Prognosis of chronic Chagas heart disease and other pending clinical challenges.

In this chapter, the main prognostic markers of Chagas heart disease are addressed, with an emphasis on the most recent findings and questions, establishing the basis for a broad discussion of recommendations and new approaches to managing Chagas cardiopathy. The main biological and genetic markers and the contribution of the electrocardiogram, echocardiogram and cardiac magnetic resonance are presented. We also discuss the most recent therapeutic proposals for heart failure, thromboembolism and arrhythmias, as well as current experience in heart transplantation in patients suffering from severe Chagas cardiomyopathy. The clinical and epidemiological challenges introduced by acute Chagas disease due to oral contamination are discussed. In addition, we highlight the importance of ageing and comorbidities in influencing the outcome of chronic Chagas heart disease. Finally, we discuss the importance of public policies, the vital role of funding agencies, universities, the scientific community and health professionals, and the application of new technologies in finding solutions for better management of Chagas heart disease.

Sequential measurement of Trypanosoma cruzi parasitic load in endomyocardial biopsies for early detection and follow-up of Chagas disease reactivation after heart transplantation.

BACKGROUND: Reactivation of Chagas disease after heart transplantation is characterized by proliferation and dissemination of Trypanosoma cruzi parasites to several organs. Reactivation affecting the allograft can simulate acute cellular rejection, from which it should be distinguished through the analysis of endomyocardial biopsies (EMB). METHODS: We evaluated retrospectively 100 EMB collected in the first year of follow-up from 13 heart-transplanted, chagasic patients who presented reactivation and were successfully treated. Additionally, 37 EMB from 8 patients who did not present reactivation constituted the control group. We reviewed histopathology and performed a real-time PCR-based assay in order to evaluate the T cruzi parasitic load of each EMB. RESULTS: The parasitic load of the EMB at the time of reactivation ranged from 22.80 to 190 000/106 cells (median: 1555). In 6 patients, none of the EMB obtained prior to reactivation amplified T cruzi DNA. On the other hand, 10 EMB from 7 patients, obtained 9-105 days before reactivation (median: 26 days), showed parasitic load ranging from 8.25 to 625/106 cells (median: 167.55). In all patients, the parasitic load increased at the time of reactivation, usually sharply. After initiation of treatment, all patients showed negative PCR or a dramatic reduction of the parasitic load in the following EMB. None of the EMB from the control group amplified T cruzi DNA. CONCLUSIONS: Sequential measurement of T cruzi parasitic load in EMB is useful for monitoring Chagas disease reactivation after heart transplantation. Its increase suggests imminent reactivation and its decrease after treatment indicates favorable evolution for cure of the episode of reactivation.

Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association.

BACKGROUND: Chagas disease, resulting from the protozoan Trypanosoma cruzi, is an important cause of heart failure, stroke, arrhythmia, and sudden death. Traditionally regarded as a tropical disease found only in Central America and South America, Chagas disease now affects at least 300 000 residents of the United States and is growing in prevalence in other traditionally nonendemic areas. Healthcare providers and health systems outside of Latin America need to be equipped to recognize, diagnose, and treat Chagas disease and to prevent further disease transmission. METHODS AND RESULTS: The American Heart Association and the Inter-American Society of Cardiology commissioned this statement to increase global awareness among providers who may encounter patients with Chagas disease outside of traditionally endemic environments. In this document, we summarize the most updated information on diagnosis, screening, and treatment of T cruzi infection, focusing primarily on its cardiovascular aspects. This document also provides quick reference tables, highlighting salient considerations for a patient with suspected or confirmed Chagas disease. CONCLUSIONS: This statement provides a broad summary of current knowledge and practice in the diagnosis and management of Chagas cardiomyopathy. It is our intent that this document will serve to increase the recognition of Chagas cardiomyopathy in low-prevalence areas and to improve care for patients with Chagas heart disease around the world.

Ventricular arrhythmias in the Chagas disease are not random phenomena: Long-term monitoring in Chagas arrhythmias.

BACKGROUND: Variability of ventricular arrhythmias among days in patients with Chagas disease is not detected by 24 hours of Holter monitoring. OBJECTIVE: To analyze whether ventricular arrhythmias are a random phenomenon or have a reproducible behavior in patients with Chagas cardiomyopathy. METHOD: Holter monitoring was recorded in 16 subjects with a mean age of 52 ± 8 years. They were clinically stable and had ventricular couplets, isolated premature ventricular contractions (PVCs), and nonsustained ventricular tachycardia (NSVT). The recordings occurred for 7 days. Hurst exponent (HE) evaluated randomness and predictability index (PI) and repeated analysis of variance (ANOVA) assessed reproducibility. RESULTS: The HE was significantly greater than 0.5 in all 16 patients, which confirms the nonrandomness of arrhythmias in this Chagas sample. The PI for ventricular couplets and isolated PVCs was, on average, 38% and 54%, respectively. ANOVA with repeated measurement showed significant differences in the daily frequency of ventricular couplets (n = 15, P ≤ .05), isolated PVC (n = 12, P ≤ .05), and NSVT (n = 7, P ≤ .05). CONCLUSION: Ventricular arrhythmias in Chagas cardiomyopathy are not random. Dissimilarities in arrhythmias frequency make unlikely that 24 hours of Holter recording can capture this variability.

Chagas disease is associated with a worse prognosis at 1-year follow-up after implantable cardioverter-defibrillator for secondary prevention in heart failure patients.

INTRODUCTION: There are conflicting data regarding the efficacy of implantable cardioverter-defibrillator (ICD) in Chagas disease (CD) patients. This study aims to evaluate the short-term outcome after ICD for secondary prevention, in a population where CD is a prevalent cause of heart failure (HF). METHODS AND RESULTS: Consecutive patients with HF and reduced left ventricular ejection fraction (LVEF), who underwent ICD implantation for secondary prevention of SCD. Clinical and demographic data were collected to investigate mortality predictors at 1 year. During the study period, 117 patients underwent ICD implantation, of which 108 were included. The most frequent causes of HF was CD: 52 (48.1%) and ischemic cardiomyopathy: 20 (18.5%). Chagas and non-Chagas patients were well balanced-male: 32 (61.5%) vs 38 (67.9%), P = .548; age: 59.2 (±10.9) vs 56.8 (±13.4), P = .681; and LVEF: 34.1 (±0.2) vs 31.3 (±8.7), P = .064, respectively. At the mean follow-up of 15.7 months, overall mortality occurred in 14 (12.9%) patients, with a higher incidence in patients with CD cardiomyopathy, 11 (21.2%) vs 3 (5.4%), P = .021 (log-rank). In the multivariate analysis, CD remained as an independent predictor for death (hazard ratio: 4.62, confidence interval [95% CI]: 1.27-16.81, P = .021). CONCLUSION: CD was associated with a poor short-term outcome in patients with HF submitted to ICD implantation for secondary prevention when compared with other HF etiologies. In this specific HF population, ICD indication should be individualized, considering the worst prognosis of these patients.

In situ hybridization assay for the diagnosis of chagas myocarditis and orchitis in a rhesus macaque (Macaca mulatta): A case report.

We present the first documented case of Trypanosoma cruzi-induced orchitis in a rhesus macaque. Additionally, we describe an in situ hybridization-based assay to confirm T. cruzi infection in formalin-fixed tissues.

Dysregulation of insulin levels in Chagas heart disease is associated with altered adipocytokine levels.

Metabolic, inflammatory, and autonomic nervous system (ANS) dysfunction are present in patients with heart failure. However, whether these changes are due to left ventricular dysfunction or heart failure etiology is unknown. We evaluated metabolism and inflammatory activity in patients with idiopathic dilated cardiomyopathy (IDC) and Chagas cardiomyopathy (CHG) and their correlation with the ANS. Forty-six patients were divided into 3 groups: IDC, CHG, and control. We evaluated adiponectin, leptin, insulin, interleukin-6, and tumor necrosis factor-alpha. ANS were analyzed by heart rate variability in time and frequency domains on a 24-hour Holter monitor. Levels of glucose, cholesterol, leptin, and adiponectin did not show differences between groups. Insulin levels were lower in CHG group (5.4 ± 3.3 µU/mL) when compared with control (8.0 ± 4.9 µU/mL) and IDC (9.9 ± 5.0 µU/mL) groups (p = 0.007). Insulin was positively associated with LFr/HFr ratio (r = 0.562; p = 0.029) and with the LFr component (r = 0.562; p = 0.029) and negatively associated with adiponectin (r = -0.603; p = 0.017) in CHG group. The addition of an adiponectin unit reduced average insulin by 0.332 µg/mL. Insulin levels were decreased in the CHG group when compared with the IDC group and were associated with ANS indexes and adiponectin levels.

Severity of Chagasic Cardiomyopathy Is Associated With Response to a Novel Rapid Diagnostic Test for Trypanosoma cruzi TcII/V/VI.

Background: Trypanosoma cruzi causes Chagas disease in the Americas. The outcome of infection ranges from lifelong asymptomatic status to severe disease. Relationship between T. cruzi lineage (TcI-TcVI) infection history and prognosis is not understood. We previously described peptide-based lineage-specific enzyme-linked immunosorbent assay (ELISA) with trypomastigote small surface antigen (TSSA). Methods: A novel rapid diagnostic test (RDT; Chagas Sero K-SeT) that incorporates a peptide that corresponds to the TSSA II/V/VI common epitope was developed and validated by comparison with ELISA. Patients from Bolivia and Peru, including individuals with varying cardiac pathology, and matched mothers and neonates, were then tested using Chagas Sero K-SeT. Results: Chagas Sero K-SeT and ELISA results, with a Bolivian subset of cardiac patients, mothers, and neonates, were in accord. In adult chronic infections (n = 121), comparison of severity class A (no evidence of Chagas cardiomyopathy) with class B (electrocardiogram suggestive of Chagas cardiomyopathy) and class C/D (decreased left ventricular ejection fraction; moderate/severe Chagas cardiomyopathy) revealed a statistically significant increase in Chagas Sero K-SeT reactivity with increasing severity (χ2 for trend, 7.39; P = .007). In Peru, Chagas Sero K-SeT detected the sporadic TcII/V/VI infections. Conclusions: We developed a low cost RDT that can replace ELISA for identification of TSSA II/V/VI immunoglobulin G. Most importantly, we show that response to this RDT is associated with severity of Chagas cardiomyopathy and thus may have prognostic value. Repeated challenge with T. cruzi infection may both exacerbate disease progression and boost the immune response to the TSSApep-II/V/VI epitope.

A cohort study of cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy.

Aims: Cardiac resynchronization therapy (CRT) is an established procedure for patients with heart failure. However, trials evaluating its efficacy did not include patients with chronic Chagas cardiomyopathy (CCC). We aimed to assess the role of CRT in a cohort of patients with CCC. Methods and results: This retrospective study compared the outcomes of CCC patients who underwent CRT with those of dilated (DCM) and ischaemic cardiomyopathies (ICM). The primary endpoint was all-cause mortality and the secondary endpoints were the rate of non-advanced New York Heart Association (NYHA) class 12 months after CRT and echocardiographic changes evaluated at least 6 months after CRT. There were 115 patients in the CCC group, 177 with DCM, and 134 with ICM. The annual mortality rates were 25.4%, 10.4%, and 11.3%, respectively (P < 0.001). Multivariate analysis adjusted for potential confounders showed that the CCC group had a two-fold [hazard ratio 2.34 (1.47-3.71), P < 0.001] higher risk of death compared to the DCM group. The rate of non-advanced NYHA class 12 months after CRT was significantly higher in non-CCC groups than in the CCC group (DCM 74.0% vs. ICM 73.9% vs. 56.5%, P < 0.001). Chronic Chagas cardiomyopathy and ICM patients had no improvement in the echocardiographic evaluation, but patients in the DCM group had an increase in left ventricular ejection fraction and a decrease in left ventricular end-diastolic diameter. Conclusion: This study showed that CCC patients submitted to CRT have worse prognosis compared to patients with DCM and ICM who undergo CRT. Studies comparing CCC patients with and without CRT are warranted.

Diagnosis and Management of Chagas Cardiomyopathy in the United States.

PURPOSE OF REVIEW: Chagas cardiomyopathy is an emerging form of non-ischemic cardiomyopathy in the USA. This review aims to summarize current concepts in pathophysiology, disease transmission, medical therapy, and heart transplantation for patients with chronic Chagas cardiomyopathy. RECENT FINDINGS: The incidence of Chagas cardiomyopathy is increasing in the USA, driven mainly by immigration from countries where Chagas disease is endemic. Chagas cardiomyopathy is a chronic, progressive myocarditis, with hallmark features of biventricular dysfunction, ventricular arrhythmias, thromboembolic complications, and a high risk of mortality. Currently, there is no effective treatment for chronic Chagas cardiomyopathy. Heart transplantation is the only treatment for patients with end-stage Chagas cardiomyopathy, but is associated with unique challenges including risk of reactivation. As the prevalence of Chagas cardiomyopathy increases in the USA, practitioners must be aware of the unique challenges in diagnosis and management that Chagas cardiomyopathy presents.

Cardiac surgery for Chagas disease.

Although Chagas disease is a rare entity in North America, it is associated with significant cardiac morbidity. It is estimated that 20-30% of those who are infected will eventually develop cardiovascular disease secondary to Chagas disease. We review the literature and share our experience on the surgical management of this challenging patient population.

Etiological Classification of Stroke in Patients with Chagas Disease Using TOAST, Causative Classification System TOAST, and ASCOD Phenotyping.

BACKGROUND: Cardioembolism is considered a major pathophysiological mechanism in patients with ischemic stroke (IS) and Chagas disease (CD). However, a previous study reported that other stroke subtypes are present in more than 40% of CD patients according to the TOAST classification. Therefore, the aim of our study was to evaluate the etiologic classification of stroke in patients with CD using the Causative Classification System (CCS), the ASCOD, and the TOAST classifications in a prospective cohort of patients. METHODS: Patients evaluated in our outpatient clinic from 2012 to 2015 with IS and CD were included and underwent full investigation for stroke etiology. TOAST, CCS TOAST, and the ASCOD classifications were compared. FINDINGS: We Included 32 patients (18 men; mean age 62.7 +/-10.1 years). A total of 93.8% had at least 1 vascular risk factor; the most frequent was hypertension (87.5%). According to TOAST, we defined 87.5% as having cardioembolic stroke, being 9.4% as large-artery atherosclerotic (LAA) and 3.1% as undetermined cause. Using the CCS TOAST, 62.5% were classified as cardioaortic embolism evident and 15.6% as possible, 6.3% as small artery occlusion evident and 3.1% as probable, and 12.5% as LAA evident. When ASCOD phenotyping was applied, atherosclerosis was present in 50.1% of patients (A1 = 6.3%, A3 = 43.8%), cardiac pathology in 84.4% (C1 = 62.5%, C2 = 15.6%, C3 = 6.3%), and small-vessel disease in 66% (S1 = 9.4%, S2 = 3.1%, S3 = 3.1%). FINDINGS: In conclusion, the use of the CCS and the ASCOD phenotyping in patients with CD confirmed a high frequency of cardioembolic IS but also showed that other etiologies are prevalent, such as large-artery atherosclerosis and small-vessel occlusion.

[Chagasic Cardiopathy in a child: Case report]. / Cardiopatía Chagásica en un escolar: Reporte de caso.

Chagas disease also known as American Trypanosomiasis is mainly caused by haematophagous insects widely distributed from Mexico to Argentina. According to the Panamerican Health Organization, 7.7 to 10 million people are living with chronic infection. Chagas disease is caused by Trypanosoma cruzi, a protozoan transmitted by triatomine vectors. After an initial acute phase, Chagas is followed by a silent phase that lasts 15-20 years before debuting with cardiac, neurological or gastrointestinal manifestations. OBJECTIVE: To analyze the atypical clinical course of chagasic cardiopathy in a pediatric patient from southern Mexico. CASE REPORT: The patient was treated by a chagoma in his left leg. Five months later an electrocardiogram showed evidence of sinus tachycardia and left atrium distension with P wave enlargement and prolonged QT interval. The thorax radiography showed cardiomegaly (Cardio-thoracic index = 0.52); the trans-thoracic echocardiogram showed left atrial and ventricular dilation. CONCLUSION: It is important to develop early cardiac evaluations even in pediatric patients with Chagas disease, it should not be assumed that the patients will undergo a long asymptomatic phase or that they will not develop an early cardiopathy.

A 12-mer repetitive antigenic epitope from Trypanosoma cruzi is a potential marker of therapeutic efficacy in chronic Chagas' disease.

OBJECTIVES: The objective was to characterize a Trypanosoma cruzi repetitive amino acid sequence that can be used as a marker of therapeutic drug efficacy in patients with chronic Chagas' disease. METHODS: Reactivities to the 3973 peptide were measured in 85 patients with Chagas' disease (41 in the asymptomatic stage and 44 in the cardiomyopathy stage) before and 9 and 24 months after benznidazole administration. Additionally, the levels of IL-6 and C-reactive protein were measured in serum samples from patients with cardiomyopathy. RESULTS: In 85% of the asymptomatic patients and 73% of the symptomatic chronic patients, modifications of the reactivity to the 3973 peptide were observed at 9 and 24 months post-benznidazole treatment. Significant variations in reactivities to the total antigens of T. cruzi were not observed at these times. Significant decreases in the reactivity to the 3973 peptide were observed after treatment in 20 of 41 (49%) asymptomatic patients and 15 of 44 (34%) cardiac chagasic patients (P < 0.001). In these patients, the decreases in reactivity at 24 months post-treatment were at least 40% lower than those detected before treatment. No correlations were found of the detected modifications in reactivity to the 3973 peptide after treatment with the levels of C-reactive protein or IL-6. CONCLUSIONS: Decreases in reactivity to the 3973 peptide may be relevant in the post-treatment follow-up of chronic chagasic patients.

The Prevalence of Atrial Fibrillation and Conduction Abnormalities in Chagas' Disease: A Meta-Analysis.

BACKGROUND/OBJECTIVES: Chagas' disease (CD) has been associated with atrial fibrillation (AF) and electrocardiographic (ECG) conduction defects. However, prior studies have shown conflicting results. We performed a meta-analysis comparing the prevalence of AF and conduction abnormalities between CD and non-CD patients. METHODS: PubMed, EMBASE, Cochrane Central, and Latin American databases were searched for studies that directly compared the prevalence of AF and conduction defects in CD and non-CD patients. Odds ratios (OR) were computed using random-effects model due to anticipated heterogeneity. We further performed subanalyses limited to studies that included only patients with cardiomyopathy. RESULTS: A total of 17,238 patients from 30 studies were included, of whom 6,840 (40%) had a positive serology for CD. In the pooled data, AF was significantly more prevalent in the CD group (OR 1.62; 95%CI 1.21-2.15; P = 0.001). However, no significant difference was observed between groups when the analysis included only patients with cardiomyopathy (OR 1.21; 95%CI 0.97-1.50; P = 0.08) or heart failure (OR 1.09; 95%CI 0.81-1.47; P = 0.55). The combination of right bundle branch block (RBBB) and left anterior fascicular block (LAFB) had the highest OR for increased prevalence in patients with Chagas' cardiomyopathy compared to non-CD etiologies (OR 5.31; 95%CI 1.23-22.86; P = 0.03). CONCLUSIONS: Our meta-analysis suggests that the prevalence of AF in patients with Chagas' cardiomyopathy is not significantly different from non-CD cardiomyopathies. The pattern of RBBB and LAFB in patients with cardiomyopathy of unknown etiology and epidemiologic risk factors should raise the possibility of CD and prompt specific diagnostic testing.

Comprehensive left ventricular mechanics analysis by speckle tracking echocardiography in Chagas disease.

BACKGROUND: Chagas disease (CD) is a frequent cause of dilated cardiomyopathy (CMP) in developing countries, leading to clinical heart failure and worse prognosis. Therefore, the development and evolution of this CMP has always been a major topic in numbers of previous studies. A comprehensive echocardiographic study of left ventricular (LV) mechanics, fully assessing myocardial contraction, has never been done before. This could help characterize and improve the understanding of the evolution of this prevalent CMP. METHODS: A total of 47 chagasic and 84 control patients were included in this study and allocated in groups according to LV ejection fraction. 2D-Echocardiogram was acquired for LV mechanics analysis by speckle tracking echocardiography. RESULTS: Mean age of chagasic individuals was 55y and 16 (34 %) were men. Significant difference was found in global longitudinal velocity analysis, with lower values in indeterminate form. In the group with severe systolic dysfunction, a paradoxical increase in longitudinal and apical radial displacements were demonstrated. In parallel, segmental analyzes highlighted lower values of radial displacement, strain and strain rate into inferior and inferolateral walls, with increase of these values in septal and anterior walls. CONCLUSION: Chagasic CMP has a vicarious pattern of contraction in the course of its evolution, defined by reduced displacement and strain into inferior and posterior walls with paradoxical increase in septal and anterior segments. Also, lower longitudinal velocities were demonstrated in CD indeterminate form, which may indicate an incipient myocardial injury.

Chagas cardiomyopathy is associated with higher incidence of stroke: a meta-analysis of observational studies.

BACKGROUND: Chagas disease (CD) has been associated with an elevated risk of stroke, but current data are conflicting and prospective controlled studies are lacking. We performed a systematic review and meta-analysis examining the association between stroke and CD. METHODS: Pubmed, Embase, Cochrane Central, Latin American database, and unpublished data were searched with the use of the following terms: ("Chagas" OR "American trypanosomiasis") AND ("dilated" OR "ischemic" OR "idiopathic" OR "nonChagasic" OR "stroke" OR "cerebrovascular"). We included studies that reported prevalence or incidence of stroke in a CD group compared with a non-CD control group. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed with the use of a random-effects model. RESULTS: A total of 8 studies and 4,158 patients were included, of whom 1,528 (36.7%) had CD. Risk of stroke was elevated in the group of patients with CD (OR 2.10, 95% CI 1.17-3.78). Similar results were observed in a subanalysis of cardiomyopathy patients (OR 1.74, 95% CI 1.02-3.00) and in sensitivity analysis with removal of each individual study. Furthermore, exclusion of studies at higher risk for bias also yielded consistent results (OR 1.70, 95% CI 1.06-2.71). Subanalysis restricted to studies that included patients with the indeterminate form found no significant difference in the stroke prevalence between CD and non-CD patients (OR 3.10, 95% CI 0.89-10.77). CONCLUSIONS: CD is significantly associated with cerebrovascular events, particularly among patients with cardiomyopathy. These findings underline the need for prospective controlled studies in patients with Chagas cardiomyopathy to ascertain the prognostic significance of cerebrovascular events and to evaluate the role of therapeutic anticoagulation in primary prevention.