported416.
126.96.36.199. Oral transmission
In the past, oral transmission events have been described in Argentina, Mexico, and in the Brazilian states of Pará, Rio Grande do Sul, and Paraíba, and, more recently, in other the Amazon regions (especially states of Pará and Amapá), Venezuela, Colombia, and in the Brazilian states of Santa Catarina, Ceará, and Bahia. Several types of contaminated food, especially juices (sugar cane, açaí fruit, bacabá fruit, guava), milk, soups, and raw game meat, could be implicated. Except for the breast milk of an infected mother (extremely rare and unlikely event) and poorly cooked meat of infected mammals (armadillo, for example), the events described seem to correspond to contamination of foods with infected triatomine bugs or their feces, in environments with peridomiciliary infestation or near a wild area. An outbreak of probable contamination with urine or gland secretion of a marsupial has been reported81.
188.8.131.52. Transmission via organ transplantations
It presupposes an infected donor and susceptible recipient, and has been described in transplantations of kidneys (the most frequent), heart, pancreas, liver and bone marrow. The risks increase in donors with more intense parasitemia (acute phase) and immunosuppressed recipients (due to the underlying disease or the medication received after transplantation)416.
11.3. Major programs and strategies to control CD
Chagas disease is not eradicable because of the persistence of T. cruzi wild cycle and oral transmission cases. However, proper control (of domiciliary vectors and blood banks) is highly effective, resulting in the virtual elimination of transmission, which reduces the risks of congenital and transfusional transmission81,283. In general, CD control is the responsibility of public health systems, and, to a lesser extent, of private health systems, particularly private blood banks. In Uruguay and Brazil417, once controlled the major vector and blood banks, the disease transmission has decreased to minimal levels in the past decades; occasional cases of congenital transmission are currently reported, along with unpredictable outbreaks of oral transmission21. The consolidation of control in those countries will depend on the continuity of sustained surveillance programs81,413.
11.3.1. Control of vectorial transmission
It is based on the chemical fight against domiciliary vectors and housing improvement actions.
It is the most common isolated measure, with faster results, performed with the systematic and continuous application of insecticides in contiguous areas. In Brazil, until 1999, it depended on centralized teams (SUCAM, FNS, SUCEN); after that, the actions were decentralized to the municipalities, becoming under state coordination. The program presupposes steps of investigation, planning, massive attack and surveillance414,415. Until 1980, the major insecticides were organochlorine (BHC, Dieldrin®) and organophosphate (Malathion®, Fenitrothion®) insecticides. They have been currently replaced by synthetic pyrethroids, with greater residual action and lower human and environmental risks. They have long residual action through contact, affecting mainly the nervous system of the insect.
184.108.40.206. Use of insecticides
The major products used and their recommended doses are as follows416:
They are mainly applied inside the houses (residual action longer than six months) and peridomiciliary annexes (shorter action). The best formulations are the wettable powder, microcapsules and suspension concentrate416. They have low toxicity on people, usually limited to skin and mucosa irritations. The current great challenge is the peridomiciliary environment, which concentrates most of the residual foci in the country. Chemical fight is not justified in the wild environment, but environmental planning and removal of natural ecotopes and wild reservoirs from the household are recommended. In surveillance, domiciliary foci are notified by the population and eliminated by municipal teams when indicated. Triatomine resistance to pyrethroids has appeared in focal areas of Bolivia and Argentina416. In such cases, the use of carbamates, another family of insecticides, is indicated.
220.127.116.11 Household improvement
Implies the improvement of house sectors (walls, roofs) or new constructions. In general, that is a longer lasting measure, but does not replace the use of insecticides in endemic areas. In addition to life promotion, it is a protection measure against CD, because it makes the vector entrance and colonization difficult. A growing body of evidence accumulated over many years has shown that sustained control levels depend mainly on the population's participation in the entomological surveillance of CD81.
11.3.2. Control of transfusional transmission
The basic strategies comprise the selection of donors through previous serology and chemoprophylaxis417. The former is more used and foreseen in the legislation of several Latin American countries. In Brazil, until 2004, serological screening was required through two different techniques. Since 2004, considering the low prevalence of CD infection in donors, only one technique has been required, as long as it has an immunoenzymatic basis, with high sensitivity rates417. Seropositive donors are considered permanently unsuitable and should be referred to a medical service for assessment and treatment. Chemoprophylaxis is performed by adding gentian violet (1:4,000) to suspected blood for 24 hours, time necessary for T. cruzi eradication. In the past, that was useful in highly endemic regions for CD, being currently used in some areas of Bolivia. Another control possibility would be the use of cellular filters for leukocytes, capable of retaining the parasite, but extremely expensive. It is worth noting that better use and indication of hemotherapy (avoiding arm-to-arm and total blood transfusions) and the elimination of paid donors are fundamental measures to the definitive control of transfusional CD417.
11.3.3. Control of congenital transmission
Primary prevention is not possible, because the specific treatment of pregnant women with currently available drugs is not indicated. In addition, prognostic markers of transmission do not exist. Therapeutic abortion in chagasic pregnant women is not prescribed, except for extremely severe cases of cardiopathy. Detection and specific treatment are indicated as early as possible for infected children, who usually heal and tolerate the medication well81,382. Because newborns maintain the antibodies (IgG class) passively transferred from their mothers up to the fifth or sixth month of life, an early positive serology will not indicate infection until that age. For the children of chagasic individuals, conventional serology should be performed at the age of seven months, and specific treatment immediately initiated for the seropositive ones81. For newborns strongly suspected of having congenital disease, the parasitological test should be performed for some days, at least three times a day, to increase sensitivity382.
11.3.4. Prevention of laboratory accidents
All professionals manipulating T. cruzi should undergo conventional serology at the beginning of their activities. If negative, they should repeat it annually while their activity lasts, which will allow the detection of inapparent infection and enable specific treatment. It is important to promote awareness and technical training, to keep an environment suitable for handling the parasite and mandatory use of equipment for individual protection (goggles, masks, gloves, closed shoes). In case of accident, one should proceed to immediate local disinfection with iodine alcohol or silver nitrate eye drops, if eye contamination occurs. Blood for conventional serology should be immediately collected. Specific treatment should be initiated immediately at the usual doses of the medications available (nifurtimox or benznidazole) for ten days. After 30 days, repeat serology, and, if it is positive, integral treatment (60 days) should be performed81.
11.3.5. Prevention of oral transmission
Because of the unpredictability and sparsity of oral transmission, there is little to be done regarding primary prevention. Removal of houses and annex from the wild environment, good hygiene in food handling and preparation, and no ingestion of raw or poorly cooked game meat are valuable general measures. Similarly to congenital transmission, the most practical measure is early detection and specific treatment, and the immediate epidemiological study of the occurrence to find out other cases. Transmission through maternal breast milk is extremely rare, thus, maternal breastfeeding should not be contraindicated, except for acute maternal CD and nipple bleedings21. Acute CD is of mandatory notification, the local/regional health system being responsible for its confirmation and epidemiological study. That allows the adoption of pertinent measures, such as the disease active screening in individuals exposed to common factors and triatomine control. In the Brazilian Amazon region, malaria microscopists are being trained to detect T. cruzi on blood smears of individuals with fever21.
11.4.1. Serological diagnosis of chronic T. cruzi infection
This completes the previous topics and has been well established in recent documents81,88,382,392,414,415,417.
Basically, two serological techniques among those available and recommended by the WHO, such as IIF, enzyme-linked immunosorbent assay (ELISA) and IHA, are used. When concordant, the serological results will be positive or negative. When discordant, the tests should be repeated. If the discrepancy persists, a new test should be performed using PCR or Western blot techniques (Figure 6)81.
11.4.2. Practical notes
a. For postmortem diagnosis, serology of the pericardial fluid is viable;
b. For extensive field survey, blood collection by use of digital puncture on 2-cm filter-paper discs (Whatmann Nº 4) is very practical. Seropositive results should be confirmed by use of venous blood collection as follows;
c. Negative initial serology followed by a positive one after 30 days indicates acute CD;
d. Unconventional tests14,18 are modern techniques that use recombinant antigens, synthetic peptides and mixtures capable of identifying multi epitopes of high specificity. Examples: "PaGIA" (particle agglutination of sensitized polymers), "INNO-LIA" (nitrocellulose strips loaded with recombinant antigens), "Chembio" (immunochromatography rapid test);
e. A PCR test can be negative in infected individuals, mainly in the chronic phase, and should be repeated in doubtful cases of doubt or high clinical suspicion;
f. Extremely rare cases of persistently negative serological and parasitological tests in certainly infected individuals not submitted to specific treatment mean spontaneous healing of the infection, according to some reports5.
12. Brief retrospective and perspectives
Regarding CD, much has been accomplished since Carlos Chagas' discovery one century ago. But there is still much to be done in coming decades. Popular wisdom has established the notion that 'every cloud has a silver lining'. This can be applied to CD globalization and the recent substantial diversification of its epidemiology in traditionally endemic countries. This context has aroused the interest in the social and medical problems related to CD of public health agencies and related national and international entities, research institutions and even industrial groups. There is currently a notable activation of several efforts to control CD epidemiology, to better know T. cruzi biology, its interaction with man, and the pathogenesis and pathophysiology of chronic phase complications, in addition to more properly and effectively treat the late cardiac and digestive manifestations. From that promising scenario, the following several aspects that deserve special attention emerge.
Although most vectorial and transfusional CD transmissions have been controlled in several countries, the need for sustained surveillance of the measures leading to that accomplishment persists. In addition, the changing ecological situation of extensive regions, such as the Amazon region, where new epidemiological aspects of the disease have the potential to develop and constitute more complex and difficult challenges, is matter of concern.
Furthermore, it is necessary to adopt initiatives that enable the proper management of the social and medical conditions resulting from the migration of infected individuals to countries where the disease never existed. The standardization of more reliable methods to detect T. cruzi infection is awaited, not only for diagnosis, but, more importantly, for healing criteria.
The etiological treatment of millions of patients in the chronic phase of the disease is a mystery to be unveiled. There is currently a renewed interest in the area, including the perspective of studies focusing on the association of drugs, such as benznidazole and posaconazole, because of their potential to act synergically against circulating (benznidazole, more active) and tissue (posaconazole, maybe more efficient) parasites. Confirmation of the real efficacy of the etiological treatment to favorably impact on the natural history of chronic disease is awaited, as is the development of new more effective trypanocidal agents with fewer side effects. Innumerous preferential targets for the pharmacological attack to T. cruzi have been identified based on the deeper knowledge of its interaction with the host cells and of its recently decoded genome.
Finally, cardiologists have to perfect the clinical management of their chagasic patients, properly administering drugs and interventions, respecting the peculiar pathophysiology of the disease, without using measures of no confirmed benefit, and not missing reasonable therapeutic opportunities.
13. Abbreviations used in the text and tables
2. Chagas C. Nova tripanozomiase humana: estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n.gen.n.sp, ajente etiolojico de nova entidade morbida do homem. Mem Inst Oswaldo Cruz. 1909;1:159-218. [ Links ]
3. Chagas CRJ. Estado actual da Tripanosomiase americana. Revista de Biologia e Hygiene. 1934;5:58-64. [ Links ]
4. Pittella JEH. O processo de avaliação em ciência e a indicação de Carlos Chagas ao prêmio Nobel de Fisiologia ou Medicina. Rev Soc Bras Med Trop. 2009;42(1):67-72. [ Links ]
5. La Iniciativa del Cono Sur. Incorsur. III Reunión de Ministros de Salud del Mercosur: Resolución 04-3-CS, Brasília, Junio; 1991. [ Links ]
6. Pan American Health Organization 2007. PAHO. XVI Reunión de la Comisión Intergubernamental de La Iniciativa del Cono Sur(Incorsur). Brasilia, Junio de 2007. [Acesso em 2010 ago 23]. Disponível em: http://www.paho.org. [ Links ]
7. Schmunis GA. Enfermedad de Chagas em un mundo global. In: Silveira AC, editor. La enfermedad de Chagas a la puerta de los 100 años del conocimiento de una endemia americana ancestral. Buenos Aires: Organización Panamericana de la Salud/ Fundación Mundo Sano; 2007. p. 251-66. [ Links ]
8. Akhavan D. Analysis of cost-effectiveness of the Chagas disease control programme. Brasília: Ministry of Health, National Health Foundation; 1997. [ Links ]
9. Wilson LS, Strosberg AM, Barrio K. Cost-effectiveness of Chagas disease interventions in Latin America and the Caribbean: Markov models. Am J Trop Med Hyg. 2005;73(5):901-10. [ Links ]
10. Pinto AY, Valente SA, Valente VC. Emerging acute Chagas disease in Amazonian Brazil: case reports with serious cardiac involvement. Braz J Infect Dis. 2004;8(6):454-60. [ Links ]
11. Xavier SS, Sousa AS, Viñas PA, Junqueira AC, Bóia MN, Coura JR. Cardiopatia chagásica crônica no Rio Negro, Estado do Amazonas. Relato de três novos casos autóctones, comprovados por exames sorológicos, clínicos, radiográficos do tórax, eletro e ecocardiográficos. Rev Soc Bras Med Trop. 2006;39(2):211-6. [ Links ]
12. OPS/OMS - Organización Panamericana de la Salud 2005. Conclusiones y recomendaciones generales. 2ª Reunión de la Iniciativa Intergubernamental de Vigilancia y Prevención de la Enfermedad de Chagas en la Amazonia (AMCHA) (Cayenne, Guayana Francesa; 2-4 noviembre 2005). [Accessed on 2010 Ago 24]. Available from: http://www.paho.org/spanish/ad/dpc/cd/dch-amcha-2-recom.pdf. [ Links ]
13. Silveira AC, Vinhaes M, OPS/OMS-Brasil. Doença de Chagas: aspectos epidemiológicos e de controle. Rev Soc Bras Med Trop. 1998;31(Suppl 2):15-60. [ Links ]
14. Dias JCP, Machado EM, Borges EC, Moreira EF, Gontijo C, Azeredo BV. Doença de Chagas em Lassance, Minas Gerais Reavaliação clínico-epidemiológica 90 anos após a descoberta de Carlos Chagas. Rev Soc Bras Med Trop. 2002;35(2):167-76 [ Links ]
15. Maguire JH. Chagas' disease - - can we stop the deaths? N Engl J Med. 2006; 355(8):760-1. [ Links ]
16. Voelker R. A century after Chagas disease discovery, hurdles to tackling the infection remain. JAMA. 2009;302(10):1045-7. [ Links ]
17. Bern C, Montgomery SP. An estimate of the burden of Chagas disease in the United States. Clin Infect Dis. 2009;49(5):e52-4. [ Links ]
18. Bern C, Montgomery SP, Katz L, Caglioti S, Stramer SL. Chagas disease and the US blood supply. Curr Opin Infect Dis. 2008;21(5):476-82. [ Links ]
19. Gonzalez-Granado LI, Rojo-Conejo P, Ruiz-Contreras J, Gonzalez-Tomé MI. Chagas disease travels to Europe. Lancet. 2009;373(9680):2025. [ Links ]
20. Schmunis GH. The globalization of Chagas disease. ISBT Science Series. 2007;2(1):6-11. [ Links ]
21. Coura JR, Dias JCP. Epidemiology, control and surveillance of Chagas disease: 100 years after its discovery. Mem. Inst. Oswaldo Cruz. 2009;104(Suppl 1):31-40. [ Links ]
22. Moncayo A, Silveira AC. Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy. Mem Inst Oswaldo Cruz. 2009;104(Supl 1):17-30. [ Links ]
23. Dias JC. Control of Chagas disease in Brazil. Parasitol Today. 1987;3(11):336-41. [ Links ]
24. Marin-Neto JA, Cunha-Neto E, Maciel BC, Simões MV. Pathogenesis of chronic Chagas heart disease. Circulation. 2007;115(9):1109-23. [ Links ]
25. Kierszenbaum F. Mechanisms of pathogenesis in Chagas disease. Acta Parasitol. 2007;52:1-12. [ Links ]
26. Bonney KM, Engman DM. Chagas heart disease pathogenesis: one mechanism or many? Curr Mol Med. 2008; 8(6):510-8. [ Links ]
27. Dutra WO, Gollob KJ. Current concepts in immunoregulation and pathology of human Chagas disease. Curr Opin Infect Dis. 2008; 21(3):287-92. [ Links ]
28. Tanowitz HB, Machado FS, Jelicks LA, Shirani J, Carvalho ACC, Spray DC, et al. Perspectives on Trypanosoma cruziinduced heart disease (Chagas disease). Prog Cardiovasc Dis. 2009; 51(6):524-39. [ Links ]
29. Köberle F. Chagas' heart disease and Chagas' syndromes: the pathology of american trypanosomiasis. Adv Parasitol. 1968; 6:63-116. [ Links ]
30. Amorim DS, Manço JC, Gallo L Jr, Marin-Neto JA. Chagas' heart disease as an experimental model for studies of cardiac autonomic function in man. Mayo Clin Proc. 1982;57(Suppl):48-60. [ Links ]
31. Ribeiro AL, Moraes RS, Ribeiro JP, Ferlin EL, Torres RM, Oliveira E, et al. Parasympathetic dysautonomia precedes left ventricular systolic dysfunction in Chagas disease. Am Heart J. 2001;141(2):260-5. [ Links ]
32. Simões MV, Pintya AO, Bromberg-Marin G, Sarabanda AV, Antloga CM, Pazin-Filho A, et al. Relation of regional sympathetic denervation and myocardial perfusion disturbance to wall motion impairment in Chagas' cardiomyopathy. Am J Cardiol. 2000;86(9):975-81. [ Links ]
33. Medei EH, Nascimento JH, Pedrosa RC, Barcellos L, Masuda MO, Sicouri S, et al. Antibodies with beta-adrenergic activity from chronic chagasic patients modulate the QT interval and M cell action potential duration. Europace. 2008;10(7):868-76. [ Links ]
34. Talvani A, Rocha MO, Ribeiro AL, Borda E, Sterin-Borda L, Teixeira MM. Levels of anti-M2 and anti-b1 autoantibodies do not correlate with the degree of heart dysfunction in Chagas' heart disease. Microbes Infect. 2006;8(9-10):2459-64. [ Links ]
35. Rossi MA. Microvascular changes as a cause of chronic cardiomyopathy in Chagas' disease. Am Heart J. 1990;120(1):233-6. [ Links ]
36. Andrade ZA, Andrade SG, Correa R, Sadigursky M, Ferrans VJ. Myocardial changes in acute Trypanosoma cruzi infection: ultrastructural evidence of immune damage and the role of microangiopathy. Am J Pathol. 1994;144(6):1403-11. [ Links ]
37. Marin-Neto JA, Simões MV, Ayres-Neto EM, Attab-Santos JL, Gallo L Jr, Amorim DS, et al. Studies of the coronary circulation in Chagas' heart disease. São Paulo Med J. 1995;113(2):826-34. [ Links ]
38. Torres FW, Acquatella H, Condado JA, Dinsmore R, Palácios IF. Coronary vascular reactivity is abnormal in patients with Chagas' disease. Am Heart J. 1995;129(5):995-1001. [ Links ]
39. Higuchi ML, Benvenuti LA, Reis MM, Metzger M. Pathophysiology of the heart in Chagas' disease: current status and new developments. Cardiovasc Res. 2003; 60(1):96-107. [ Links ]
40. Andrade ZA, Andrade SG, Sadigursky M, Wenthold RJ Jr, Hilbert SL, Ferrans VJ. The indeterminate phase of Chagas disease: ultrastructural characterization of cardiac changes in the canine model. Am J Trop Med Hyg. 1997;57(3):328-36. [ Links ]
41. Andrade ZA. Immunopathology of Chagas disease. Mem Inst Oswaldo Cruz. 1999;94(Suppl 1):71-80. [ Links ]
42. Cunha-Neto E, Bilate AM, Hyland KV, Fonseca SG, Kalil J, Engman DM. Induction of cardiac autoimmunity in Chagas heart disease: a case for molecular mimicry. Autoimmunity. 2006;39(1):41-54. [ Links ]
43. Higuchi ML, Brito T, Reis MM, Barbosa A, Bellotti G, Pereira-Barreto AC, et al. Correlation between T cruzi parasitism and myocardial inflammation in human chronic chagasic myocarditis: light microscopy and immunohistochemical findings. Cardiovasc Pathol. 1993;2(2):101-6. [ Links ]
44. Jones EM, Colley DG, Tostes S, Lopes ER, Vnencak-Jones CL, McCurley TL. Amplification of Trypanosoma cruzi DNA sequence from inflammatory lesions in human chagasic cardiomyopathy. Am Trop Med Hyg. 1993;48(3):348-57. [ Links ]
45. Garcia S, Ramos CO, Senra JF, Vilas-Boas F, Rodrigues MM, Campos-de-Carvalho AC, et al. Treatment with benznidazole during the chronic phase of experimental Chagas' disease decreases cardiac alterations. Antimicrob Agents Chemother. 2005;49(4):1521-8. [ Links ]
46. Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med. 2006;144(10):724-34. [ Links ]
47. Rassi A, Amato Neto V, de Siqueira AF, Doles J, Leite MS, Silva OQ, et al. The influence of corticoids, in chronic Chagas disease, administered in virtue of associated disorders. Rev Soc Bras Med Trop. 1997;30(2):93-9. [ Links ]
48. Storino R, Auger S, Caravello O, Urrutia MI, Sanmartino M, Jörg M. Chagasic cardiopathy in endemic area versus sporadically infected patients. Rev Saude Publica. 2002;36(6):755-8. [ Links ]
49. Marin-Neto JA, Rassi A Jr, Morillo CA, Avezum A, Connolly SJ, Sosa-Estani S, et al. BENEFIT Investigators. Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas' cardiomyopathy: the Benznidazol Evaluation For Interrupting Trypanosomiasis (BENEFIT). Am Heart J. 2008;158(1):37-43. [ Links ]
50. Cunha-Neto E, Nogueira LG, Teixeira PC, Ramasawmy R, Drigo SA, Goldberg AC, et al. Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy. Mem Inst Oswaldo Cruz. 2009;104(Suppl 1):252-8. [ Links ]
51. Sousa AS, Xavier SS, Freitas GR, Hasslocher-Moreno A. Prevention strategies of cardioembolic ischemic stroke in Chagas' disease. Arq Bras Cardiol. 2008;91(5):306-10. [ Links ]
52. American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society; Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganjats TG, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154-e235. [ Links ]
53. Prata A. Clinical and epidemiological aspects of Chagas disease. Lancet Infect Dis. 2001;1(2):92-100. [ Links ]
54. Rassi A, Luquetti AO, Rassi A Jr. Chagas disease: clinical features. In: Wendel S, Brener Z, Camargo ME, Rassi A, editors. Chagas disease (American Trypanosomiasis): its impact on transfusion and clinical medicine. São Paulo: ISBT Brazil; 1992.p.81. [ Links ]
55. Benchimol PRB. The oral transmission of Chagas' disease: an acute form of infection responsible for regional outbreaks. Int J Cardiol. 2006;112(1):132-3. [ Links ]
56. Simoes MV, Soares FA, Marin-Neto JA. Severe myocarditis and esophagitis during reversible long standing Chagas' disease recrudescence in immunocompromised host. Int J Cardiol. 1995;49(3):271-3. [ Links ]
57. Riarte A, Luna C, Sabatiello R, Sinagra A, Schiavelli R, De Rissio A, et al. Chagas' disease in patients with kidney transplants: 7 years of experience 19891996. Clin Infect Dis. 1999;29(3):561-7. [ Links ]
58. Bocchi EA, Fiorelli A. The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology. Ann Thorac Surg. 2001;71(6):1833-8. [ Links ]
59. Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas' disease. Arq Bras Cardiol. 2001;76(1):75-96. [ Links ]
60. Primeira Reunião de Pesquisa Aplicada em Doença de Chagas. Validade do conceito de forma indeterminada. Rev Soc Bras Med Trop. 1985;18:46. [ Links ]
61. Barretto AC, Ianni BM. The undetermined form of Chagas' heart disease: concept and forensic implications. Sao Paulo Med J. 1995;113(2):797-801. [ Links ]
62. Dias JC. The indeterminate form of human chronic Chagas' disease: a clinical epidemiological review. Rev Soc Bras Med Trop. 1989;22(3):147-56. [ Links ]
63. Marin-Neto JA, Bromberg-Marin G, Pazin-Filho A, Simões MV, Maciel BC. Cardiac autonomic impairment and early myocardial damage involving the right ventricle are independent phenomena in Chagas' disease. Int J Cardiol. 1998; 65(3):261-9. [ Links ]
64. Sousa AC, Marin-Neto JA, Maciel BC, Gallo L Jr, Amorim DS, Barretto-Martins LE. Systolic and diastolic dysfunction in the indeterminate, digestive and chronic cardiac forms of Chagas' disease. Arq Bras Cardiol. 1988;50:293-9. [ Links ]
65. Barros MV, Rocha MO, Ribeiro AL, Machado FS. Doppler tissue imaging to evaluate early myocardium damage in patients with undetermined form of Chagas' disease and normal echocardiogram. Echocardiography. 2001;18(2):131-6. [ Links ]
66. Vilas-Boas F, Feitosa GS, Soares MBP, Pinho JA Fº, Nascimento T, Barojas MM, et al. Invasive and noninvasive correlations of B-type natriuretic peptide in patients with heart failure due to Chagas cardiomyopathy. Congest Heart Fail. 2008;14(3):121-6. [ Links ]
67. Coura JR, de Abreu LL, Pereira JB, Willcox HP. Morbidity in Chagas' disease IV. Longitudinal study of 10 years in Pains and Iguatama, Minas Gerais, Brazil. Mem Inst Oswaldo Cruz. 1985;80(1):73-80. [ Links ]
68. Marin-Neto JA, Rassi A Jr, Maciel BC, Simões MV, Schmidt A. Chagas' heart disease . In :Yusuf S, Camm J , Fallen EL, Gersh BJ,editors. Evidence based cardiology. 3rd ed. London: BMJ Books; 2010.p.823-41. [ Links ]
69. Dias JC, Kloetzel K. The prognostic value of the electrocardiographic features of chronic Chagas' disease. Rev Inst Med Trop São Paulo. 1968;10(3):158-62. [ Links ]
70. Rassi A Jr, Rassi AG, Rassi SG, Rassi Jr L, Rassi A. Ventricular arrhythmia in Chagas disease: diagnostic, prognostic, and therapeutic features. Arq Bras Cardiol. 1995;65(4):377-87. [ Links ]
71. Mendoza I, Camardo J, Moleiro F, Castellanos A, Medina V, Gomez J, et al. Sustained ventricular tachycardia in chronic chagasic myocarditis: electrophysiologic and pharmacologic characteristics. Am J Cardiol. 1986;57(6):423-7. [ Links ]
72. Acquatella H, Perez JE, Condado JA, Sanchez I. Limited myocardial contractile reserve and chronotropic incompetence in patients with chronic Chagas' disease. J Am Coll Cardiol. 1999;33(2):522-9. [ Links ]
73. Marin-Neto JA, Marzullo P, Sousa ACS, Marcassa C, Maciel BC, Iazigi N, et al. Radionuclide angiographic evidence for early predominant right ventricular involvement in patients with Chagas' disease. Can J Cardiol. 1988;4(5):231-6. [ Links ]
74. Acquatella H. Echocardiography in Chagas heart disease. Circulation. 2007;115(9):1124-31. [ Links ]
75. Marin-Neto JA, Marzullo P, Marcassa C, Gallo L Jr, Maciel BC, Bellina CR, et al. Myocardial perfusion abnormalities in chronic Chagas' disease as detected by thallium-201 scintigraphy. Am J Cardiol. 1992;69(8):780-4. [ Links ]
76. Samuel J, Oliveira M, Correa de Araujo RR, Navarro MA, Muccillo G. Cardiac thrombosis and thromboembolism in chronic Chagas' heart disease. Am J Cardiol. 1983;52(1):147-51. [ Links ]
77. Carod-Artal FJ, Vargas AP, Horan TA, Nunes LG. Chagasic cardiomyopathy is independently associated with ischemic stroke in Chagas disease. Stroke. 2005;36(5):965-70. [ Links ]
78. Mady C, Cardoso RH, Barretto AC, da Luz PL, Bellotti G, Pileggi F. Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy. Circulation. 1994;90(6):3098-102. [ Links ]
79. Rassi A Jr, Rassi A, Little WC, Xavier SS, Rassi SG, Rassi AG, et al. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med. 2006; 355(8):799-808. [ Links ]
80. Punukollu G, Gowda RM, Khan IA, Navarro VS, Vasavada BC. Clinical aspects of the Chagas' heart disease. Int J Cardiol. 2007;115(3):279-83. [ Links ]
81. Ministério da Saúde Secretaria de Vigilância em Saúde. Consenso Brasileiro em doença de Chagas. Rev Soc Bras Med Trop. 2005;38(Supl 3):7-29. [ Links ]
82. Ianni BM, Arteaga E, Frimm CC, Pereira Barreto ACP, Mady C. Chagas heart disease: evolutive evaluation of electrocardiographic and echocardiographic parameters in patients with the indeterminate form. Arq Bras Cardiol. 2001;77(1):59-62. [ Links ]
83. Laranja FS. Observações clínicas e experimentais. In: Cançado JR, Chuster M. (eds). Cardiopatia chagásica. Belo Horizonte: Fundação Carlos Chagas; 1985. p. 61-78. [ Links ]
84. Oliveira-Filho J, Viana LC, Vieira-de-Melo RM, Faiçal F, Torreão JA, Villar JÁ, et al. Chagas disease is an independent risk factor for stroke: baseline characteristics of a chagas disease cohort. Stroke. 2005;36(9):2015-7. [ Links ]
85. Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation. 2007;115(9):1101-8. [ Links ]
86. Nunes MC, Rocha MO, Ribeiro AL, Colosimo EA, Rezende RA, Carmo GA, et al. Right ventricular dysfunction is an independent predictor of survival in patients with dilated chronic Chagas' cardiomyopathy. Int J Cardiol. 2008;127(3):372-9. [ Links ]
87. Marin-Neto JÁ, Andrade ZA. Porque é usualmente predominante a insuficiência cardíaca direita da Doença de Chagas Arq Bras Cardiol. 1991;57(3):181-3 [ Links ]
88. Luquetti AO, Rassi A. Diagnóstico laboratorial da infecção pelo Trypanosoma cruzi. In: Brener Z, Andrade Z, Barral-Netto M. (eds. ). Trypanosoma cruzi e doença de Chagas. 2ª.ed, Rio de Janeiro: Guanabara-Koogan; 2000. p. 344-78. [ Links ]
89. Saéz-Alquézar A, Luquetti AO, Pereira JB, Moreira EF, Gadelha MFS, Garcia-Zapata MT, et al. Estudo multicêntrico: avaliação do desempenho de conjuntos diagnósticos de hemaglutinação indireta, disponíveis no Brasil, para o diagnóstico sorológico da infecção pelo Trypanosoma cruzi. Rev Patol Trop. 1997;26(2):343-74. [ Links ]
90. Ministério da Saúde. Coordenação Nacional de DST/AIDS. Manual de Doença de Chagas: triagem e diagnóstico sorológico em unidades hemoterápicas e laboratórios de saúde pública. Brasília; 1998. (Série TELELAB, n.11) [ Links ]
91. Ferreira AW, Ávila SML. Diagnóstico laboratorial das principais doenças infecciosas e autoimunes, 2ª ed. Rio de Janeiro: Guanabara-Koogan; 2001. [ Links ]
92. Silveira JF, Umezawa ES, Luquetti AO. Chagas disease: recombinant Trypanosoma cruzi antigens for serological diagnosis. Trends in Parasitol. 2001;17(6):286-91. [ Links ]
93. Luquetti AO, Ponce C, Ponce E, Esfandiari J, Schijman A, Revollo S, et al. Chagas'disease diagnosis: a multicentric evaluation of Chagas Stat-Pak, a rapid immunochromatographic assay with recombinant proteins of Trypanosoma cruzi. Diagn Microbiol Infect Dis. 2003;46(4):265-71. [ Links ]
94. Basquiera AL, Sembaj A, Aguerri AM, Omelianiuk M, Guzman S, Moreno-Barral J, et al. Risk progression to chronic Chagas cardiomyopathy: influence of male sex and of parasitaemia detected by polymerase chain reaction. Heart. 2003;89(10):1186-90. [ Links ]
95. Maguire JH, Mott KE, Lehman JS, Hoff R, Muniz TM, Guimarães AC, et al. Relationship of electrocardiographic abnormalities and seropositivity to Trypanosoma cruzi within a rural community in northeast Brazil. Am Heart J. 1983;105(2):287-94. [ Links ]
96. Rosenbaum MB, Alvarez AJ. The electrocardiogram in chronic chagasic myocarditis. Am Heart J. 1955;50(4):492-527. [ Links ]
97. Porto CC. O eletrocardiograma no prognóstico e evolução da doença e Chagas. Arq Bras Cardiol. 1964;17:313-46. [ Links ]
98. Maguire JH, Holf R, Sherlock I, Guimarães AC, Sleigh AC, Ramos NB, et al. Cardiac morbity due to Chagas heart disease. Circulation. 1987;75(6):1140-5. [ Links ]
99. Maia IG, Silva SR, Loyola LH, de Araújo PP, Monteiro SM, Amino Jg, et al. O nódulo sinusal na cardiopatia chagásica crônica. Arq Bras Cardiol. 1983;40(2):91-6. [ Links ]
100. Myerburg RJ, Kessler KM, Bassett AL, Castellanos A. A biological approach to sudden cardiac death: structure, function and cause. Am J Cardiol. 1989;63(20):1512-6. [ Links ]
101. Viotti RJ, Vigliano C, Laucella S, Lococo B, Petti M, Bertocchi G, et al. Value of echocardiography for diagnosis and prognosis of chronic Chagas disease cardiomyopathy without heart failure. Heart. 2004;90(6):655-60. [ Links ]
102. Xavier SS, de Sousa AS, Americano do Brasil PEA, Gabriel FG, de Holanda MT, Hasslocher-Moreno A. Apical aneurysm in the chronic phase of Chagas disease: prevalence and prognostic value in an urban cohort of 1053 patients. Rev SOCERJ. 2005;18(4):351-6. [ Links ]
103. Barros MVL, Ribeiro AL, Machado FS, Rocha MO. Doppler tissue imaging to assess systolic function in Chagas disease. Arq Bras Cardiol. 2003;80(1):36-40. [ Links ]
104. Barros MV, Machado FS, Ribeiro AL, Da Costa Rocha MO. Detection of early right ventricular dysfunction in Chagas disease using Doppler tissue imaging. J Am Soc Echocardiogr. 2002;15(10 Pt 2):1197-201. [ Links ]
105. Barros MVL, Rocha MOC, Ribeiro AL, Machado FS. Tissue Doppler imaging enables the identification of diastolic dysfunction of pseudonormal pattern in Chagas disease. J Am Soc Echocardiogr. 2001;14(5):353-9. [ Links ]
106. Adaniya ME, Migliore RA, Miramont G, Barranco M, Guerrero FT, Tamagusuku H. Influence of apical segmental dysfunction in the spatiotemporal velocity propagation of mitral inflow: a color M-mode Doppler study [abstract]. J Am Soc Echocardiogr. 2000;13:473. [ Links ]
107. Yacoub S, Birks EJ, Slavik Z, Henein M. Early detection of myocardial dysfunction in Chagas disease using novel echocardiographic indices. Trans R Soc Trop Med Hyg. 2003; 97(5):528-34. [ Links ]
108. Viotti R, Vigliano C, Lococo B, Petti M, Bertocchi G, De Cecco F, et al. Exercise stress testing as a predictor of progression of early chronic Chagas heart disease. Heart. 2006;92(3):403-4. [ Links ]
109. Rodriguez-Salas LA, Klein E, Acquatella H, Catalioti F, Davalos V, Gomez-Mancebo JR, et al. Echocardiographic and clinical predictors of mortality in chronic Chagas Disease. Echocardiography. 1998;15(3):271-8. [ Links ]
110. Rochitte CE, Oliveira PF, Andrade JM, Ianni BM, Parga JR, Ávila LF, et al. Myocardial delayed enhancement by magnetic resonance imaging in patients with Chagas' disease: a marker of disease severity. J Am Coll Cardiol. 2005;46(8):1553-8. [ Links ]
111. Hiss FC, Lascala TF, Maciel BC, Marin-Neto JA, Simões MV. Changes in myocardial perfusion correlate with deterioration of left ventricular systolic function in chronic Chagas' cardiomyopathy JACC Cardiovasc Imaging. 2009;2(2):164-72. [ Links ]
112. Pedrosa RC, Campos MC. Teste ergométrico e Holter 24 horas na detecção de arritmias ventriculares complexas em diferentes estágios da cardiopatia chagásica cronica. Rev Bras Med Trop. 2004;37(5):376-83. [ Links ]
113. Scanavacca M, Sosa E. Electrophysiologic study in chronic Chagas' heart disease. São Paulo Med J. 1995;113(2):841-50. [ Links ]
114. Rassi A, Rassi Jr. A , Rassi GG. Fase aguda. In: Brener Z, Andrade ZA, Barral Neto M. (org). Trypanosoma cruzi e doença de Chagas. 2ª ed. Rio de Janeiro: Guanabara Koogan; 2000. p. 231-45. [ Links ]
115. Marin Neto JA, Almeida Filho OC, Pazin Filho A, Maciel BC. Ponto de vista: forma indeterminada da molestia de Chagas:proposta de novos critérios de caracterização e perspectivas de tratamento precoce da cardiomiopatia. [ Links ]Arq Bras Cardiol.2002;79(6):623-7.
116. Pazin Filho A, Romano MMD, Almeida OC Fº, Furuta MS, Viviani IF, Schmidt A, et al. Minor segmental wall motion abnormalities detected in patients with Chagas disease have adverse prognostic implication. Braz J Med Biol Res.2006;39(4):483-7. [ Links ]
117. Pereira-Barretto AC, Serro Azul LG, Mady C, Ianni BM, Vianna CB, Bellotti G, et al. Forma indeterminada da doença de Chagas: uma doença polimórfica. Arq Bras Cardiol. 1990;55(6):347-53. [ Links ]
118. Freitas HF, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas' heart disease. Int J Cardiol. 2005;102(2):239-47. [ Links ]
119. Silva CP, Del Carlo CH, Oliveira Jr MT, Scipioni A, Strunz-Cassaro C, Ramires JAF, et al. Porque os portadores de cardiomiopatia chagásica têm pior evolução que os não chagásicos? Arq Bras Cardiol. 2008;91(6):358-62. [ Links ]
120. Viotti R, Vigliano C, Lococo B, Petti M, Bertocchi G, Alvarez MG, et al. Indicadores clínicos de progresión de la miocarditis chagásica crónica. Rev Esp Cardiol. 2005;58(9):1037-44. [ Links ]
121. Bestetti RB, Dalbo CM, Freitas OC, Teno LA, Castilho OT, Oliveira JS. Noninvasive predictors of mortality for patients with Chagas' heart disease: a multivariate stepwise logistic regression study. Cardiology. 1994;84(4-5):261-7. [ Links ]
122. Theodoropoulos TAD, Bestetti RB, Otaviano AP, Cordeiro JA, Rodrigues VC, Silva AC. Predictors of all-cause mortality in chronic Chagas' heart disease in the current era of heart failure therapy. Int J Cardiol. 2008;128(1):22-9. [ Links ]
123. Higuchi ML. O parasita e a patogenia da forma crônica da doença de Chagas. Arq Bras Cardiol. 1995;64(3):251-4. [ Links ]
124. Pinto AY, Ferreira AG Jr, Valente VC, Harada GS, Valente SAS. Urban outbreak of acute Chagas disease in Amazon region of Brazil: four-year follow-up after treatment with benznidazole. Rev Panam Salud Publica. 2009;25(1):77-83. [ Links ]
125. Viotti R, Vigliano C, Lococo B, Alvarez MA, Petti M, Bertocchi G, et al. Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther. 2009;7(2):157-63. [ Links ]
126. Fragata Filho AA. Tratamento etiológico da doença de Chagas. Rev Soc Cardiol Estado de São Paulo. 2009;19(1):2-5. [ Links ]
127. OPAS / OMS 1998. Tratamiento etiológico de la enfermedad de Chagas: conclusiones de uma consulta técnica, OPC/HPC/HCT/140/99.32p. Rev Patol Trop. 1999;28:247-79. [ Links ]
128. Cançado JR. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop São Paulo. 2002;44(1):29-37. [ Links ]
129. Coura JR, Castro SL. A critical review on Chagas' disease chemotherapy. Mem Inst Oswaldo Cruz. 2002;97(1):3-24. [ Links ]
130. Fragata Filho AA, Ostermayer AL, Prata A, Rassi AG, Dias E. Tratamento etiológico da doença de Chagas. Brasilia: Fundação Nacional de Saúde;1996. [ Links ]
131. Dias JCP. História natural da doença de Chagas. Arq Bras Cardiol. 1995;65(4):359-66. [ Links ]
132. Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375(9723):1388-402. [ Links ]
133. Bern C, Montgomery SP, Herwaldt BL, Rassi A Jr, Marin Neto J, Danas RO, et al. Evaluation and treatment of Chagas' desease in United States: a systemic review. JAMA. 2007;298(18):2171-81. [ Links ]
134. Andrade AL, Zicker F, Oliveira RM, Silva AS, Luquetti AO, Travassos LR, et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. 1996;348(9039):1407-13. [ Links ]
135. Andrade AL, Martelli CM, Oliveira RM, Silva SA, Aires AI, Soussumi LM, et al. Short report: benznidazole efficacy among Trypanosoma cruzi - infected adolescents after a six-year follow-up. Am J Trop Med Hyg. 2004;71(5):594-7. [ Links ]
136. Sosa-Estani S, Segura EL, Ruiz AM, Velasquez E, Porcel BM, Yampotis C. Efficacy of chemoterapy with benznidazole in children in the indeterminate phase of Chagas' disease. Am J Trop Med Hyg. 1998;59:526-9. [ Links ]
137. Ianni BM, Arteaga E, Mady C. Uso do benznidazol em chagásicos na forma indeterminada: resultados a longo prazo. Arq Bras Cardiol. 1993;61(Suppl 2):130. [ Links ]
138. Fragata Filho AA, Silva MAD, Boainain E. Tratamento etiológico da doença de Chagas na fase aguda e crônica. Rev Soc Cardiol Estado de São Paulo. 1994;4:192-7. [ Links ]
139. Miranda L, Miranda L, Campos G. História natural da forma crônica da doença de Chagas x tratamento específico. Rev Centro-Oeste Cardiol. 1994;1:25-9. [ Links ]
140. Fragata Filho AA, Correia EB, Borges Filho R. Tratamento parasiticida na forma indeterminada da doença de Chagas previne o aparecimento de cardiopatia. Rev Soc Cardiol Estado de São Paulo. 2005;15(5 supl B):44. [ Links ]
141. Fabbro DL, Streiger ML, Arias ED, Bizai ML, del Barco M, Amicone NA. Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe city (Argentina), over a mean follow-up of 21 years: parasitological, serological and clinical evolution. Rev Soc Bras Med Trop. 2007;40(1):1-10. [ Links ]
142. Urbina JA. Parasitological cure of Chagas disease: is it possible? Is it relevant? Mem Inst Oswaldo Cruz. 1999;94(Suppl I):349-55. [ Links ]
143. Reunião de debate sobre doença de Chagas. Rio de Janeiro; 19 a 21 de março,1962. Anais. Rev Goiana Medicina. 1963;9(supl):1-300. [ Links ]
144. Rassi A. , Luquetti AO. Therapy of Chagas disease. In: Wendel S, Brener Z, Camargo ME, Rassi A. (editors. ) Chagas disease (American Trypanosomiasis), its impact on transfusion and clinical medicine. São Paulo: Sociedade Brasileira de Hematologia e Hemoterapia. 1992. p. 237-47. [ Links ]
145. Rassi A, Luquetti AO. Specific treatment for Trypanosoma cruzi infection (Chagas disease). In: Tyler KM, Miles MA. (editors). American trypanosomiasis. Boston: Kluwer Academic Publishers; 2003. p. 117-25. [ Links ]
146. Congenital infection with Trypanosoma cruzi: from mechanisms of transmission to strategies for diagnosis and control. Rev Soc Bras Med Trop. 2003;36(6):767-71. [ Links ]
147. Luquetti AO, Rassi A. Tratamiento específico de la enfermedad de Chagas en la fase crónica: criterios de cura convencionales: xenodiagnóstico, hemocultivo y serologia. Rev Patol Trop. 1998;27(supl):37-50. [ Links ]
148. 2009 Focused update incorporated into the ACC/AHA 2005;Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. American College of Cardiology Foundation; American Heart Association. 2009 Focused update incorporated into the ACC/AHA 2005. Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53(15):e1-e90. [ Links ]
149. Mady C, Ianni BM, Arteaga E, Montes GS, Caldini EG, Andrade G, et al. Relation between interstitial myocardial collagen and the degree of clinical impairment in Chagas' disease. Am J Cardiol. 1999;84(3):354-6,A9. [ Links ]
150. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure.The SOLVD Investigators. N Engl J Med. 1991;325(5):293-302. [ Links ]
151. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).The CONSENSUS Trial Study Group. N Engl J Med. 1987;316(23):1429-35. [ Links ]
152. Cohn JN, Tognoni G. Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667-75. [ Links ]
153. Roberti RR, Martinez EE, Andrade JL, Araujo VL, Brito FS, Portugal OP, et al. Chagas' cardiomyopathy and captopril. Eur Heart J. 1992;13(7):966-7. [ Links ]
154. Leon JS, Wang K, Engman DM. Captopril ameliorates myocarditis in acute experimental Chagas' disease. Circulation. 2003;107(17):2264-9. [ Links ]
155. Batlouni M, Barretto AC, Armaganijan D, Vichi FL, Spritzer N, Simões R, et al. Treatment of mild and moderate cardiac failure with captopril: a multicenter study. Arq Bras Cardiol. 1992;58(5):417-21. [ Links ]
156. Botoni FA, Poole-Wilson PA, Ribeiro AL, Okonko DO, Oliveira BM, Pinto AS, et al. A randomized trial of carvedilol after renin-angiotensin system inhibition in chronic Chagas cardiomyopathy. Am Heart J. 2007;153(4):544.e1-8. [ Links ]
157. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al; CHARM. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362(9386):767-71. [ Links ]
158. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-21. [ Links ]
159. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-17. [ Links ]
160. Ramires FJ, Salemi VM, Ianni BM, Fernandes F, Martins DG, Billate A, et al. Aldosterone antagonism in an inflammatory state: evidence for myocardial protection. J Renin Angiotensin Aldosterone Syst. 2006;7(3):162-7. [ Links ]
161. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet. 1999;353(9146):9-13. [ Links ]
162. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al, for the U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334(2):1349-55. [ Links ]
163. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651-8. [ Links ]
164. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomized trial. Lancet. 2001;357(9266):1385-90. [ Links ]
165. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, et al, for the US Carvedilol Heart Failure Study Group. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation. 1996;94(11):2800-6. [ Links ]
166. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. for the MERIT-HF Study Group. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). JAMA. 2000; 283(10):1295-302. [ Links ]
167. Amorim DS, Olsen EG. Assessment of heart neurons in dilated (congestive) cardiomyopathy. Br Heart J. 1982;47(1):111-8. [ Links ]
168. Borda ES, Borda SL. Antiadrenergic and muscarinic receptor antibodies in Chagas cardiomyopathy. Int J Cardiol. 1996;54(2):149-56. [ Links ]
169. Quiros FR, Morillo CA, Casas JP, Cubillos LA, Silva FA. CHARITY: Chagas cardiomyopathy bisoprolol intervention study: a randomized double-blind placebo force-titration controlled study with Bisoprolol in patients with chronic heart failure secondary to Chagas cardiomyopathy [NCT00323973]. Trials. 2006;7:21. [ Links ]
170. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999;5(3):178-87. [ Links ]
171. Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K, et al ;African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049-57. [ Links ]
172. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525-33. [ Links ]
173. Ramires FJA, Pimentel WS. Formas clínicas e tratamento Tratamento farmacológico da disfunção miocárdica. ( Parte III. ) In: Ianni BM, Mady C (eds. ). A cardiopatia da doença de Chagas. São Paulo: Roca; 2009. p. 247-55. [ Links ]
174. Brater DC. Diuretic therapy. N Engl J Med. 1998;339(6):387-95. [ Links ]
175. Bocchi EA, Braga FGM, Ferreira SMA, Rohde LEP, Oliveira WA, Almeida DR, et al;Sociedade Brasileira de Cardiologia. III Diretriz brasileira de insuficiência cardíaca crônica. Arq Bras Cardiol. 2009;93(Suppl1):1-71. [ Links ]
176. Bestetti RB. Stroke in a hospital-derived cohort of patients with chronic Chagas' disease. Acta Cardiol. 2000;55(1):33-8. [ Links ]
177. Nunes MCP, Barbosa MM, Ribeiro ALP, Barbosa FBL, Rocha MOC. Ischemic cerebrovascular events in patients with Chagas' cardiomyopathy: a prospective follow up study. J Neurol Sci. 2009;278(1-2):96-101. [ Links ]
178. Arteaga-Fernández E, Barretto AC, Ianni BM, Mady C, Lopes EA, Vianna CB, et al. Cardiac thrombosis and embolism in patients having died of chronic Chagas' cardiopathy. Arq Bras Cardiol. 1989;52(4):189-92. [ Links ]
179. Nunes MC, Barbosa MM, Rocha MO. Peculiar aspects of cardiogenic embolism in patients with Chagas' cardiomyopathy: a transthoracic and transesophageal echocardiographic study. J Am Soc Echocardiogr. 2005;18(7):761-7. [ Links ]
180. Parada H, Carrasco HA, Anez N, Fuenmayor C, Inglessis I. Cardiac involvement is a constant finding in acute Chagas disease: a clinical, parasitological and histopathological study. Int J Cardiol. 1997;60(1):49-54. [ Links ]
181. Magnani JW, Dec GW. Myocarditis: current trends in diagnosis and treatment. Circulation. 2006;113(6):876-90. [ Links ]
182. Feldman AM, McNamara D. Myocarditis. N Engl J Med. 2000;343(19):1388-98. [ Links ]
183. Bestetti RB, Theodoropoulos TAD, Cardinalli-Neto A, Cury PM. Treatment of chronic systolic heart failure secondary to Chagas heart disease in the current era of heart failure therapy. Am Heart J. 2008;156(3):422-30. [ Links ]
184. Marin-Neto JA, Secches AL, Maciel BC, Gallo L Jr, Terra-Filho J, Manço JC, et al. Chronic Chagas' cardiopathy - - use of vasodilators in uncompensated heart failure. Arq Bras Cardiol. 1982; 38(4): 291-9. [ Links ]
185. Manço JC, Gallo L Jr, Godoy RA, Marin-Neto JA, Amorim DS. Efeitos hemodinâmicos do digital na cardiopatia chagásica crônica. Arq Bras Cardiol. 1974;27:25-35. [ Links ]
186. Khoury AM, Davila DF, Bellabarba GA, Donnis JH, Torres A, Lemorvan C, et al. Acute effects of digitalis and enalapril on the neurohormonal profile of chagasic patients with severe congestive heart failure. Int J Cardiol. 1996;57(1):21-9. [ Links ]
187. Lopez M, Silva OA, Amaral CFS, Lopes JÁ, Silveira JC, Fonseca JG, et al. Tratamento da síndrome de baixo débito na Cardiopatia Chagásica Crônica. Arq Bras Cardiol 1980;34(3):185-9. [ Links ]
188. de March Ronsoni R, Feijó RV Jr, Melo LH, Schwingel FL, Filho WJ, de Albernaz Muniz RZ, et al. The use of Levosimendan for myocardiopathy due to acute Chagas' disease. Int J Cardiol. 2009:136(2):233-5. [ Links ]
189. Rassi A Jr, Rassi A, Marin-Neto JA. Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Mem Inst Oswaldo Cruz. 2009;104(Suppl 1):152-8. [ Links ]
190. Bestetti RB, Cardinalli-Neto A. Sudden cardiac death in Chagas' heart disease in the contemporary era. Int J Cardiol. 2008;131(1):9-17. [ Links ]
191. Sosa E, Scanavacca M, D'Avila A, Bellotti G, Pileggi F. Radiofrequency catheter ablation of ventricular tachycardia guided by nonsurgical epicardial mapping in chronic Chagasic heart disease. Pacing Clin Electrophysiol. 1999;22(1 Pt 1):128-30. [ Links ]
192. Távora MZ, Mehta N, Silva RM, Gondim FAA, Hara VM, Paola AV. Characteristics and identification of sites of chagasic ventricular tachycardia by endocardial mapping. Arq Bras Cardiol. 1999;72(4):451-74. [ Links ]
193. Adesse D, Garzoni LR, Huang H, Tanowitz HB, Nazaret MN, Spray DC. Trypanosoma cruzi induces changes in cardiac connexin 43 expression. Microbes Infect. 2008;10(1):21-8. [ Links ]
194. Chiale PS, Halpern MS, Nau GJ, Przybylski J, Tambussi AM, Lazzara JO, et al. Malignant ventricular arrhythmias in chronic chagasic miocarditis. Pacing Clin Electrophysiol. 1982;5(2):162-72. [ Links ]
195. Mendoza I, Moleiro F, Marques J. Morte súbita na doença de Chagas. Arq Bras Cardiol. 1992;59(1):3-4. [ Links ]
196. Casado J, Davila DF, Donis JH, Torres A, Payares A, Colmenares R, et al. Electrocardiographic abnormalities and left ventricular function in Chagas' heart disease. Int J Cardiol. 1990;27(1):55-62. [ Links ]
197. Mendoza I, Guiniger A, Kushni E, Sosa E, Velazco V. Consenso do Comitê de Eletrofisiologia da "USCAS" sobre o tratamento das arritmias ventriculares na doença de Chagas. Arq Bras Cardiol. 1994;62(1):41-3. [ Links ]
198. Henz BD, do Nascimento TA, Dietrich CD, Dalegrave C, Hernandez V, Mesas C, et al. Simultaneous epicardial and endocardial substrate mapping and radiofrequency catheter ablation as first-line treatment for ventricular tachycardia and frequent ICD shocks in chronic chagasic cardiomyopathy. J Interv Card Electrophysiol. 2009;26(3):195-205. [ Links ]
199. de Paola AA, Gomes JA, Terzian AB, Miyamoto MH, Martinez Fº EE. Ventricular tachycardia during exercise testing as a predictor of sudden death in patients with chronic chagasic cardiomyopathy and ventricular arrhythmias. Br Heart J. 1995;74(3):293-5. [ Links ]
200. Silva RM, Tavora MZ, Gondim FA, Metha N, Hara VM, Paola AA. Predictive value of clinical and electrophysiological variables in patients with chronic chagasic cardiomyopathy and nonsustained ventricular tachycardia. Arq Bras Cardiol. 2000;75(1):33-47. [ Links ]
201. Pellizzon OA, Beloscar JS, Mariani E. Adrenergic nervous system influences on the induction of ventricular tachycardia. Ann Noninvasive Electrocardiol. 2002;7(4):281-8. [ Links ]
202. Ribeiro AL, Ferreira LM, Oliveira E, Cruzeiro PC, Torres RM, Rocha MO. Active orthostatic stress and respiratory sinus arrhythmia in patients with Chagas' disease with preserved left ventricular global systolic function. Arq Bras Cardiol. 2004;83(1):40-4;35-9. [ Links ]
203. Câmara EJ. Segmental changes in contractility of the left heart ventricle in Chagas cardiomyopathy with and without ventricular dilatation. Arq Bras Cardiol. 1993;60(3):151-5. [ Links ]
204. de Paola AA, Horowitz LN, Miyamoto MH, Pinheiro R, Ferreira DF, Terzian AB, et al. Angiographic and electrophysiologic substrates of ventricular tachycardia in chronic Chagasic myocarditis. Am J Cardiol.1990;65(5):360-3. [ Links ]
205. Leite LR, Fenelon G, Simões A Jr, Silva GG, Friedman PA, de Paola AA. Clinical usefulness of electrophysiologic testing in patients with ventricular tachycardia and chronic chagasic cardiomyopathy treated with amiodarone or sotalol. J Cardiovasc Electrophysiol. 2003;14(6):567-73. [ Links ]
206. Leite LR, Fenelon G, Paes AT, de Paola AA. The impact of syncope during clinical presentation of sustained ventricular tachycardia on total and cardiac mortality in patients with chronic Chagasic heart disease. Arq Bras Cardiol. 2001;77(5):439-52. [ Links ]
207. Scanavacca MI, Sosa EA, Lee JH, Bellotti G, Pileggi F. Terapêutica empírica com amiodarona em portadores de miocardiopatia chagásica crônica e taquicardia ventricular sustentada. Arq Bras Cardiol. 1990;54(6):367-71. [ Links ]
208. de Paola AA, Gondin FAA, Hara V, Mendonça A. Medical treatment of cardiac arrhythmias in Chagas heart disease. São Paulo Med J. 1995;113(2):858-61. [ Links ]
209. Rosembaum MB, Chiale PA, Haedo A, Lazzari JO, Elizari MV. Ten years of experience with amiodarone. Am Heart J. 1983;106(4 Pt 2):957-64. [ Links ]
210. Chiale PA, Halpern MS, Nau GS, Tambussi AM, Przybylski J, Lazzari JO, et al. Efficacy of amiodarone during long-term treatment of malignant ventricular arruthmias in patients with chronic chagasic myocarditis. Am Heart J. 1984;107(4):656-64. [ Links ]
211. Chiale PA, Haedo AH, Chiale PA, Bandieri J, Lazzari JO, Elizari MV,et al. Comparative antiarrhytmic efficacy of Verapamil 17 monochloracetylajmaline, mexiletine and amiodarone in patients with severe chagasic myocarditis: relation with the underlying arrhythmogenic mechanisms. J Am Coll Cardiol.1986;7(5):1114-20. [ Links ]
212. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomized trials. Amiodarone Trials Meta-analysis Investigators. Lancet. 1997;350(9089):1417-24. [ Links ]
213. Piccini JP, Berger JS, O'Connor CM. Amiodarone for the prevention of sudden cardiac death: a meta-analysis of randomized trials. Eur Heart J. 2009; 30 (10): 1245-53. [ Links ]
214. Hohnloser SH, Dorian P, Roberts R, Gent M, Israel CW, Fain E, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial. Circulation. 2006;114(2):104-9. [ Links ]
215. Sternick EB, Martinelli M, Sampaio R, Gerken LM, Teixeira RA, Scarpelli R, et al. Sudden cardiac death in patients with chagas heart disease and preserved left ventricular function. J Cardiovasc Electrophysiol. 2006;17(1):113-6. [ Links ]
216. Sosa E, Scanavacca M, D'Ávila A. Surgery and catheter ablation for the treatment of ventricular tachycardia in Chagas' disease. In: Tentori MC, Segura EL, Haynes DL. (eds). Arrhythmias management in Chagas' disease. Armonk: Futura Publishing; 1999. p. 117-28. [ Links ]
217. Lamourier EN, Herrman JLV, Martines FEE, Buffolo E, Andrade JLA, Korkes N, et al. Aneurismectomia como tratamento de taquiarritmias refratárias em pacientes portadores de aneurisma ventricular de etiologia chagásica. Arq Bras Cardiol. 1975;28(5):549-55. [ Links ]
218. D'Avila A, Splinter R, Svenson RH, Scanavacca M, Pruitt E, Kasell J, et al. New perspectives on catheter-based ablation of ventricular tachycardia complicating Chagas' disease: experimental evidence of the efficacy of near infrared lasers for catheter ablation of Chagas' VT. J Interv Card Electrophysiol. 2002;7(1):23-38. [ Links ]
219. Takehara K, Scanavacca M, Sosa E, Lopes E, Barbero Marcial M, Consolim FM, et al. Aspectos anatomopatológicos do foco da taquicardia ventricular sustentada recorrente da cardiopatia chagásica cronica (abstract). Arq Bras Cardiol. 1990;55:B-68. [ Links ]
220. Sosa E, Scanavacca M, D'Avila A, Piccioni J, Sanchez O, Velarde JL, et al. Endocardial and epicardial ablation guided by nonsurgical transthoracic epicardial mapping to treat recurrent ventricular tachycardia. J Cardiovasc Electrophysiol. 1998;9(3):229-39. [ Links ]
221. Scanavacca M, Sosa E. Epicardial ablation of ventricular tachycardia in Chagas heart disease. Card Electrophysiol Clin. 2010;2(1):55-67. [ Links ]
222. Rocha A, da Cunha JA, Daud W, Heredia RA, Gomes HB, Mantese O, et al. Chronic Chagas cardiopathy causing congestive heart failure in childhood: a clinical and histopathology study of a case with emphasis on the lesions of intracardiac conduction and autonomic nervous systems. Rev Soc Bras Med Trop. 1993;26(4):243-9. [ Links ]
223. Borrotchin M, Carvalho SM, Veloso DP. O eletrocardiograma em 70 pacientes com a forma crônica da doença de Chagas. Arq Bras Cardiol. 1954;7(1):26-39. [ Links ]
224. Kormann DS, Araujo HC, Bembom JC. Marcapasso cardíaco de frequência baixa em chagásicos com grande cardiomegalia. Arq Bras Cardiol. 1975;28(Suppl 2):302-3. [ Links ]
225. Lorga AM, Ayoud JCA, Fedozzi N. História natural do bloqueio átrio-ventricular total chagásico com marcapasso: estudo evolutivo em 5 anos. Arq Bras Cardiol. 1976;29(1):233-4. [ Links ]
226. Rodrigues DA, Jumbo L, Rosas F, Velasco VM. Marcapassos definitivos y cardiomiopatia de Chagas. Rev Col Cardiol. 1999;7(6):353-8. [ Links ]
227. Martinelli Filho M, Zimerman LI, Vasconcelos JTM; Sociedade Brasileira de Cardiologia. Diretrizes brasileiras de dispositivos eletrônicos implantáveis (DCEI). Arq Bras Cardiol. 2007;89(6):210-37. [ Links ]
228. Muratore C, Rabinovich R, Iglesias R, Gonzalez M, Daru V, Liprandi AS. Implantable cardioverter defibrillators in patients with Chagas disease: are they different from patients with coronary disease? Pacing Clin Electrophysiol. 1997; 20(1 Pt 2):194-7. [ Links ]
229. Rabinovich R, Muratore C, Iglesias R, Gonzalez M, Daru V, Valentino M, et al. Time to first shock in implantable cardioverter defibrillator (ICD) patients with Chagas Cardiomyopathy. Pacing Clin Electrophysiol. 1999;22(1 Pt 2):202-5. [ Links ]
230. Martinelli-Filho M, Siqueira SF, Moreira H, Fagundes A, Pedrosa A, Nishioka SD, et al. Probability of occurrence of life-threatening ventricular arrhythmias in Chagas' disease versus non-Chagas' disease. Pacing Clin Electrophysiol. 2000;23(11 Pt 2):1944-6. [ Links ]
231. Dubner S, Valero E, Pesce R, Zuelgaray JG, Mateos JCP, Galvão-Filho S, et al. A Latin American registry of implantable cardioverter defibrillators: the ICD-LABOR study. Ann Noninvasive Electrocardiol. 2005;10(4):420-8. [ Links ]
232. Cardinalli-Neto A, Greco O, Bestetti R. Automatic implantable cardioverter defibrillators in Chagas heart disease patients with malignant ventricular arrhythmias. Pacing Clin Electrophysiol. 2006;29(5):467-70. [ Links ]
233. Cardinalli-Neto A, Bestetti R, Cordeiro J, Rodrigues V. Predictors of all-cause mortality for patients with chronic Chagas' heart disease receiving implantable cardioverter defibrillator therapy. J Cardiovasc Electrophysiol. 2007;18(12):1236-40. [ Links ]
234. Muratore CA, Batista Sá LA, Chiale PA, Eloy R, Tentori MC, Escudero J, et al. Implantable cardioverter defibrillators and Chagas' disease: results of the ICD Registry Latin America. Europace. 2009; 11(2):164-8. [ Links ]
235. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-53. [ Links ]
236. Bramlet DA, Morris KG, Coleman RE, Albert D, Cobb FR. Effect of rate-dependent left bundle branch block on global and regional left ventricular function. Circulation. 1983; 67 (5): 1059-65. [ Links ]
237. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, et al. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) Study: rationale, design and end-points of a prospective randomized multicenter study. Am J Cardiol. 1999;83(5B):130D-135D. [ Links ]
238. McAlister FA, Ezekowitz JA, Wiebe N, Rowe R, Spooner C, Crumley E, et al. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med. 2004;141(5):381-90. [ Links ]
239. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-49. [ Links ]
240. Souza FSO. Avaliação de variáveis prognosticadoras de melhora clínica aguda na terapia de ressincronização cardíaca. Reblampa. 2003;16(2):59-67. [ Links ]
241. Arteaga Fernandez E, Barretto Ac, Mady C, Ianni BM, Bellotti G, Pileggi F, et al. O eletrocardiograma em pacientes com reações sorológicas positivas para doença de Chagas: estudo de 600 casos. Arq Bras Cardiol. 1985;44(5):333-7. [ Links ]
242. Silva RT, Martinelli Filho M, de Oliveira JC, Lima CE, Martins DG, Guirao CI, et al. Remodelamento ventricular na estimulação cardiaca apical do ventrículo direito. Arq Bras Cardiol. 2007;88(2):152-8. [ Links ]
243. Silva RT, Martinelli Filho M, Lima CE, Martins DG, Nishioka AS, Pedrosa AA, et al. Comportamento funcional dos portadores de marcapasso convencional submetidos à ressincronização cardíaca. Arq Bras Cardiol. 2008;90(2):138-43. [ Links ]
244. Bestetti RB, Ariolli MT, do Carmo JL, Passos AD, Santos CR, Machado Júnior O, et al. Clinical characteristics of acute myocardial infarction in patients with Chagas' disease. Int J Cardiol. 1992;35(3):371-6. [ Links ]
245. Almeida EA, Martin CF. Estudo clínico e necroscópico de 65 casos de chagásicos crônicos referente à pesquisa de aterosclerose coronariana e sua repercussão no miocárdio. Rev Soc Bras Med Trop. 1992;25(supl 3):87-8. [ Links ]
246. Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D'Agostino RB, Kannel WB, et al. Framingham Heart Study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106(24):3068-72. [ Links ]
247. Nagajyothi F, Desruisseaux MS, Weiss LM, Chua S, Albanese C, Machado FS, et al. Chagas disease, adipose tissue and the metabolic syndrome. Mem Inst Oswaldo Cruz. 2009;104(Suppl 1):219-25. [ Links ]
248. Dargie HJ, Hildebrandt PR, Riegger GA, McMurray JJ, McMorn SO, Roberts JN, et al. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure. J Am Coll Cardiol. 2007;49(16):1696-704. [ Links ]
249. Silva JR, Guariento ME, Fernandes GA, Maciel RMB, Ward LS. Impact of long-term administration of amiodarone on the thyroid function of patients with Chagas' disease. Thyroid. 2004;14(5):371-7. [ Links ]
250. Guariento ME, Orosz JEB, Gontijo JAR. Interação clínica entre moléstia de Chagas e hipertensão arterial primária em um serviço de referência ambulatorial. Arq Bras Cardiol. 1998;70(6):431-4. [ Links ]
251. Ianni BM, Mady C, Arteaga E, Fernandes F. Doenças cardiovasculares observadas durante o seguimento de um grupo de pacientes na forma indeterminada da doença de Chagas. Arq Bras Cardiol. 1998;71(1):21-4. [ Links ]
252. Lopes ER, de Mesquita PM, de Mesquita LF, Chapadeiro E. Coronary arteriosclerosis and myocardial infarction in chronic Chagas' disease. Arq Bras Cardiol. 1995;65(2):143-5. [ Links ]
253. Bocchi E, Vilas-Boas F, Bacal F, Moreira LF, Fiorelli A, Stolf N, et al. Hemodynamic evaluation during isotonic exercise of patients with orthotopic heart transplantation. Arq Bras Cardiol. 1994; 63(1):7-12. [ Links ]
254. Bocchi EA. Heart transplants for patients with Chagas' heart disease. Sao Paulo Med J. 1995; 113(2):873-9. [ Links ]
255. Bocchi EA, Fiorelli A, First Guideline Group for Heart Transplantation of the Brazilian Society of Cardiology. The Brazilian experience with heart transplantation: a multicenter report. J Heart Lung Transplant. 2001;20(6):637-45. [ Links ]
256. Stolf NA, Higuchi ML, Bocchi E, Bellotti G, Auler JO, Uip D, et al. Heart transplantation in patients with Chagas' disease cardiomyopathy. J Heart Transplant. 1987;6(5):307-12. [ Links ]
257. Fiorelli AI, Coelho GH, Lima JL, Lourenço DD, Gutierres P, Bacal F, et al. Massive degeneration and atrophy of the native heart after heterotopic transplantation: a case report. Transplant Proc. 2009;41(3):965-6. [ Links ]
258. Fiorelli AI, Abreu Filho CA, Santos RH, Buco FH, Fiorelli LR, Bacal F, et al. Cardiac transplantation with bicaval anastomosis and prophylactic graft tricuspid annuloplasty Rev Bras Cir Cardiovasc. 2008;23(1):7-13. [ Links ]
259. Fiorelli AI, Stolf NA, Abreu Filho CA, Santos RH, Buco FH, Fiorelli LR, et al. Prophylactic donor tricuspid annuloplasty in orthotopic bicaval heart transplantation. Transplant Proc. 2007;39(8):2527-30. [ Links ]
260. Bocchi EA, Ahualli L, Amuchastegui M, Boullon F, Cerutti B, Colque R, et al. Recommendations for use of everolimus after heart transplantation: results from a Latin-American Consensus Meeting. Transplant Proc. 2006;38(3):937-42. [ Links ]
261. Assef MA, Valbuena PF, Correia EB, Vasconcelos M, Marique R, Souza HM. Transplante cardiaco no Instituto Dante Pazzanese de Cardiologia: análise de sobrevida. Rev Bras Cir Cardiovasc. 2001; 16(4):289-304. [ Links ]
262. Higuchi ML, Brito T, Reis MM. Correlation between T.cruzi parasitism and myocardial inflammation in human chronic chagasic myocarditis: light microscopy and immunohistochemical findings. Cardiovasc Pathol. 1993;2:101-6. [ Links ]
263. Ben Younes-Chennoufi A, Hontebeyrie-Joskowicz M, Tricottet V, et al. Persistence of Trypanosoma cruzi antigens in the inflammatory lesions of chronically infected mice. Trans R Soc Trop Med Hyg. 1988; 82(1):77-83. [ Links ]
264. Higuchi ML, Reis MM, Aiello VD, Benvenutti LA, Gutierrez PS, Bellotti G, et al. Asssociation of an increase in CD8+ T cells with the presence of Trypanosoma cruzi antigens in chronic, human, chagasic myocarditis. Am J Trop Med Hyg. 1997;56(5):485-89. [ Links ]
265. Fonseca SG, Reis MM, Coelho V, Nogueira LG, Monteiro SM, Mairena EC. Locally produced survival cytokines IL-15 and IL-7 may be associated to the predominance of CD8+ T cells at heart lesions of human chronic Chagas disease cardiomyopathy. Scand J Immunol. 2007;66(2-3):362-71. [ Links ]
266. Higuchi ML, Kawakami J, Ikegami R, Clementino MBM, Kawamoto F, Reis MM, et al. Do archaea and bacteria co-infection have a role in the pathogenesis of chronic chagasic cardiopathy? Mem Inst Oswaldo Cruz. 2009;104(Suppl I):199-207. [ Links ]
267. Azeka E, Loures DR, Jatene MB, Favarato ME. I Guidelines of the Brazilian Society for Heart Transplantation. II Heart transplantation in children. Arq Bras Cardiol. 1999;73(Suppl. 5):6-11. [ Links ]
268. Mehra MR, Kobashigawa J, Starling R, Russell S, Uber PA, Parameshwar J, et al. Listing criteria for heart transplantation International Society for Heart and Lung Transplantation Guidelines for the care of cardiac transplant candidates. J Heart Lung Transplant. 2006; 25(9):1024-42. [ Links ]
269. Parra AV, Rodrigues V, Cancella S, Cordeiro JA, Bestetti RB. Impact of socioeconomic status on outcome of a Brazilian heart transplant recipients cohort. Int J Cardiol. 2008;125(1):142-3. [ Links ]
270. Bacal F, Bocchi EA. Cardiac transplantation for Chagas' disease. Rev Insuf Cardiaca. 2008;3:85-7. [ Links ]
271. Kun H, Moore A, Mascola L, Steurer F, Lawrence G, Kubak B, et al. Transmission of Trypanosoma cruzi by heart transplantation. Chagas Disease in Transplant Recipients Investigation Team. Clin Infect Dis. 2009;48(11):1534-40. [ Links ]
272. Centers for Disease Control and Prevention (CDC).Chagas disease after organ transplantation--Los Angeles, California, 2006. MMWR Morb Mortal Wkly Rep. 2006;55(29):798-800. [ Links ]
273. Amato Neto V, Matsubara L, Uip DE, Strabelli TM, Bocchi EA, Stolf NA, et al. Heart transplantation: donor with Chagas' disease and clinical course of the receptor. Rev Hosp Clin Fac Med Sao Paulo. 1992;47(2):92-4. [ Links ]
274. Souza FF, Castro-E-Silva O, Marin Neto JA, Sankarankutty AK, Teixeira AC, Martinelli AL, et al. Acute chagasic myocardiopathy after orthotopic liver transplantation with donor and recipient serologically negative for Trypanosoma cruzi: a case report. Transplant Proc. 2008;40(3):875-8. [ Links ]
275. Bocchi EA, Bellotti G, Uip D, Kalil J, de Lourdes Higuchi ML, Fiorelli A, et al. Long-term follow-up after heart transplantation in Chagas' disease. Transplant Proc. 1993;25(1 Pt 1):1329-30. [ Links ]
276. Vila JHA, Zerbini E, Bitencourt D, Carvalho V, Macruz R, Da Silva JP, et al. A 23 years of uneventful evolution in a heart-transplanted patient with chagasic cardiomyopathy on a two-drug immunosuppressive protocol. Transplantation. 2009;87(3):454-5. [ Links ]
277. Carvalho VB, Sousa EF, Vila JH, da Silva JP, Caiado MR, Araujo SR, et al. Heart transplantation in Chagas' disease: 10 years after the initial experience. Circulation. 1996;94(8):1815-7. [ Links ]
278. Ahualli L, Amuchastegui M, Boullon F, Cerutti B, Colque R, et al. Recommendations for use of everolimus after heart transplantation: results from a Latin-American Consensus Meeting. Transplant Proc. 2006;38(3):937-42. [ Links ]
279. Bacal F, Sodré GL, Fernandes DA, Aiello VD, Stolf N, Bocchi E, et al. Methotrexate in acute persistent humoral rejection: an option for graft rescue. Ann Thorac Surg. 2003; 76(2):607-10. [ Links ]
280. Bacal F, Silva CP, Bocchi EA, Pires PV, Moreira LF, Issa VS, et al. Mychophenolate mofetil increased chagas disease reactivation in heart transplanted patients: comparison between two different protocols. Am J Transplant. 2005;5(8):2017-21. [ Links ]
281. Bacal F, Veiga VC, Fiorelli AI, Bellotti G, Bocchi EA, Stolf NA, Ramires JA. Treatment of persistent rejection with methotrexate in stable patients submitted to heart transplantation. Arq Bras Cardiol. 2000; 74(5):141-8. [ Links ]
282. The International Society for Heart & Lung Transplantation. Registries - Heart / Lung Registries > Slides. [Accessed on 2009 Jul 13]. Available from: http://www.ishlt.org/registries/slides.asp?slides=heartlungregistry [ Links ]
283. WHO Expert Committee. Control of Chagas Disease. World Health Organ Tech Rep Ser. 2002;905:i-vi, 1-109. [ Links ]
284. Storino R, Barragán H. Epidemiología. In: Storino R, Milei J. Enfermedad de Chagas. Buenos Aires: Ed. Doyma;1994. p. 51-74. [ Links ]
285. Segura E, Ruiz M. Tripanosoma cruzi. In: Perea E. Enfermedades infecciosas y microbiología clínica. Barcelona: Ed Doyma;1992. p. 989. [ Links ]
286. Storino R, Milei J. Enfermedad de Chagas. Buenos Aires: Doyma;1994. [ Links ]
287. Freilij H, Storino R. Diagnóstico de laboratorio. In: Storino R, Milei J. Enfermedad de Chagas. Buenos Aires: Ed. Doyma;1994. p. 343-57. [ Links ]
288. Schijman AG, Vigliano C, Burgos J, Favaloro R, Perrone S, Laguens R, et al. Early diagnosis of recurrence of Trypanosoma cruzi infection by polymerase chain reaction after heart transplantation of a chronic Chagas' heart disease patient. J Heart Lung Transplant. 2000;19:(11) 1114-7. [ Links ]
289. Higuchi ML, Gutierrez PS, Aiello VD, Palomino S, Bocchi E, Kalil J, et al. Immunohistochemical characterization of infiltrating cells in human chronic chagasic myocarditis: comparison with myocardial rejection process. Virchows Arch A Pathol Anat Histopathol. 1993;423(3):157-60. [ Links ]
290. Higuchi ML, Assis RV, Sambiase NV, Reis MM, Kalil J, Bocchi E, et al. Usefulness of T-cell phenotype characterization in endomyocardial biopsy fragments from human cardiac allografts. J Heart Lung Transplant. 1991;10(2):235-42. [ Links ]
291. Souza MM, Franco M, Almeida DR, Diniz RV, Mortara RA, Silva S, et al. Comparative histopathology of endomyocardial biopsies in chagasic and non-chagasic heart transplant recipients. J Heart Lung Transplant. 2001;20(5):534-43. [ Links ]
292. Benvenuti LA, Roggerio A, Sambiase NV. Polymerase chain reaction in endomyocardial biopsies for monitoring reactivation of Chagas' disease in heart transplantation: a case report and review of the literature. Cardiovasc Pathol. 2005;14(5):265-8. [ Links ]
293. Bacal F, Pires PV, Moreira LF, Silva CP, Filho JR, Costa UM, et al. Normalization of right ventricular performance and remodeling evaluated by magnetic resonance imaging at late follow-up of heart transplantation: relationship between function, exercise capacity and pulmonary vascular resistance. J Heart Lung Transplant. 2005;24(12):2031-6. [ Links ]
294. Godoy HL, Guerra CM, Viegas RF, Dinis RZ, Branco JN, Neto VA, et al. Infections in heart transplant recipients in Brazil: the challenge of Chagas' disease. J Heart Lung Transplant. 2010;29(3):286-90. [ Links ]
295. Fiorelli A, Stolf NA, Honorato R, Bocchi E, Uip D, Strabelli T, et al. Later evolution after cardiac transplantation in Chagas' disease. Transplant Proc. 2005;84(6):2793-8. [ Links ]
296. Bestetti RB, Theodoropoulos TAD. A systematic review of studies on heart transplantation for patients with end-stage Chagas' heart disease. J Card Fail. 2009;15(3):249-55. [ Links ]
297. Bocchi EA, Bellotti G, Mocelin AO, Uip D, Bacal F, Higuchi ML, et al. Heart transplantation for chronic Chagas' disease. Ann Thorac Surg. 1996;61(6):1727-33. [ Links ]
298. Blanche C, Aleksic I, Takkenberg JJ, Czer LS, Fishbein MC, Trento A. Heart transplantation for Chagas' cardiomyopathy. Ann Thorac Surg. 1995;60(5):1406-8. [ Links ]
299. Kierszenbaum F, Cunha W, Beltz L, Sztein M. Trypanosomal immunosuppressive factor: a secretion products of T. cruzi that's inhibits proliferation and IL-2 receptor expression by activated human peripheral blood mononuclear cells. J Immunol. 1990;144:4000-4. [ Links ]
300. Hall CS, Fields K. Cutaneous presentation of Chagas' disease reactivation in a heart-transplant patient in Utah. J Am Acad Dermatol. 2008;58(3):529-30. [ Links ]
301. D'Avila SC, D'Avila AM, Pagliari C, Gonçalves VM, Duarte MI. Erythema nodoso in reactivation of Chagas' disease after cardiac transplantation. Rev Soc Bras Med Trop. 2005;38(1):61-3. [ Links ]
302. Campos SV, Strabelli TM, Amato Neto V, Silva CP, Bacal F, Bocchi EA, et al. Risk factors for Chagas' disease reactivation after heart transplantation. J Heart Lung Transplant. 2008;27(6):597-602. [ Links ]
303. Bestetti RB, Souza TR, Lima MF, Theodoropoulos TA, Cordeiro JA, Burdmann EA. Effects of a mycophenolate mofetil-based immunosuppressive regimen in Chagas' heart transplant recipients. Transplantation. 2007;84(3):441-2. [ Links ]
304. Lahura PN, Matsubara L, Amato Neto V, Okumura M, Bocchi EA. Characterization of Trypanosoma cruzi strains isolated from patients with heart transplantation Rev Hosp Clin Fac Med Sao Paulo. 1995;50(2):97-100. [ Links ]
305. Teixeira ARL, Calixto MA, Teixeira ML. Chagas' disease: carcinogenic activity of the antitrypanosomal nitroarenes in mice. Mutation Res. 1994;305(2):189-96. [ Links ]
306. Viotti R, Vigliano C, Armenti H, Segura E. Treatment of Chaga's disease with beznidazole: clinical and serological evolution of patients with long term follow-up. Am Heart J. 1994;127(1):151-62. [ Links ]
307. Sosa-Estani S, Armenti A, Araujo G, Viotti R, Lococo B, Ruiz Vera B, et al. Tratamiento de la enfermedad de Chagas con benznidazole y acido tioctico. Medicina.Buenos Aires. 2004;64:1-6. [ Links ]
308. Almeida DR, Carvalho AC, Branco JN, Pereira AP, Correa L, Vianna PV, et al. Chagas' disease reactivation after heart transplantation: efficacy of allopurinol treatment. J Heart Lung Transplant. 1996;15(10):988-92. [ Links ]
309. Tomimori-Yamashita J, Deps PD, Almeida DR, Enokihara MM, De Seixas MT, Freymüller E. Cutaneous manifestation of Chagas' disease after heart transplantation: successful treatment with allopurinol. Br J Dermatol. 1997;137(4):626-30. [ Links ]
310. Gluckstein D, Ciferri F, Ruskin J. Chaga's disease: another cause of cerebral mass in the acquired immunodeficiency syndrome. Am J Med. 1992;92(4):429-32. [ Links ]
311. Bacal F, Andrade AC, Migueletto BC, Bocchi EA, Stolf NA, Fiorelli AI, et al. Histoplasmosis as a late infectious complication following heart transplantation in a patient with Chagas' disease. Arq Bras Cardiol. 2001;76(5):403-8. [ Links ]
312. Stolf NA, Fiorelli AI, Bacal F, Camargo LF, Bocchi EA, Freitas A, et al. Mediastinitis after cardiac transplantation. Arq Bras Cardiol. 2000;74(5):419-30. [ Links ]
313. Uip DE, Neto VA, Strabelli TM, Bocchi EA, Pileggi F, Jatene AD, et al. Infective endocarditis in 100 patients subjected to heart transplantation. Arq Bras Cardiol. 1996;66(1):1-3. [ Links ]
314. Higuchi ML, Bocchi E, Fiorelli A, Aiello VD, Saldanha LB, Stolf N, et al. Histopathologic aspects of hyperacute graft rejection in human cardiac transplantation: a case report. Arq Bras Cardiol. 1989;52(1):39-41. [ Links ]
315. Theodoropoulos TAD, Silva AG, Bestetti RB. Eosinophil blood count and anemia are associated with Trypanosoma cruzi infection reactivation in Chagas' heart transplant recipients. Cardiovasc Pathol. 2009;19(3):191-2. [ Links ]
316. Bocchi EA, Mocelin AO, de Moraes AV, Menegheti C, de Lourdes Higuchi M, Bacal F, et al. Comparison between two strategies for rejection detection after heart transplantation: routine endomyocardial biopsy versus gallium-67 cardiac imaging. Transplant Proc. 1997;29(1-2):586-8. [ Links ]
317. Meneguetti JC, Camargo EE, Soares J Jr, Bellotti G, Bocchi E, Higuchi ML, et al. Gallium-67 imaging in human heart transplantation: correlation with endomyocardial biopsy. J Heart Transplant. 1987;6(3):171-6. [ Links ]
318. Bocchi EA, Higuchi ML, Vieira ML, Stolf N, Bellotti G, Fiorelli A, et al. Higher incidence of malignant neoplasms after heart transplantation for treatment of chronic Chagas' heart disease. J Heart Lung Transplant. 1998;17(4):399-405. [ Links ]
319. Bocchi EA, Vilas-Boas F, Pedrosa AA, Bacal F, Fiorelli A, Ariê S, et al. Percutaneous transluminal coronary angioplasty after orthotopic heart transplantation. Arq Bras Cardiol. 1994;62(3):177-9. [ Links ]
320. Rodrigues AC, Bacal F, Medeiros CC, Bocchi E, Sbano J, Morhy SS, et al. Noninvasive detection of coronary allograft vasculopathy by myocardial contrast echocardiography. J Am Soc Echocardiogr. 2005;18:(2) 116-21. [ Links ]
321. Bacal F, Moreira L, Souza G, Rodrigues AC, Fiorelli A, Stolf N, et al. Dobutamine stress echocardiography predicts cardiac events or death in asymptomatic patients long-term after heart transplantation: 4-year prospective evaluation. J Heart Lung Transplant. 2004;23(11):1238-44. [ Links ]
322. Bacal F, Stolf NA, Veiga VC, Chalela WA, Grupi C, Rodrigues AC, et al. Noninvasive diagnosis of allograft vascular disease after heart transplantation. Arq Bras Cardiol. 2001;76(1):29-42. [ Links ]
323. Bacal F, Veiga VC, Fiorelli AI, Bellotti G, Bocchi EA, Stolf NA, et al. Analysis of the risk factors for allograft vasculopathy in asymptomatic patients after cardiac transplantation. Arq Bras Cardiol. 2000;75(5):421-8. [ Links ]
324. Guimaraes GV, D'Avila VM, Pires P, Bacal F, Stolf N, Bocchi E. Acute effects of a single dose of phosphodiesterase type 5 inhibitor (sildenafil) on systemic arterial blood pressure during exercise and 24-hour ambulatory blood pressure monitoring in heart transplant recipients. Transplant Proc. 2007;39(10):3142-9. [ Links ]
325. Goldenberg RC, Jelicks LA, Fortes FS, Weiss LM, Rocha LL, Zhao D, et al. Bone marrow cell therapy ameliorates and reverses chagasic cardiomyopathy in a mouse model. J Infect Dis. 2008;197(4):544-7. [ Links ]
326. Soares MB, Pontes-de Carvalho L, Ribeiro dos Santos R. A patogênese da doença de Chagas: quando auto imunes e parasita resposta imune específica cumprir. An Acad Bras Cienc. 2001;73(4):547-59. [ Links ]
327. Soares MB, Garcia S, Campos de Carvalho AC, Ribeiro dos Santos R. Cellular therapy in Chagas' disease: potential applications in patients with chronic cardiomyopathy. Regen Med. 2007;2(3):257-64. [ Links ]
328. Bocchi EA, Guimarães G, Bacal F, Mendroni A, Chamone D, Issa I, et al. Stem cells mobilization treatment removing severe congestive heart failure patients from heart transplantation indication-preliminary results. J Heart Lung Transplant. 2003;22:S124. [ Links ]
329. Vilas-Boas F, Feitosa GS, Soares MB, Mota A, Pinho-Filho JA, Almeida AJ, et al. Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas disease. Arq Bras Cardiol. 2006;87(2):159-66. [ Links ]
330. Vilas-Boas F, Feitosa GS, Soares MB, Pinho-Filho JA, Mota A, Almeida AJ, et al. Bone marrow cell transplantation to the myocardium of a patient with heart failure due to Chagas' disease. Arq Bras Cardiol. 2004;82(2):185-7. [ Links ]
331. Jacob JL, Salis FV, Ruiz MA, Greco OT. Labeled stem cells transplantation to the myocardium of a patient with Chagas' disease. Arq Bras Cardiol. 2007;89:e10-11. [ Links ]
332. Tura BR, Martino HF, Gowdak LH, Ribeiro dos Santos R, Dohmann HF, Krieger JE, et al. Multicenter randomized trial of cell therapy in cardiopathies: MiHeart Study. Trials. 2007;8:2. [ Links ]
333. Macambira SG, Vasconcelos JF, Costa CR, Klein W, Lima RS, Guimarães P, et al. Granulocyte colony-stimulating factor treatment in chronic Chagas disease: preservation and improvement of cardiac structure and function. FASEB J. 2009;23(11):3843-50. [ Links ]
334. Moraes BN, Bacal F, Teixeira MC, Fiorelli AI, Leite PL, Fiorelli LR, et al. Behavior profile of family members of donors and nondonors of organs. Transplant Proc. 2009;41(3):799-801. [ Links ]
335. Moreira LF, Benício A, Bacal F, Bocchi EA, Stolf NA, Oliveira SA. Determinants of long-term mortality of current palliative surgical treatment for dilated cardiomyopathy. Eur J Cardiothorac Surg. 2003;23(5):756-63. [ Links ]
336. Bocchi EA. Cardiomyoplasty for treatment of heart failure. Eur J Heart Fail. 2001;3(4):403-6. [ Links ]
337. Bocchi EA, Guimarães GV, Moreira LF, Bacal F, de Moraes AV, Barreto AC, et al. Peak oxygen consumption and resting left ventricular ejection fraction changes after cardiomyoplasty at 6-month follow-up. .Circulation. 1995;92(9 Suppl):II216-22. [ Links ]
338. Moreira LF, Bocchi EA, Stolf NA, Bellotti G, Jatene AD. Dynamic cardiomyoplasty in the treatment of dilated cardiomyopathy: current results and perspectives. J Card Surg. 1996;11(3):207-16. [ Links ]
339. Moreira LF, Bocchi EA, Bacal F, Stolf NA, Bellotti G, Jatene AD. Present trends in clinical experience with dynamic cardiomyoplasty. Artif Organs. 1995;19(3):211-6. [ Links ]
340. Borghetti-Maio SA, Romano BW, Bocchi EA, Moreira LF, Barreto AC, Stolf NA, et al. Quality of life after cardiomyoplasty. J Heart Lung Transplant. 1994;13(2):271-5. [ Links ]
341. Braile DM, Godoy MF, Thèvenard GH, Thèvenard RS, Braile MC, Leal JC, et al. Dynamic cardiomyoplasty: long-term clinical results in patients with dilated cardiomyopathy. Ann Thorac Surg. 2000;69(5):1445-7. [ Links ]
342. Buffolo E, Branco JN, Catani R; RESTORE Group. End-stage cardiomyopathy and secondary mitral insufficiency surgical alternative with prosthesis implant and left ventricular restoration. Eur J Cardiothorac Surg. 2006;29(Suppl 1):S266-71 [ Links ]
343. Moreira LF, Stolf NA, Bocchi EA, Bacal F, Pêgo-Fernandes PM, Jatene AD. Cardiomyoplasty perspectives in the treatment of heart failure. Arq Bras Cardiol. 1994;63:261-6. [ Links ]
344. Bocchi EA, Esteves-Filho A, Bellotti G, Bacal F, Moreira LF, Stolf N, et al. Left ventricular regional wall motion, ejection fraction, and geometry after partial left ventriculectomy: influence of associated mitral valve repair. Eur J Cardiothorac Surg. 2000;18:458-65. [ Links ]
345. Bocchi EA, Bellotti G, Vilella de Moraes A, Bacal F, Moreira LF, Esteves-Filho A, et al. Clinical outcome after left ventricular surgical remodeling in patients with idiopathic dilated cardiomyopathy referred for heart transplantation: short-term results. Circulation. 1997;96(9 Suppl):II-165-71. [ Links ]
346. Bocchi EA, Moreira LF, de Moraes AV, Bacal F, Sosa E, Stolf NA, et al. Arrhythmias and sudden death after dynamic cardiomyoplasty. Circulation. 1994;90(5 Pt 2):II107-11. [ Links ]
347. Bellotti G, Moraes A, Bocchi E, Esteves Filho A, Stolf N, Bacal F, et al. Effects of partial ventriculectomy on left ventricular mechanical properties, shape, and geometry in patients with dilated cardiomyopathy. Arq Bras Cardiol. 1996;67(6):395-400. [ Links ]
348. Bocchi EA, Bellotti G, Moreira LF, Bacal F, de Moraes AV, Fiorelli A, et al. Mid-term results of heart transplantation, cardiomyoplasty, and medical treatment of refractory heart failure caused by idiopathic dilated cardiomyopathy. J Heart Lung Transplant. 1996;15(7):736-45. [ Links ]
349. Moreira LF, Stolf NA, Higuchi ML, Bacal F, Bocchi EA, Oliveira SA. Current perspectives of partial left ventriculectomy in the treatment of dilated cardiomyopathy. Eur J Cardiothorac Surg. 2001;19(1):54-60. [ Links ]
350. Metzger M, Higuchi ML, Moreira LF, Chaves MJ, Castelli JB, Silvestre JM, et al. Relevance of apoptosis and cell proliferation for survival of patients with dilated cardiomyopathy undergoing partial left ventriculectomy. Eur J Clin Invest. 2002;32(6):394-9. [ Links ]
351. Cury PM, Higuchi ML, Gutierrez PS, Moreira LF, Bocchi EA, Stolf NA, et al. Autopsy findings in early and late postoperative death after partial left ventriculectomy. Ann Thorac Surg. 2000;6(3):769-73. [ Links ]
352. Kawaguchi AT, Sugimachi M, Sunagawa K, Bergsland J, Koide S, Batista RJ. Improved left ventricular contraction and energetics in a patient with Chagas' disease undergoing partial left ventriculectomy. J Card Surg. 2001;16(3):30-3. [ Links ]
353. Moreira LF, Stolf NA, Bocchi EA, Bacal F, Giorgi MC, Parga JR, et al. Partial left ventriculectomy with mitral valve preservation in the treatment of patients with dilated cardiomyopathy. J Thorac Cardiovasc Surg. 1998;115(4):800-7. [ Links ]
354. Bocchi EA, Moreira LF, Bellotti G, Barreto AC, Azul LG, Stolf N, et al. Hemodynamic study during upright isotonic exercise before and six months after dynamic cardiomyoplasty for idiopathic dilated cardiomyopathy or Chagas' disease. Am J Cardiol. 1991;67(2):213-4. [ Links ]
355. Jatene AD, Moreira LF, Stolf NA, Bocchi EA, Seferian P Jr, Fernandes PM, et al. Left ventricular function changes after cardiomyoplasty in patients with dilated cardiomyopathy. J Thorac Cardiovasc Surg. 1991;102(1):132-8. [ Links ]
356. Moreira LF, Seferian P Jr, Bocchi EA, Pêgo-Fernandes PM, Stolf NA, Pereira-Barretto AC, et al. Survival improvement with dynamic cardiomyoplasty in patients with dilated cardiomyopathy. Circulation. 1991;84(5 Suppl):III296-302. [ Links ]
357. Bocchi EA, Moreira LF, de Moraes AV, Bellotti G, Gama M, Stolf NA, et al. Effects of dynamic cardiomyoplasty on regional wall motion, ejection fraction, and geometry of left ventricle. Circulation. 1992;86(5 Suppl):II231-5. [ Links ]
358. Moreira LF, Bocchi EA, Stolf NA, Pileggi F, Jatene AD. Current expectations in dynamic cardiomyoplasty. Ann Thorac Surg. 1993;55(1):299-303. [ Links ]
359. Stolf NA, Moreira LF, Bocchi EA, Higuchi ML, Bacal F, Bellotti G, et al. Determinants of midterm outcome of partial left ventriculectomy in dilated cardiomyopathy. Ann Thorac Surg. 1998;66:1585-91. [ Links ]
360. Kalil-Filho R, Bocchi E, Weiss RG, Rosemberg L, Bacal F, Moreira LF, et al. Magnetic resonance imaging evaluation of chronic changes in latissimus dorsi cardiomyoplasty. Circulation. 1994;90(5 Pt 2):II102-6. [ Links ]
361. Bocchi EA, Vieira ML, Fiorelli A, Hayashida S, Mayzato M, Leirner A, et al. Hemodynamic and neurohormonal profile during assisted circulation with heterotopic artificial ventricle followed by heart transplantation. Arq Bras Cardiol. 1994;62(1):23-7. [ Links ]
362. Ministério da Saúde. Secretaria de Vigilância em Saúde. Programa Nacional de Controle de Doença de Chagas. Recomendações para diagnóstico, tratamento e acompanhamento da co-infecção Trypanosoma cruzi/ vírus da imunodeficiência humana. Brasília;2007. (A. Normas e Manuais Técnicos, 81). [ Links ]
363. Sartori AM, Ibrahim KY, Nunes Westphalen EV, Braz LM, Oliviera OC Jr, Gakiya E, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol. 2007;101(1):31-50. [ Links ]
364. Vaidian AK, Weiss LM, Tanowitz HB. Chagas' disease and AIDS. Kinetoplastid Biol Dis. 2004. 3(1):2. [ Links ]
365. Sartori AM, Lin S, Franku FM, Malchiodi EL, de Fabro SP. Trypanosoma cruzi parasitemia in chronic Chagas disease: comparison between human immunodeficiency virus (HIV)-positive and HIV-negative patients. J Infect Dis. 2002;186(6):872-5. [ Links ]
366. Cordova E, Boschi A, Ambrosini J, Cudos C, Corti M. Reactivation of Chagas disease with central nervous system involvement in HIV-infected patients in Argentina, 1992-2007. Int J Infect Dis. 2008;12(6):587-92. [ Links ]
367. Scapellato PG, Bottaro EG, Rodriguez-Brieschke MT. Mother-child transmission of Chagas disease: could coinfection with human immunodeficiency virus increase the risk? Rev Soc Bras Med Trop. 2009;42(2):107-9. [ Links ]
368. Diazgranados CA, Saavedra-Trujillo CH, Mantilla M, Valderrama SL, Alguichire C, Franco-Paredes C. Chagasic encephalitis in HIV patients: common presentation of an evolving epidemiological and clinical association. Lancet Infec Dis. 2009;9(5):324-30. [ Links ]
369. Braga PE, Cardoso MR, Segurado AC. Gender differences among persons with HIV admitted to a university reference center in Sao Paulo, Brazil. Cad Saude Publica. 2007;23(11):2653-62. [ Links ]
370. Dolcini G, Ambrosioni J, Andreani G, Pando MA, Martinez Peralta L, Benetucci L. Prevalence of human immunodeficiency virus (HIV)-Trypanosoma cruzi co-infection and injectable-drugs abuse in a Buenos Aires health center. Rev Argent Microbiol. 2008;40(3):164-6. [ Links ]
371. Sartori AM, Lopes MH, Benvenuti LA, Caramelli B, di Pietro A, Nunes EV, et al. Reactivation of Chagas' disease in a human immunodeficiency virus-infected patient leading to severe heart disease with a late positive direct microscopic examination of the blood. Am J Trop Med Hyg. 1998;59(5):784-6. [ Links ]
372. Apt B, Heitmann G, Jercic L, Jofre M, Munoz C, Noemi H. Comité de Parasitologia - Departamento de Enfermedades Emergentes y Re-emergentes. Ministerio de La Salud de Chile. Rev Chilena Infectol. 2008;25(4):289-92. [ Links ]
373. Coura JR. Present situation and new strategies for Chagas disease chemotherapy: a proposal. Mem Inst Oswaldo Cruz. 2009;104(4):549-54. [ Links ]
374. Franco-Paredes C, Jacob JT, Hidron A, Rodriguez-Morales AJ, Kuhar D, Caliendo AM. Transplantation and tropical infectious diseases. Int J Infect Dis. 2010;14(3):e189-96. [ Links ]
375. Diez M, Favaloro L, Bertolotti A, Burgos JM, Vigliano C, Lastra MP, et al. Usefulness of PCR strategies for early diagnoses of Chagas' disease reactivation and treatment follow-up in heart transplantation. Am J Transplant. 2007;7(6):1633-40 [ Links ]
376. Altclas JD, Sinagra A, Dictar M. Chagas disease in bone marrow tranplantation. Bone Marrow Transplant. 2005;36(2):123-9. [ Links ]
377. Altclas JD, Barcan L, Nagel G, Lattes R, Riatte A. Organ transplantation and Chagas disease. JAMA. 2008;299(10):1134-5. [ Links ]
378. D'Albuquerque LA, Gonzalez AM, Filho HL, Copstein JL, Larrea FI, Mansero JM, et al. Liver transplantation from deceased donors serologically positive for Chagas disease. Am J Transplant. 2007;7(3):680-4. [ Links ]
379. Ferreira MS, Nishioka AS, Rocha A, Silva AM. Doença de Chagas e imunosupressão. In: Pinto Dias JC, Coura JR (orgs. ). Clínica e terapêutica da doença de Chagas: uma abordagem prática para o clínico geral. Rio de Janeiro: Fiocruz;1997.p. 365-79. [ Links ]
380. Rassi A, Amato-Neto V, Siqueira AF, Ferriolli Filho F, AmatoVS, Rassi Junior A, et al. Benznidazol as a prophylactic drug to prevent reactivation in chronic chagasic patients treated with corticoid for associated diseases. Rev Soc Bras Med Trop. 1999;32:475-82 [ Links ]
381. Nishioka SA. Benznidazol na quimioprofilaxia primária da reativação de doença de Chagas em chagásicos crônicos em uso de corticosteróides em doses imunodepressoras: há evidência suficiente para a recomendação do seu uso? Rev Soc Bras Med Trop. 2000;33:83-5 [ Links ]
382. Moretti E, Basso B, Castro I, Paez MC, Cahul M, Barbieir G, et al. Chagas' disease: study of congenital transmission in cases of acute maternal infection. Rev Soc Bras Med Trop. 2005;38(1):53-5. [ Links ]
383. Rassi A, Amato Neto V, Rassi GG, Amato VS, Rassi A Jr, Luquetti AO, et al. A retrospective search for maternal transmission of Chagas infection from patients in the chronic phase. Rev Soc Bras Med Trop. 2004;37(6):485-9. [ Links ]
384. Torrico F, Castro M, Solano M, Rodriguez P, Torrico MC, Truyens C, et al. Effects of maternal infection with Trypanosoma cruzi in pregnancy development and in the newborn infant. Rev Soc Bras Med Trop. 2005;38(supl. 2):73-5. [ Links ]
385. Sala MA, Rocha JES, Matheus M. Chagas' disease in pregnancy: maternal and perinatal aspects. Rev bras ginecol obstet. 1996;18(5):427-33, 436. [ Links ]
386. Batlouni M. Gravidez e a cirurgia na cardiopata. In: Carvalho AA. Cardiologia. São Paulo: Sarvier;1988. p. 240-55. [ Links ]
387. Gürtler RE, Segura EL, Cohen JE. Congenital transmission of Trypanosoma cruzi infection in Argentina. Emerg Infect Dis. 2003;9(1):29-32. [ Links ]
388. Freilij H, Altcheh J. Congenital Chagas' disease: diagnostic and clinical aspects. Clin Infect Dis. 1995;21(3):551-5. [ Links ]
389. Schijman AG, Altcheh J, Burgos JM, Biancardi M, Bisio M, Levin MJ, et al. Aetiological treatment of congenital Chagas' disease diagnosed and monitored by the polymerase chain reaction. J Antimicrob Chemother. 2003;52(3):441-9. [ Links ]
390. Sosa-Estani S, Segura EL. Etiological treatment in patients infected by Trypanosoma cruzi: experiences in Argentina. Curr Opin Infect Dis. 2006;19(6):583-7. [ Links ]
391. Dias JCP, Schofield CJ. Controle da transmissão transfusional da doença de Chagas na iniciativa do Cone Sul. Rev Soc Bras Med Trop. 1998;31(4):373-83. [ Links ]
392. Dias JCP. Southern cone initiative for the elimination of domestic populations of Triatoma infestans and the interruption of transfusional Chagas disease: historical aspects, present situation, and perspectives. Mem Inst Oswaldo Cruz, Rio de Janeiro. 2007;102(Suppl. I):11-8. [ Links ]
393. Silva EF, Oliveira AL, Siefer MW, Gazetta ML, Bertani IF. Demografic profile and work situacion of patient with Chagas disease. Arq Bras Cardiol. 1995;65:43-6. [ Links ]
394. Seabra TMR, Ide AC, A dimensão psicossocial do cuidar na enfermagem. In: Ide AC, De Domenico EBL. Ensinando e aprendendo um novo estilo de cuidar. São Paulo: Atheneu;2001. p. 39-58. [ Links ]
395. Mc Alister FA, Stewarts, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review orf randomized trials. J Am Coll Cardiol. 2004;44(4):810-9. [ Links ]
396. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196(4286):129-36. [ Links ]
397. Engel GL. The clinical aplication of biopsychosocial model. Am J Psychiatr. 1980;137(5):535-44. [ Links ]
398. Engel GL. Physicians-scientists and scientist-physicians: resolving the humanism science dichotomy. Am J Med. 1987;82(1):107-11. [ Links ]
399. De Castro RBA, Milanim Siqueira BG. Abordagem multidisciplinar do paciente com insuficiência cardíaca. In: Nobre F, Serrano Jr CV. Tratado de cardiologia SOCESP. São Paulo: Manole;2005. p. 807-13. [ Links ]
400. Gimenez L. Mintelman J. Recuperacion del enfermo chagásico. In: Gimenez L. Mintelman J. (orgs). Enfermedad de Chagas / mazza en la grandes ciudades. Buenos Aires: Roemmeres;2008. p. 153-4. [ Links ]
401. Ministério da Saúde. Relação Nacional de Medicamentos Essenciais RENAME [Acesso em nov. 2 2009]. Disponível em http://ww2.prefeitura.sp.gov.br//arquivos/secretarias/saude/ass_farmaceutica/0002/rename02.pdf [ Links ]
402. Gontijo ED, Rocha MOC, Oliveira UT. Perfil clínico-epidemiológico de chagásicos atendidos em ambulatório de referência e proposição de modelo de atenção ao chagásico na perspectiva do SUS. Rev Soc Bras Med Trop. 1996;29(2):101-8. [ Links ]
403. Gontijo ED, Guariento ME, Almeida EA. Modelo de atenção ao chagásico no Sistema Único de Saúde. In: Dias JCP, Coura JR. Clínica e terapêutica da doença de Chagas: uma abordagem prática para o clínico geral. Rio de Janeiro: Fiocruz;1997. p. 445-52. [ Links ]
404. Vallejo M, Montenegro P, Reis P. Cúanto cuesta la atención de la cardiopatia chagásica crónica? Costo directos en un hospital de cardiología. Arch Cardio Mex. 2002;72(2):129-37. [ Links ]
405. Dias JCP, Briceño-Leon R, Storino R. Aspectos sociales, econômicos, culturales y psicológicos. In: Storino R, Milei J. (orgs). Enfermidad de Chagas. Buenos Ayres: Doyma;1994. p. 525-60. [ Links ]
406. Dias JCP, Dias RB. Aspectos sociais, econômicos e culturais da doença de Chagas. Ciência e Cultura. 1979;31(supl. 1):105-17. [ Links ]
407. Oliveira Jr W. Cardiopata chagásico em situações especiais. In: Dias JCP, Coura JR. (orgs). Clínica e terapêutica da doença de Chagas: uma abordagem prática para o clínico geral. Rio de Janeiro: Editora Fundação Oswaldo Cruz;1997. p. 299-320. [ Links ]
408. Amato Neto V, Lopes MH, Umezawa ES, Dias JCP. Outras formas de transmissão do Trypanosoma cruzi. Rev Patol Trop. 2000;29(supl. 1):115-29. [ Links ]
409. Camargo EP. Perspectives of Chagas disease vaccination revisited. Mem Inst Oswaldo Cruz. 2009;. 104(Suppl. 1):275-80. [ Links ]
410. Gomes YM, Lorena VMB, Luquetti AO. Diagnosis of Chagas disease: what has been achieved? What remains to be done with regard to diagnosis and follow up studies? Mem Inst Oswaldo Cruz. 2009;104(Suppl. 1):115-21. [ Links ]
411. Guhl F, Nicholls S. Manual de procedimientos para el diagnóstico de La enfermedad de Chagas. Bogotá: Universidad Los Andes, 2001. [ Links ]
412. Moraes-Souza H, Martins PRJ, Pereira G, Ferreira-Silva MM, Abud MB. Perfil sorológico para doença de Chagas dos doadores de sangue do Hemocentro Regional de Uberaba. Rev Bras Hematol Hemoter. 2006;28(2):110-4. [ Links ]
413. Moraes-Souza H, Ramirez LE, Bordin JO. Doença de Chagas transfusional: medidas de controle. In Dias JCP, Coura JR (orgs. ) Clínica e terapêutica da doença de Chagas: um manual prático para o clínico geral. Rio de Janeiro: Editora Fiocruz;1997.p. 429-4. [ Links ]
414. Organización Panamericana de La Salud. Estimación cuantitativa de la enfermedad de Chagas en las Américas. Washington;2006. [ Links ]
415. Salvatella RA. Achievements in controlling Chagas disease in Latin America. Geneva: Word Health Organization;2007. [ Links ]
416. Sociedad Argentina de Cardiologia. Guias clínicas prácticas de prevención, diagnóstico y tratamiento de la enfermedad de Chagas. Buenos Aires, Gobierno de la Ciudad de Buenos Aires;2004. [ Links ]
417. Umezawa ES, Luquetti AO, Levitus G, Ponce C, Ponce E, Henriquez D, et al. Serodiagnosis of chronic and acute Chagas' Disease with Trypanosoma cruzi recombinant proteins: results of a collaborative study in six Latin American Countries. J Clin Microbiol. 2004;42:449-52. [ Links ]
418. Andrade SG, Stocker-Guerret S, Pimentel AS, Grimaud JA. Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy. Mem Inst Oswaldo Cruz 1991;86:187-200. [ Links ]
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