Chagas Cardiomyopathy—Where Do We Stand After a Hundred Years?

Progress in Cardiovascular Diseases 52 (2010) 300 – 316 www.onlinepcd.com Chagas Cardiomyopathy—Where Do We Stand After a Hundred Years? Andréia Biolo,a Antonio L. Ribeiro,b Nadine Clausella,⁎ a Division of Cardiology, Hospital de Clínicas de Porto Alegre and Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil b Service of Cardiology, University Hospital and Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil Abstract A hundred years from its description, Chagas cardiomyopathy remains a challenging disease. Although successful vector-control strategies have decreased the incidence of Chagas disease in several Latin American countries, both migration to urban areas and immigration have spread the disease worldwide; and now, blood transfusion, organ transplantation, and vertical transmission are a concern. The pathogenesis of Chagas cardiomyopathy involves complex host-parasite interactions, where low-grade but incessant systemic infection and triggered autoimmune reaction are the main mechanisms for its development, with the contribution of autonomic damage and microvascular disturbances. Chagas cardiomyopathy is the most important clinical presentation of Chagas disease and comprises a wide range of manifestations, including heart failure, arrhythmias, heart blocks, sudden death, thromboembolism, and stroke. Recently, simple clinical prognostic scores have been developed to identify high-risk patients and help with management. The treatment of Chagas cardiomyopathy focuses mostly on managing heart failure, arrhythmias, and thromboembolism. The role of specific antiparasitic therapy in the chronic form is not yet defined, and a randomized trial is now under way to address this crucial point. In this article, we review the main clinical aspects of Chagas cardiomyopathy and underscore some upcoming challenges for the appropriate control, diagnosis, and management of this complex disease. (Prog Cardiovasc Dis 2010;52:300-316) © 2010 Elsevier Inc. All rights reserved. Keywords: Chagas disease; Cardiomyopathy; T. cruzi The year 2009 marks the 100th anniversary of the description of Chagas disease by the Brazilian physician Carlos Chagas.1 Chagas described not only the clinical features of the disease, but also its causal agent, Trypanosoma cruzi, and the main mechanism of transmission, transcutaneous inoculation of the parasite by excreta of infected hematophagous insects. Infection with T cruzi is an enzootic disease, which can lead to human disease when the insect vectors—triatomine bugs—reach their domestic cycle by adapting to human dwellings.2 A hundred years from its description, Chagas cardiomyopathy still is a challenging disease. Many questions regarding pathogenesis, clinical characteristics, and even treatment of Chagas cardiomyopathy remain unsolved. Nonetheless, increased worldwide awareness, initiatives to control dissemination, and research on mechanisms and specific therapies have brought progress into our understanding and capacity to deal with this complex disease. Epidemiology and natural history Statement of Conflict of Interest: see page 311. ⁎ Address for reprint requests to Nadine Clausell, MD, PhD, Heart Failure and Transplant Unit, Cardiology Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Sala 2061, 90035-003 Porto Alegre, RS, Brazil. E-mail address: clausell@portoweb.com.br (N. Clausell). 0033-0620/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2009.11.008 Chagas disease has a wide distribution in Central and Latin America; epidemiologic studies carried out in 1980 to 1985 estimated a prevalence of 16 to 18 million persons infected and 100 million at risk.3 Fortunately, successful A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 vector-control strategies reduced the transmission ACE = angiotensinof Chagas disease in sevconverting enzyme eral Latin American BNP = brain natriuretic countries; and therefore, peptide its incidence was reduced by more than 65% in ECG = electrocardiogram 2000. Initially a disease ELISA = enzyme-linked of rural areas in endemic immunosorbent assay countries, the disease has HRV = heart rate variability spread to cities with ICD = implantable urban migration. Immicardioverter-defibrillator gration has also spread Chagas disease to nonenPCR = polymerase chain reaction demic, developed countries, a process mostVPB = ventricular premature ly described in Australia, beat Canada, the United States, and Europe.4,5 In fact, most of the estimated 100,000 infected persons in the United States acquired the disease while residing in endemic regions, although T cruzi–infected vectors and animals are found in many parts of the United States and rare cases of autochthonous transmission have been documented.6 Started in 2006, a screening program for Chagas disease in blood banks in the United States detected more than 500 confirmed T cruzi–infected donations, helping prevent blood-borne transmission and increase awareness of the disease.7 In nonendemic countries, blood transfusion, organ transplantation, and vertical transmission are more likely routes of infection with T cruzi.2 There are 2 successive stages in Chagas disease: an acute phase and a chronic phase. In the acute phase, there is an intense inflammatory reaction at the entry point for T cruzi (chagoma). On conjunctiva, it may result in unilateral periorbital edema, eyelid swelling, and preauricular adenopathy (Romana sign). Main manifestations include fever, myalgias, malaise, muscle pains, sweating, hepatosplenomegaly, heart failure from myocarditis, pericardial effusion, lymphocytosis, and, less often, meningoencephalitis. Cardiac involvement occurs in more than 90% of cases.8 The electrocardiogram (ECG) may show low-voltage, diffuse ST-T changes and conduction abnormalities. Serologic test results for T cruzi infection are negative during the first weeks, but the circulating parasites can be detected by xenodiagnosis. However, diagnosis is established in few patients because of scarcity or absence of clinical manifestations. The acute phase lasts 6 to 8 weeks, with spontaneous recovery in more than 95% of patients.2,9 Once the acute phase subsides, most infected patients have no physical signs or clinical evidence of organ damage. The infection can be detected only by serologic or parasitologic tests. This form of the chronic phase of Chagas disease is called the indeterminate form and, in Abbreviations and Acronyms 301 most patients, persists indefinitely. Nonetheless, patients in the indeterminate form have a subclinical degree of cardiac involvement when tested by Holter monitoring or echocardiography, although the clinical and prognostic significance of those findings is not defined.2,3,10 Several years after the chronic phase has started, 10% to 40% of infected individuals will develop chronic symptoms from involvement of various organs, mainly the heart and the digestive system. Heart involvement is the most important clinical aspect of Chagas disease because of its characteristics, frequency, and severity. The chronic phase lasts throughout life and results in a shortening in life expectancy.2 Pathogenesis The pathogenesis of Chagas cardiomyopathy is not completely understood, partially because disease progression depends on complex host-parasite interactions. Four main pathogenetic mechanisms have been described: direct parasite damage to the myocardium, immunologic mechanisms, dysautonomia, and microvascular disturbances.11,12 Direct parasite damage to the myocardium The inflammatory process that characterizes Chagas cardiomyopathy is accentuated during the acute phase of disease; and although it may be clinically silent after that, inflammation is continuously present in patients with the indeterminate and chronic phases.13,14 Moreover, the presence of inflammation, with consequent cell loss and fibrosis, seems to correlate with severity of heart failure.15 Parasite persistence is believed to be a trigger for lymphocytic infiltration of the myocardium, and persistent T cruzi antigens or its genomic material is found in inflammatory foci.16-20 Nonetheless, the exact mechanism whereby parasitism causes tissue damage in the chronic phase is unclear; and a definitive cause-effect relationship between progression of disease and parasite persistence has not been conclusively demonstrated. Although direct aggression by the parasite is one possibility, the stimulation of immune responses is the most likely cause of inflammation.9,11 Immunologic mechanisms The diffuse myocarditis with myocytolysis and reparative fibrosis seen in chronic Chagas heart disease is characteristic of delayed hypersensitivity reaction, with Tcell–rich inflammatory infiltrates.21,22 However, the scarcity of T cruzi parasites and the lack of temporal and topographic correlation with the development of myocardial pathology point to an autoimmunity/antigenic mimicry hypothesis, with several mechanisms implicated: antigen exposure secondary to tissue damage and environment 302 A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 sensitization, molecular mimicry by structurally similar epitopes between the parasite and host antigens with crossreactive autoimmune response, and polyclonal activation with autoantibody production.11,22 Autoantibodies specific for various autoantigens expressed in cardiac, nervous, and other tissues have been found both in experimental models of T cruzi infection and in sera from infected patients. Cross-reactive antibodies between T cruzi and human proteins, such as β-adrenergic receptors and cardiac myosin heavy chain, have also been identified. Experimentally, induction of immunologic tolerance to heart antigens resulted in milder disease in a model of chronic Chagas myocarditis.23-27 Therefore, Chagas cardiomyopathy is one example of postinfectious autoimmunity, where the infectious agent T cruzi triggers molecular mimicryrelated target organ immune damage. Dysautonomia There is both pathologic and functional evidence of cardiac denervation in Chagas heart disease. Several studies demonstrated intense neuronal depopulation in chagasic patients, with ganglionic damage and absolute reduction in subepicardial intramural neuronal countings.11 It is believed that the neuronal loss in Chagas heart disease occurs mostly during the acute phase of infection, through direct parasitism of neurons, periganglionic inflammation, and antineuronal autoimmune reaction. The observed denervation, as well as the presence of autoantibodies with antagonistic effects,28 results in abnormal cardiac autonomic regulation, which has been demonstrated in chagasic patients. Several studies using either pharmacologic or physiologic stimuli demonstrated impaired parasympathetic heart rate regulation, with deprivation of the tonic inhibitory action normally exerted by the parasympathetic system on the sinus node, and lack of the vagally mediated mechanism to respond with rapid brady- or tachycardia to transient changes in blood pressure or venous return.29-33 The parasympathetic dysautonomia is an early phenomenon; and it may be present even before left ventricular systolic dysfunction,34 as opposed to other cardiomyopathies where autonomic impairment occurs as a result of neurohumoral activation and adrenergic receptor desensitization. Sympathetic nervous system denervation has also been described both by pathologic35 and scintigraphic studies,36 but its the clinical meaning is controversial. Whereas it is unlikely that autonomic dysfunction plays an essential pathogenic role for the development of chagasic cardiomyopathy, all these neurogenic disturbances may indeed contribute to the progression of Chagas heart disease: parasympathetic impairment could be a mechanism of increased vulnerability to malignant arrhythmias and sudden death37; lack of adequate heart-rate responses increases the dependency of cardiac output increase on volume and shape modifications, requiring more ventricular dilation and forceful contraction38 ; also, autonomic derangements may trigger microcirculatory vasospasm, another important mechanism in Chagas cardiomyopathy.11 Microvascular disturbances Both functional and structural microvascular abnormalities occur in Chagas cardiomyopathy, possibly associated with an underlying inflammatory process causing perivascular inflammation of several vascular beds.9,11 The resulting manifestations are vasospasm, decreased blood flow, focal ischemia, platelet thrombi, increased platelet aggregation, and elevated levels of thromboxane A-2 and endothelin-1.39-42 It is believed that microvascular ischemia may contribute by amplifying the chronic inflammatory aggression toward myocardial tissue. Furthermore, the focal distribution of cell necrosis and reparative fibrosis suggests a role for transient microvascular ischemic insults.39 Patients with Chagas cardiomyopathy may have chest pain in the absence of coronary artery disease, segmental left ventricular dysfunction, ST-T changes, and abnormal coronary flow regulation related to endothelial and nonendothelial dysfunction; and in fact, myocardial perfusion abnormalities have been shown in these patients.43,44 Chronic myocardial hypoperfusion would therefore contribute to Chagas cardiomyopathy as does hibernating myocardium in chronic coronary artery disease. In summary, the 2 main mechanisms underlying chronic Chagas heart disease include low-grade but incessant systemic infection and triggered autoimmune reaction, such that parasite persistence and immunologic activity result in myocardial aggression and damage (Fig 1). Autonomic derangements and microcirculatory disturbances are also involved and contribute to some particular characteristics of Chagas cardiomyopathy. Once left ventricular remodeling and failure are established, neurohumoral activation and other compensatory mechanisms take place and ensure progression of the disease, similar to what happens with other cardiomyopathies. Nonetheless, several aspects of Chagas disease pathogenesis are still intriguing and unsolved. For example, the determination of whether autoimmunity or parasite-driven damage is the predominant mechanism may help delineate more efficacious treatment strategies such as immunologic interventions, trypanocidal therapies, and other strategies to abrogate the development and progression of Chagas cardiomyopathy. Etiologic diagnosis The diagnosis of T cruzi infection is usually established by the detection of the parasite using parasitologic tests, during acute infection, or by A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 303 Fig 1. Pathogenesis of chronic Chagas cardiomyopathy. The 2 main mechanisms of persistent parasite damage and immunologic response cause myocardial damage and fibrosis with progressive LV remodeling and failure. Nervous tissue damage and microvascular disturbances are triggered and contribute to further LV remodeling. Cardiac arrhythmias result from LV remodeling and failure, as well as nervous tissue damage, with consequent increased risk of sudden death (adapted from Marin-Neto et al11). Abbreviation: LV, left ventricular. immunodiagnosis, through detection of circulating antibodies against T cruzi antigens, in the chronic phase of disease. In the acute phase of disease, laboratory confirmation is based on the detection of parasites using the fresh-blood test, the more sensitive and preferred one, or by smear and thick drop tests. Concentration tests should be performed in highly suspicious cases with negative fresh-blood test results.45 During the chronic phase of T cruzi infection, the concentration of circulating parasites is too low for parasitologic detection, so that the diagnosis relies on antibody detection. Two parallel tests should be performed: a test with high sensitivity (enzyme-linked immunosorbent assay [ELISA] with total antigen or semipurified fractions of the parasite, indirect immunofluorescence, or indirect hemaglutination) in combination with a highly specific one (ELISA using T cruzi–specific recombinant antigens).45 If the results are inconclusive (1 positive and 1 negative test result), samples must be retested; and if still inconclusive, samples should be sent to referral laboratories to be tested using polymerase chain reaction (PCR) or Western blot methods. Recent studies show promising results on standardized PCR techniques and arrays for detection of multiple recombinant proteins that may increase accuracy and reliability on T cruzi infection diagnosis.46,47 Clinical manifestations and clinical assessment Chagas cardiomyopathy is the most important clinical presentation of Chagas disease and comprises a wide range of manifestations, including heart failure, arrhythmias, heart blocks, sudden death, thromboembolism, and stroke.48 Clinical presentation typically varies widely according to the degree of myocardial damage; and most patients present a mild form of heart disease, frequently characterized only by the presence of asymptomatic abnormalities on the ECG or in other complimentary examinations. Considering that the presence of ECG abnormalities is the most prevalent feature of Chagas cardiomyopathy and that it has a definite prognostic meaning,49-51 a Brazilian Expert Consensus defined Chagas cardiomyopathy by the presence of typical ECG abnormalities (Table 1) and a positive serology result for T cruzi, independently of the presence of symptoms; those with nonspecific ECG alterations should be classified as Chagas cardiomyopathy if they present typical clinical manifestations or abnormalities in other laboratory examinations.45 On average, cardiac involvement is fully developed around 20 years after the primary infection, although it takes place earlier in some subjects and later in others.52 Most untreated acute cases evolve into the so-called 304 A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 Table 1 Typical and nonspecific ECG abnormalities in Chagas cardiomyopathy, according to the Brazilian Expert Consensus in Chagas disease Typical ECG Changes for Chagas Disease Right bundle-branch block, associated or not to left anterior fascicular block Frequent VPBs (N1 by ECG), polymorphous or repetitive Nonsustained ventricular tachycardia 2nd- and 3rd-degree atrioventricular block Sinus bradycardia with heart rate b40 beat/min Sinus node dysfunction Left bundle-branch block AF Electrical inactive segment Primary alterations of ST-T wave Nonspecific ECG changes observed in Chagas disease Sinus bradycardia with heart rate ≥40 beat/min Low limb voltage Nonspecific ST-T changes Incomplete right bundle-branch block Left anterior fascicular block Isolated VPBs 1st-degree atrioventricular block indeterminate form of chronic Chagas disease, defined by the presence of infection, confirmed by either serologic or parasitologic tests, and the absence of symptoms and of electrocardiographic and radiologic abnormalities (comprising heart, esophagus, and colon evaluation).49 Patients with the indeterminate form constitute the majority of infected people in endemic areas, and around 40% of these patients may persist in this clinical situation forever.50 Patients classified as possessing the indeterminate form of the disease have an excellent prognosis, and deaths due to the infection are rare.49,50 The transition from the indeterminate form to cardiomyopathy generally occurs in a slow and progressive fashion, occurring in 2% to 3% of patients each year.49,50 Clinical manifestations of severe chronic Chagas heart disease comprise 3 main syndromes: (a) heart failure, (b) cardiac arrhythmia, and (c) thromboembolism.53 Heart failure is usually biventricular, and signs and symptoms of both left and right ventricular failure may be observed. Left ventricular systolic dysfunction is a major feature of Chagas cardiomyopathy, as well as the main predictor of the risk of death.54 Clinical manifestations of right ventricular failure were formerly reported as more prevalent and more pronounced than those of left-sided failure55; but recently, it has been demonstrated that right ventricular dysfunction is clinically significant only when there is also a significant associated involvement of the left side, especially when left ventricular filling pressure and pulmonary pressure are elevated.56 However, right ventricular involvement can occur early in the evolution of Chagas cardiomyopathy 57,58 and is an independent predictor of death.59 Although diastolic left ventricular abnormalities have been noted in the absence of regional or global left ventricular systolic dysfunction, a strong correlation between systolic dysfunction and impairment of left ventricular filling is usually observed in Chagas disease.60 Left atrial volume, a marker of chronically elevated left ventricular filling pressures, is also a predictor of prognosis in patients with Chagas cardiomyopathy.61 Chronic Chagas cardiomyopathy is considered one of the most arrhythmogenic cardiomyopathies; and both tachy- and bradyarrhythmias can occur, frequently coexisting in the same patient. Ventricular arrhythmias, including ventricular premature beats (VPBs) and nonsustained ventricular tachycardia, are frequent in most patients; and malignant sustained ventricular tachycardia is not uncommon.62 Indeed, episodes of malignant ventricular arrhythmia seem to be much more frequent in patients with Chagas cardiomyopathy than those with other types of underlying heart disease.63 The severity of ventricular arrhythmias tends to correlate with the degree of left ventricular dysfunction,64 although it is not uncommon to have patients with ventricular tachycardia and preserved global ventricular performance.65 The presence of VPBs in the standard ECG is a well-known prognostic marker, especially when associated to intraventricular conduction disturbances.51,66 More recently, it has been established that the most powerful and independent arrhythmic risk factor in Chagas cardiomyopathy is the occurrence of nonsustained ventricular tachycardia, observed during 24-hour Holter monitoring or at the exercise testing.54,67-69 Atrial fibrillation (AF) has also been observed in 4% to 12% of patients with Chagas cardiomyopathy,70 occurring mainly in those with advanced heart failure, related to large atria and reduced left ventricular systolic function.71 In Chagas cardiomyopathy, AF is characterized by relatively low ventricular rate, related to the coexistence of ventricular conduction disturbances and to an ominous prognosis. 70,72 Intraventricular and atrioventricular conduction disturbances are common manifestations of Chagas heart disease and are generally related to the presence of left ventricular dysfunction and ventricular arrhythmias.51,66 Right bundle-branch block, associated or not with left anterior fascicular block, is the most typical ECG abnormality of Chagas cardiomyopathy, although left posterior fascicular block and left bundle-branch block may also occur. There is an inverse correlation between QRS duration and left ventricular ejection fraction73; and in a recent study, both the filtered, signal-averaged and the standard ECGs were described as independent prognostic markers.69,74 Chagas disease is a main cause of atrioventricular block in Latin American countries; and although functional atrioventricular node abnormalities may occur, they are generally caused by widespread and distal fibrosis of the conduction system. Sinus node dysfunction is also a A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 concern, and Chagas disease is a main underlying reason for implantation of pacemakers in many endemic regions. In comparison with pacemaker patients without Chagas disease, those patients with Chagas cardiomyopathy are significantly younger and have lower left ventricular ejection fraction and more frequent ventricular arrhythmia during Holter monitoring.75 Sudden cardiac death is the most frequent mechanism of death in Chagas cardiomyopathy 62 and generally occurs in patients with more severe disease, although it may rarely occur in previously asymptomatic patients.65 The final event in these patients is presumed to be ventricular tachycardia and fibrillation, but bradyarrhythmias may also occur.76 Systemic and pulmonary embolisms, arising from mural thrombi in cardiac chambers and from deep venous thrombosis due to low cardiac output, are possible complications of Chagas cardiomyopathy. Stroke may be its first manifestation; and it is associated with systolic dysfunction, increased left atrial volume, apical aneurysm, intracardiac thrombi, and cardiac arrhythmias.77-79 Chagas disease has been considered an often unrecognized cause of stroke, and it should be included in its differential diagnosis in patients of Latin American origin.80 Chest pain occurs in up to a quarter of patients with Chagas cardiomyopathy and may be related to abnormal coronary flow regulation, due to endothelial and nonendothelial dysfunction, as well as to noncardiac causes, including esophagus motility disorders, typical of Chagas disease.11 Acute myocardial infarction is not only uncommon in Chagas disease; but it may also present with atypical chest pain and, eventually, with normal coronary arteries.81 Diagnostic evaluation The ECG is the single most important examination in Chagas cardiomyopathy. Numerous epidemiologic studies have shown that patients with a normal ECG have an excellent medium-term survival. 49-51 Moreover, severe global left ventricular dysfunction, the main prognostic marker in Chagas disease, is rare in such patients. The greater the number and severity of ECG alterations registered in a same tracing, the more advanced the myocardial damage possibly is, and the worse the prognosis should be.62 Rarely, sudden death may occur in patients with a normal ECG as the initial manifestation of the disease.65 Echocardiography is the noninvasive technique most often used in the assessment of cardiac function and represents an important method in the evaluation of Chagas cardiomyopathy, allowing the recognition of left ventricular systolic and diastolic dysfunction, right ventricle 305 involvement, and regional contractility abnormalities, including typical apical aneurysms. New echocardiography methodologies, such as tissue Doppler57,60,82-85 and strain rate,86 may help in the evaluation of the Chagas cardiomyopathy. Global systolic left ventricular dysfunction is the strongest predictor of morbidity and mortality in Chagas disease,59,61,69,74,87-90 and asymptomatic left ventricular systolic dysfunction is as common or even more prevalent than symptomatic heart failure. Identification and treatment of patients with left ventricular global systolic dysfunction improve survival and reduce morbidity. Because it is costly to submit all patients with Chagas disease to echocardiographic evaluation, it is desirable to develop screening methods to indicate which patients should be submitted to complete left ventricular evaluation. Enlarged heart silhouette at the chest x-ray, although a specific sign for cardiac dilatation, lacks sensitivity and has an overall poor diagnostic performance.91 The blood level of brain natriuretic peptide (BNP), a reliable indicator of systolic left ventricular dysfunction in different clinical and epidemiologic settings, is a promising screening method.92-97 In patients with abnormal ECG and/or chest x-ray findings, BNP elevation has a positive predictive value of 80% and a negative predictive value of 97% for the detection of patients with depressed left ventricular ejection fraction.93 A diagnostic strategy including ECG and BNP performed better than the classic approach with ECG and chest x-ray.95 Moreover, BNP is also a marker of ventricular arrhythmia97 and diastolic dysfunction.92,98 One of the most interesting findings in the heart in Chagas cardiomyopathy is the pattern of segmental myocardial contractility disturbance that makes this disease in some way closer to ischemic rather than to idiopathic cardiomyopathy. The segments predominantly involved are left ventricular apex and inferior-posterior wall.83,84 These latter changes appear even in the indeterminate form of Chagas cardiomyopathy (about 20%-30% of cases) and are universally present in cases of severe heart failure.83,84 Echocardiography allows the identification of almost all apical lesions, even the small ones. It is important to note that the apical lesion in Chagas disease is generally not associated with contractile dysfunction in the anteroseptal segment of the left ventricle, which distinguishes Chagas disease from patients with coronary artery disease complicated with infarction. The involvement of other left ventricular segments in Chagas disease does not differ from that seen in coronary artery disease, and the clinical and epidemiologic aspects are essential for the differential diagnosis. The use of transesophageal echocardiography allows the identification of possible cardiac sources of emboli with high accuracy. 77 As Chagas disease can be complicated by embolic events, transesophageal echocardiography may be important in deciding the benefit of anticoagulant therapy. 306 A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 Dynamic ECG recording (Holter monitoring) is especially important in Chagas disease because of the relatively frequent occurrence of asymptomatic transitory arrhythmias.99 Identification of complex forms of ventricular arrhythmias, such as couplets and nonsustained ventricular tachycardia, has prognostic relevance.54,68 The detection of potentially lethal arrhythmias, such as sustained ventricular tachycardia or transient advanced heart blocks, may indicate the necessity of specific antiarrhythmic therapy or devices. Sick sinus syndrome is also frequent in Chagas cardiomyopathy and can be recognized by Holter monitoring. The lack of significant ventricular arrhythmia in 24-hour ECG does not, however, preclude risk of death due to arrhythmia. Ambulatory monitoring may also be used in the investigation of palpitations and syncope99,100 and in the assessment of the efficacy of antiarrhythmic therapy.75 Holter monitoring is also a valuable tool to assess heart rate variability (HRV), an indirect measure of autonomic nervous system control of the heart. Reduced indexes of HRV could be found in Chagas cardiomyopathy before the development of overt cardiac disease, 34,101 indicating mainly vagal involvement.102 Some HRV methods, such as heart rate turbulence,103,104 useful as prognostic markers in other cardiomyopathies may be evaluated using Holter monitoring and might help in the identification of patients prone to present malignant arrhythmias, an attractive hypothesis that deserves to be tested. In selected patients, invasive electrophysiologic study may be useful for identifying the cause of syncope (when noninvasive test results are inconclusive)100 or for guiding the use of antiarrhythmic devices, such as cardiac pacemakers and implantable cardioverter-defibrillators (ICDs).105 Moreover, induction of ventricular tachycardia during programmed ventricular stimulation is a predictor of cardiac death and mortality in patients with Chagas cardiomyopathy and nonsustained ventricular tachycardia.106 Maximal exercise testing is usually assessed with the use of a standard Bruce protocol and can be conducted safely in patients with Chagas disease. Exercise testing evaluates the influence of exercise in provoking arrhythmias and also plays a role in defining the type of work a patient may perform. Exercise-induced ventricular tachycardia has the same ominous prognostic significance as that observed in Holter monitoring.67,68 Chronotropic insufficiency and abnormal blood pressure response are more frequent in Chagas cardiomyopathy and may also hamper the effort capacity of these patients.107,108 Autonomic impairment, sick sinus syndrome, and left ventricular dysfunction are putative causes of these abnormalities; but it is also well known that some patients with advanced cardiomyopathy may maintain an excellent exercise capacity. Indeed, as with many other aspects of Chagas disease physiopathology, the response to exercise cannot be predicted by other means; and stress testing is an essential tool in the evaluation of patients with Chagas cardiomyopathy. Radioisotopic techniques, such as myocardial scintigraphy with thallium-201, have been performed in combination with stress testing to study the myocardial perfusion pattern in the following clinical situations: patients with (1) chest pain, (2) left ventricular segmental abnormalities, and (3) ischemic ECG changes. Both transient and irreversible perfusion defects may be detected by myocardial perfusion scanning in these patients. This finding may represent microvascular abnormalities, dysautonomia, or areas of myocardial fibrosis.36,43 In patients who complain of angina-like pain, perfusion disturbances may occur, usually in the presence of normal coronary arteries. Occasionally, cardiac and coronary catheterizations are required to exclude the presence of obstructive coronary artery disease.109 Cardiac magnetic resonance may have a role in the evaluation of Chagas cardiomyopathy because it can offer a wide variety of imaging tools to evaluate in detail morphology, cardiac function, and other tissue characteristics, such as detection of edema and fat.110 Myocardial delayed enhancement by magnetic resonance imaging can also quantify myocardial fibrosis in patients with Chagas cardiomyopathy, thus helping define severity of the disease.111 Staging and prognosis Several classification systems were developed in Chagas cardiomyopathy to take into account the great clinical pleomorphism of this disease and to aid in its clinical management. The Kuschnir et al112 and Los Andes64 classification systems are frequently used in longitudinal studies.87,90,113,114 More recently, a Brazilian committee of experts proposed another staging system,45 based mainly on international heart failure guidelines (Table 2).115,116 The main virtue of this new classification system is that it is compatible with international standards and, in general terms, with therapeutic recommendations Table 2 Stages of Chagas cardiomyopathy, according to the Brazilian Expert Consensus in Chagas disease Stage ECG Echocardiogram Heart Failure A B1 Abnormal Abnormal Absent Absent B2 Abnormal C D Abnormal Abnormal Normal Abnormal LVEF N45% Abnormal LVEF b45% Abnormal Abnormal Abbreviation: LVEF, left ventricular ejection fraction. Absent Treatable Refractory A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 for each stage of heart failure. A comprehensive and comparative evaluation of all these classification systems has not been performed yet. It must be stressed that, in any given group of patients, regardless how strict the classification is, remarkable functional individual differences among the constituents of the same clinical group will be found. Chagas disease is a notable entity not only for its clinical variety, but also for the striking individual variability, making it essential that patients should be stratified and followed up carefully.48 There are several potential prognostic markers in Chagas disease, and this issue has been recently reviewed.54 As stated above, impaired left ventricular function by echocardiogram or ventriculography was found to be the most common and consistent independent predictor of death.59,61,69,74,87-90 New York Heart Association functional class III/IV, cardiomegaly on the chest radiography, and nonsustained ventricular tachycardia on 24-hour Holter monitoring or stress testing were also independently associated with higher mortality. Typical ECG69,74,90,117 and echocardiographic abnormalities59 may show additional prognostic value, although their practical use remains controversial.54 Electrophysiologic variables, obtained by invasive study105,106 or evaluated by ECG analysis, such as QT dispersion and duration,89 were shown to have additional prognostic value in selected studies. A potentially helpful simple risk score was developed to predict death in Chagas heart disease68; moreover, the score was successfully validated in independent cohorts.68,118 Six independent prognostic factors were identified, and each was assigned a number of points: New York Heart Association class III or IV (5 points), evidence of cardiomegaly on radiography (5 points), left ventricular systolic dysfunction on echocardiography (3 points), nonsustained ventricular tachycardia on 24-hour Holter monitoring or stress testing (3 points), low QRS voltage on electrocardiography (2 points), and male sex (2 points).68 Patients were classified in 3 risk groups according to the final score: low risk (0-6 points), intermediate risk (7-11 points), and high risk (12-20 points). In the original study, the 5-year mortality rates for these 3 groups were 2%, 18%, and 63%, respectively68 ; and in an external validation sample, rates were 3%, 10%, and 67%.118 More recently, an alternative approach was proposed,69,74 considering only 3 risk factors: left ventricular ejection fraction less than 50%, ventricular tachycardia at either stress testing or Holter monitoring, and QRS greater than 133 milliseconds at ECG (or filtered QRS N150 milliseconds at signal-averaged ECG).69,74 Low-risk group has 0 or 1 risk factor (5-year mortality, 1%); intermediate risk, 2 factors (20% mortality); and high risk, all 3 factors (50% mortality). This simplified prognostic score had an excellent performance in predicting death in a study with 74 months of follow-up (c statistic, 0.92), and it may be an attractive alternative to the established 6-factor score. 307 Treatment of Chagas cardiomyopathy The main focus of the management of Chagas cardiomyopathy relies on the treatment of the 3 main syndromes: heart failure, arrhythmias, and thromboembolism. There are, however, clinical features characteristically Chagas related that deserve special attention in regard to therapeutic approaches. At the present time, there is limited evidence-based clinical data to support specific antiparasitic therapy; but few data and an increasingly comprehensive understanding of physiopathologic aspects support the development of a muchawaited ongoing large clinical trial that will likely answer important questions. Specific antiparasitic therapy The benefits of antitrypanosomal therapy are clear in the acute phase of Chagas disease. However, in the chronic form of the disease, where the role of the parasite is less understood, it is controversial whether its eradication is beneficial.11 Nonetheless, pathogenic hypotheses supporting the rationale for a specific antiparasite therapy include vestiges of parasites identified by more sensitive techniques (PCR) in inflamed cardiac tissue in the chronic phase and evidence that antitrypanosomal therapy reduces the inflammatory burden in cardiac tissue at least experimentally.119-121 Two nitroheterocyclic drugs described in the 1960s and 1970s, nifurtimox and benznidazole, showed clear antiparasitic effects in the acute phase of Chagas disease, acting at both the circulating and tissular forms of the parasite.122,123 Currently, only benznidazole is commercially available for the treatment of the disease. Data from 2 trials with benznidazole in the early phase of the chronic form showed encouraging results, as negative seroconversion was achieved in 58% to 62% of the cases after 3 to 4 years of follow-up in children with Chagas disease.122,124 In addition, a small nonrandomized, nonblinded study showed slower progression to severe cardiomyopathy in adults receiving benznidazole.113 Finally, a systematic review of 5 clinical trials that have studied 756 patients suggests that the use of benznidazole can be beneficial to improve parasite-related outcomes in Chagas cardiomyopathy, such as negativation of xenodiagnosis and higher negative seroconversion rates.125 The efficacy and tolerance of benznidazole are inversely related to the age of the patients, with adverse effects occurring in 30% to 50% of adult patients, including dermatitis and, more rarely, polyneuritis and depression of the bone marrow.126,127 The absence of robust evidence to support the universal treatment of all Chagas disease patients with benznidazole brought the question of the specific treatment of Chagas disease to the 308 A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 global public health agenda, with a plea for developing and testing more efficacious and safer drugs, as well as the current available ones, in patients with indeterminate and chronic forms of the disease.128,129 These observations set the stage of the rationale for the Benznidazole Evaluation for Interrupting Trypanosomiasis trial (ClinicalTrials.gov identifier: NCT00123916), which is the largest effort to appropriately address the question of whether the use of benznidazole will in fact influence positively clinically relevant outcomes in Chagas cardiomyopathy. The study consists of an international Latin American collaborative initiative including 2 phases: a pilot study addressing safety and tolerability issues as well as the efficacy of benznidazole on the burden of parasiterelated outcomes and the full-scale program addressing clinical outcomes associated with the progression of Chagas disease in patients with established cardiac disease. The study plans to enroll 3,000 patients, with a follow-up of 5 years; and its primary outcome is a composite of death, resuscitated cardiac arrest, need of pacemaker or cardio defibrillator implantation, new onset of heart failure, thromboembolism, sustained ventricular tachycardia, and stroke.130 As of June 18, 2009, more than 1,600 patients have been enrolled.131 Treatment of cardiomyopathy (heart failure, arrhythmias, thromboembolism) Traditional therapeutic strategies for heart failure such as angiotensin-converting enzyme (ACE) inhibitors and βblockers are likely as important in Chagas cardiomyopathy as in other heart failure syndromes. However, there are very poor evidence-based strategies focusing on Chagas disease specifically. Small studies have pointed similar beneficial effects of ACE inhibitors in Chagas cardiomyopathy. In fact, both captopril and enalapril have been shown to improve functional class and left ventricular ejection fraction, and reduce catecholamine and cytokine levels when used in patients with chronic heart failure due to Chagas.132,133 Similarly, the use of β-blockers is encouraged in Chagas cardiomyopathy. However, its use is based on data from large clinical trials that included few or no patients with Chagas etiology. Nonetheless, there are specific data from studies dealing with Chagas disease that reinforce the importance of β-blockade in this setting. Davila and colleagues134 have shown that the use of metoprolol improved functional capacity, left ventricular function, and blood pressure in patients with heart failure secondary to Chagas disease. In a subsequent study, Botoni and colleagues135 demonstrated a trend toward an increase in left ventricular ejection fraction when carvedilol was added after using ACE inhibitors as a first drug, showing that the addition of carvedilol was safe, hemodynamically well tolerated, and not associated with symptomatic bradycardia. On the other hand, Braga and colleagues136 showed that in less that 40% of patients already on enalapril or captopril was it possible to proceed to full doses of metoprolol, limited mainly by postural hypotension and excessive bradycardia. In fact, it has been shown that patients with Chagas cardiomyopathy have a tendency to lower blood pressure levels when compared with nonChagas heart failure, possibly limiting the progression to full doses of ACE inhibitors as well.136,137 On the other hand, experimental studies indicate that metoprolol was able to reduce the ECG changes induced by the trypanosome, suggesting that β-blockers may have a role modulating the proarrhythmogenic status associated to Chagas cardiomyopathy.138 Putting all these pieces together, one should start patients first on β-blockers followed by ACE inhibitors to prioritize the highly proarrhythmogenic environment associated with Chagas physiopathology where blockade of the adrenergic system might be an attractive strategy to prevent sudden cardiac death.139,140 Similarly to ACE inhibitors, aldosterone blockade in Chagas cardiomyopathy has little specific evidence from clinical trials. However, one study has shown that it may be beneficial to add spironolactone to patients already using ACE inhibitors with heart failure secondary to Chagas disease, as decreased neurohumoral activation was seen.135 Hence, it is reasonable to use spironolactone for patients with Chagas once they fulfill clinical and laboratory criteria as considered for nonChagas patients. Digoxin Digoxin is an important drug used in heart failure to ameliorate symptoms and quality of life. In Chagas cardiomyopathy, it has also a number of salutary effects that make its use almost universal, unless adverse events occur or are anticipated. In fact, use of digoxin modulates sympathetic drive and rennin and aldosterone release as well as improves several hemodynamic parameters when administered acutely.141 On the other hand, because of the extensive myocardial tissue fibrosis/damage and consequent highly arrhythmogenic milieu seen in Chagas cardiomyopathy, use of digoxin should be strictly monitored to avoid potential toxicity related to disturbances in the conduction system.142 Thromboembolism Oral anticoagulation is controversial in Chagas disease. Patients with Chagas cardiomyopathy traditionally come from low socioeconomic and educational strata, configuring a challenging scenario to manage A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 anticoagulation protocols. Conversely, the presence of systolic dysfunction, increased left atrial volume, apical aneurysm, intracardiac thrombi, and cardiac arrhythmias are known predictors of stroke in patients with Chagas cardiomyopathy.77-79 Because specific studies about the efficacy and safety of anticoagulation in Chagas disease are not available, management has been traditionally adapted from international guidelines. More recently, a cardioembolic risk score for Chagas disease patients was developed and a risk-based strategy was proposed.143 The risk score was calculated adding 2 points for the presence of systolic dysfunction and 1 point for each of the other factors: apical aneurism, primary alteration of the ventricular repolarization at the ECG, and age more than 48 years. Based on the risk-benefit analysis, warfarin prophylaxis for cardioembolic stroke in Chagas disease was recommended for patients with a score of 4 to 5 points, in whom the risk of cardioembolism overweighs the risk of major bleeding. With a 3-point score, the risks of bleeding and cardioembolism are the same; hence, the medical decision of using either warfarin or aspirin has to be an individual one. With 2 points or less, anticoagulation is not warranted. Antiarrhythmic strategies Treatment of ventricular arrhythmia in Chagas cardiomyopathy is essentially empirical and not supported by large randomized controlled trials. This is to say that there are no properly designed prospective trials in larger groups of patients with Chagas disease to ascertain whether pharmacologic or device therapy for ventricular arrhythmias prevents sudden cardiac death. Thus, clinical management may be subject to large variations in different settings; and recommendations are mainly empirical. Patients with asymptomatic VPBs or few episodes of nonsustained ventricular tachycardia, without significant ventricular dysfunction, usually do not require any antiarrhythmic therapy.144 At the other side of the spectrum, those patients with sustained ventricular tachycardia and those resuscitated from sudden death may benefit from an ICD, especially in the presence of depressed left ventricular function.145 Patients with chronic Chagas heart disease who have recovered from cardiac arrest have a peculiar arrhythmogenic profile characterized by a high frequency of ventricular fibrillation and a short period for first shock.146 In patients with Chagas cardiomyopathy and ICDs, the number of shocks in the first 30 days is an independent predictor of mortality.147 The main uncertainties are observed in the management of patients with complex ventricular arrhythmias or 309 nonsustained ventricular tachycardia, in the presence of abnormal left ventricular function. In those with significant arrhythmic symptoms, such as syncope and near-syncope, the electrophysiologic study may help distinguish patients with malignant ventricular tachycardia,100,105 in whom a ICD should be implanted, from those with paroxysmal atrioventricular block, with better prognosis and candidates for a conventional pacemaker. Asymptomatic or oligosymptomatic patients represent a more complex challenge. Although indirect evidence had suggested that amiodarone could reduce the risk of death in this group, such as the subgroup analysis from the Argentinean Gesica trial,148 this benefit has never been proven. Moreover, primary prophylaxis of sudden death with the implantation of ICDs has not been evaluated in Chagas disease and may represent an unbearable financial burden for the health system of Latin America countries in which the disease is endemic. Treatment of symptomatic bradyarrhythmias does not differ from that recommended for other cardiomyopathies and is usually performed by permanent pacemaker insertion. Heart transplantation Chagas disease may account for important portions of the population referred for heart transplantation in areas where the disease is endemic. In certain parts of the world, it is the leading referring cause and in Brazil is the third indication for heart transplantation.149,150 A number of uncertainties surround the context of transplanting patients with Chagas cardiomyopathy, the important ones being when to refer for transplantation, fear of reactivation of the parasitic infestation, higher degrees of rejection, and occurrence of infections posttransplant. Indications of heart transplantation for Chagas cardiomyopathy Although there is high individual variability regarding prognosis in Chagas cardiomyopathy, it seems that Chagas disease is associated with poorer outcomes compared with other cardiomyopathies. In fact, Theodoropoulos and coworkers151 found that when 5 well-accepted risk criteria (lack of β-blocker use, hyponatremia, left ventricular ejection fraction b31%, New York Association class IV, and use of digoxin) are applied in Chagas, survival of less that 20% in 1 year was observed. Furthermore, the higher arrhythmogenic profile seen in Chagas highlights another characteristic that may add to a somber outcome in this population; in fact, patients using ICDs who had more than 4 shocks by day 30 after device implantation had a dismal survival of 21% in 2 months.147 Thus, one might consider that Chagas disease has equal or even poorer prognosis 310 A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 compared with non-Chagas heart failure and that heart transplantation might be considered even sooner. Outcome post–heart transplantation in Chagas disease is also matter of debate. However, the concerns appear to be mostly speculative, possibly reflecting the fear of the unknown about its physiopathology. Data from centers that have been transplanting these patients regularly and that therefore developed sound experience are encouraging.152 Early perioperative mortality appears to be no different in Chagas and non-Chagas recipients, according to data deriving from centers that have performed this procedure in both groups of patients. Late follow-up data from Chagas transplant recipients indicate that reactivation of T cruzi may occur in 27% to 90% of patients as detected by showing the mastigote in the blood or by immunohistochemistry in tissue samples; but it seldom has major clinical impact, under the contemporaneous immunosuppressive regimens used.153,154 Several mechanisms may account for reactivation of T cruzi infection, including use of mycophenolate mofetil, rejection episodes, and steroid pulse therapies. However, because treatment of T cruzi reactivation is easily accomplished using benznidazole and allopurinol, mortality observed with these rare episodes was as low as 0.7%.152 Other common concerns after heart transplant are no strangers to Chagas transplant recipients, as the magnitude of problems associated with rejection episodes, neoplasia, infection, and cardiac transplant vasculopathy appears to be no different in this population. The annual rate of grade A rejection episodes varies from 1.6 to 3.25,155,156 whereas the reported rates of rejection episodes are not consensual —in fact, when no steroid is used, de Carvalho and colleagues155 found less rejection in Chagas-transplanted patients compared with non-Chagas. Immunosuppressive regimens including steroids have shown similar or worse rates of rejection in Chagas transplant recipients.157,158 Finally, analyzing data from the percentage of patients free from rejection episodes, it seems that rates are similar in both Chagas and non-Chagas transplant recipients, which is supported by the fact that death because of rejection is similar in both patient populations.156 The incidence of neoplasia, a constant concern in long term follow-up of transplant recipients, appears to be no different in Chagas patients. The only report showing higher incidence of different tumors in these patients was later found to be associated with overimmunosuppresion.159 Thus, at the current status of immunosuppressive regimens, with lower levels of cyclosporine, the occurrence of neoplasia is similar across the spectrum of etiologies leading to cardiac transplant.155 Similarly to other transplant complications, infection episodes appear to be neither more frequent nor serious in Chagas transplant recipients. Both annual rate of infection episodes and percentage of patients free from infection episodes are similar in Chagas and nonChagas recipients. It was even reported that infection can be less frequent in Chagas patients. Moreover, approximately 30% of these patients will experience no infection episode in the first year posttransplant requiring antibiotic therapy.157 Cardiac vasculopathy, a universal late complication post–heart transplant, remains poorly studied concerning Chagas recipients exclusively. One report showed 1 in 10 cases who presented with obstructive coronary lesion that was successfully treated with percutaneous transluminal angioplasty.157 It remains to be explored whether measures different from the ones recommended to prevent this complication and that are used in nonChagas patients should be considered. At this point, use of pravastatin and strict control of traditional risk facts for atherosclerotic disease should be implemented in all patients post–heart transplant. Preventing disease Prevention in Chagas disease is 3-fold. Primary prevention aims to limit spread at the vectorial level, and blood transfusion and organ donation from infected donors. Secondary prevention aims to limit early and asymptomatic disease from progressing into fully developed syndrome. Tertiary prevention aims to limit, whenever possible, further organ damage and improve clinical outcome once the complete cardiomyopathy is established.160 Primary prevention This strategy consists of effective chemical control of vectors in endemic areas, stricter blood blank screening by means of modern serology, and screening of potential organ donors. These actions should be supported by housing and epidemiologic surveillance. Preventive actions should also involve monitoring contamination at the laboratory and dealing with unknown infected biological samples. These measures have been proven to reduce markedly the number of new cases, including via congenital route. Secondary prevention The strategies at this level consist of finding newly infected, young, yet asymptomatic cases and treating them with antiparasitic drugs aiming at avoiding established organ damage and disease spread among family members and via congenital route, as well limiting blood and organ donation from infected individuals. This will hopefully eradicate the parasite and interfere with the chain of disease.160 The challenge at this level is to appropriately diagnose acute Chagas A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 infection and institute therapy in a timely fashion. In most cases, it may be totally silent; in others, it resembles nonspecific viral infection syndrome with fever and malaise. Antiparasitic therapy at this stage may reduce significantly parasite burden and halt progression to full disease, which was proven in children but not in adults (“specific antiparasitic therapy”). Secondary prevention in Chagas disease should be regarded as a key element to contain the development of new cases in several different scenarios and also limits the potential for establishing a severely debilitating health condition. There are potentially many aspects that should be overcome to implement efficiently secondary prevention in Chagas disease; these include (1) difficult diagnosis at this stage (mostly silent cases); (2) misconceptions among physicians that antiparasitic treatment is not useful; (3) exaggerated and unjustified fear of adverse events with benznidazole or nifurtimox compounds; (4) lack of international guidelines on the subject; (5) limited access to benznidazole or nifurtimox (low production quantities); and (6) scarce interest from the industry to develop new, modern antitrypanosomal compounds.161 Tertiary prevention At this level, the remaining approach aims at improving quality of life and morbidity and mortality from the disease once the full spectrum of Chagas cardiomyopathy is already established. These include treating symptoms and typical clinical conditions associated with Chagas disease (“Treatment of cardiomyopathy”). Upcoming challenges Globalization has made Chagas disease a less geographically restricted health condition. In fact, growing migration involving rural to urban areas in Latin American countries and also to large metropolitan areas outside Latin America is slowly transforming the reality worldwide. It is worth noting that there has been an impressive increase in positive test results for T cruzi in screened blood bank across the United States in the last decade, which enhanced the level of awareness of health authorities, calling for stricter control of blood donors. Although voluntary, at the present time, between 75% and 90% of blood banks in the United States perform routine screening for T cruzi using the Food and Drug Administration–approved ELISA assay.162 It is imperative that a high level of screening is implemented targeting blood banks and organ transplantation protocols to avoid infected samples from spreading the disease. Moreover, although the number of new cases of Chagas disease has decreased in recent decades, continuous efforts in different scenarios from health authorities should be maintained to further reduce the 311 burden of Chagas worldwide and remove this condition from the so-called neglected disease group from public health initiatives. Future perspectives Although the number of new cases of Chagas disease has dropped markedly in the last few years because of effective control programs, there is a large population of individuals who will clearly benefit from adequate clinical management. For instance, it would be desirable to have a comprehensive knowledge about some neglected clinical manifestations such as embolic stroke and chest pain. The identification of early markers of worse prognosis would be also an important advance, helping identify a group of patients who would benefit the most from early and, perhaps, more aggressive intervention. More data are needed on epidemiology and specific clinical features of the disease in specific populations, such as in the elderly, as well as on the mechanisms involved in the progression from the indeterminate form to clinical syndromes. At the present time, treatment of Chagas cardiomyopathy is based on heart failure–related symptoms control. There are 2 main reasons for that: (1) there is little evidence that, other than in small children, antiparasitic drugs can change outcome; and (2) most diagnosis are made in advanced stages of the disease (when reversing damage is less likely) because for decades the Trypanosoma infection remains clinically silent. Nonetheless, as existent drugs such as benznidazole possess numerous adverse effects, efforts should be carried to develop new, modern compounds if an effective, well-tolerated, and beneficial therapy is to be reached. Furthermore, it is imperative that earlier diagnosis be made in potentially infected individuals to limit blood, congenital, and organ donation transmissions, especially outside well-known endemic areas. To this end, health authorities must be capable of dealing with migration from rural to urban areas in endemic regions; and nonendemic countries must set policies to prevent transmission efficaciously. In summary, more sensitive and accessible diagnostic and screening tests, better-tolerated drugs, and increased awareness regarding Chagas disease are necessary to better deal with a potential worldwide spread and to provide efficacious therapy in a timely manner to a great number of individuals. Statement of Conflict of Interest All authors declare that there are no conflicts of interest. 312 A. Biolo et al. / Progress in Cardiovascular Diseases 52 (2010) 300–316 References 1. Chagas C: Uber eine neue Trypanosomiasis des Menschen. Arch Schiffs Tropenhyg 1909;13:351-353. 2. 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