Interleukin‐10 and tumour necrosis factor‐alpha serum levels in chronic Chagas disease patients

In Chagas disease, chronically infected individuals may be asymptomatic or may present cardiac or digestive complications, and it is well known that the human immune response is related to different clinical manifestations. Different patterns of cytokine levels have been previously described in different clinical forms of this disease, but contradictory results are reported. Our aim was to evaluate the serum levels of interleukin‐10 and tumour necrosis factor‐alpha in patients with asymptomatic and cardiac Chagas disease. The serum interleukin‐10 levels in patients with cardiomyopathy were higher than those in asymptomatic patients, mainly in those without heart enlargement. Although no significant difference was observed in serum tumour necrosis factor‐alpha levels among the patients, we found that cardiac patients also present high levels of this cytokine, largely those with heart dilatation. Therefore, these cytokines play an important role in chronic Chagas disease cardiomyopathy. Follow‐up investigations of these and other cytokines in patients with chronic Chagas disease need to be conducted to improve the understanding of the immunopathology of this disease.     

A Latin American Registry of Implantable Cardioverter Defibrillators: The ICD‐LABOR Study

Objective: Despite the progress that has been reached in emergency medical systems and resuscitation, sudden cardiac death (SCD) continues to be the major cause of the death, and remains a significant public health problem. In this publication we are reporting our Latin American experience in the secondary prevention of SCD, by means of an ongoing registry involving seven Latin American countries and 770 patients. Methods: Every individual within the present registry to date has presented with antecedents of aborted sudden death or cardiac arrest due to ventricular tachycardia or ventricular fibrillation. Patients included have fulfilled the Class I indication for implantable cardioverter defibrillator (ICD) and they were implanted with a Biotronik ICD (all models). The study was not sponsored by Biotronik, nor did they have access to the data. A specific protocol was designed for implantation and follow‐up of patients. The database was completely registered through the Internet and a personal password was assigned to each group of investigators. The primary end point was death from all causes. Secondary end points were SCD and death due to congestive heart failure (CHF). Results: The etiology of cardiac disease was found to be predominantly coronary artery disease (CAD) 39.7% (306 patients), followed by Chagas disease (ChD), 26.1% (201 patients), and idiopathic dilated cardiomyopathy (DCM), 17% (131 patients). Any remaining pathologies were included as miscellaneous 13.2% (101 patients). In 31 patients (4%) the etiology was unknown. The age did not differ within the principal pathologies, but was significantly older than the miscellaneous group (62.0 ± 11.3 years vs 48.2 ± 18.9 years, P < 0.0001). The follow‐up period was 27 ± 25 months (1–113 months) for the whole group. The mortality in functional classes I–II was significantly lower than mortality for functional classes III–IV (relative risk 1.46, CI 95%, P < 0.0001). Mean left ventricular ejection fraction (LVEF) for the whole group was 37.7 ± 14.3%. Male LVEF was 36.1 ± 14.1% and female LVEF was 42.2 ± 13.8% P < 0.0001. During the follow‐up period, 130 deaths were reported (global mortality 16.9 ± 9.7%), out of which 84 (64.6%) were attributed to cardiac causes (10.9 ± 5.1% of the total population). The annual adjusted cardiac mortality was 5.2 ± 1.72% (range 3.5–7.0%). Among cardiac deaths the most common cause was progressive heart failure, 48 patients (57%) including 3 patients with pulmonary embolism. The second main cause of cardiac death was SCD, 36 patients (43%), including 4 patients with electrical storm and 3 patients with electromechanical dissociation after multiple shock therapy treatments. Conclusions: Despite the differences in terms of pathologies between the ICD‐LABOR (Latin American bioelectronic ongoing registry) and randomized ICD trials, a parallel evolution in all cause mortality and cardiac mortality was observed. Independent risk factors for mortality included age >70 years, male gender, NYHA III/IV, and ejection fraction <0.30. The etiology of heart disease (Chagas vs Coronary Disease) was not found to be a risk factor.     

Benznidazole treatment reduces the induction of indoleamine 2,3‐dioxygenase (IDO) enzymatic activity in Chagas disease symptomatic patients

The enzyme indoleamine 2,3‐dioxigenase (IDO) is critical for the regulation of immune responses in pro‐tolerogenic antigen‐presenting cell. To address the profile of immune responses associated with Chagas disease, we measured IDO activity of peripheral blood mononuclear cells from 168 chronic patients and 13 healthy donors. We found that IDO activity was increased in patients with Chagas disease when compared with controls. Moreover, the IDO activity of patients with Chagas disease in the symptomatic chronic phase, involving cardiac or digestive alterations, was higher than that detected in asymptomatic patients and correlated with the severity of the symptoms. Furthermore, benznidazole treatment induced a long‐lasting decrease in IDO activity in symptomatic patients, reaching levels comparable with those of healthy donors. These results suggest that a pro‐tolerogenic state is associated with the severity of Chagas disease and that benznidazole treatment is a valuable tool for breaking the parasite‐driven immune tolerance in the symptomatic chronic phase of Chagas disease.     

Primer choque apropiado del desfibrilador automático implantable en pacientes con cardiopatía chagásica

Objetives:

To assess if patients with Chagasic heart disease (CHD) received effective automatic implantable defibrillator (AID) shocks earlier than patients with ischemic heart disease (IHD).

Methods:

Retrospective cohort of patients with CHD and IHD who received an implantable cardioverter defibrillator (ICD) between 2009 and 2018, in a tertiary hospital. We evaluated the time between the implant of ICD and the first effective shock in patients with CHD and compared it with the IHD control population.

Results:

We included a total of 64 patients, 20 with CHD and 44 with IHD. CHD patients presented earlier an effective shock than patients with IHD during the first year (hazard ratio [HR]: 8.4; 95% confidence interval [95% CI]: 2.09-34.02; p = 0.0027), and at three years (HR: 4.61; 95% CI: 1.51-14.07; p = 0.0072). 100% of CHD patients who received the ICD as secondary prevention of sudden cardiac death presented an effective shock during the first 26 months of follow-up.

Conclusions:

Patients with CHD received effective ICD shocks earlier than the IHD patients. All patients with CHD and ICD as secondary prevention had an appropriate ICD shock at short term, representing the highest risk population, and supporting the indication of the device in a setting where randomized clinical trials are lacking.     

Cardiac damage induced by immunization with heat‐killed Trypanosoma cruzi is not antibody mediated

Cardiac inflammation that develops during infection with Trypanosoma cruzi may result in part from autoimmunity, which may occur after bystander activation, after parasite‐induced cardiomyocyte damage, or molecular mimicry. A/J mice infected with T. cruzi or immunized with heat‐killed T. cruzi (HKTC) develop strong autoimmunity accompanied by cardiac damage. To determine whether this cardiac damage occurs via an antibody‐dependent mechanism, we analysed T. cruzi‐infected and HKTC‐immunized mice for the presence of autoantibodies, cardiac antibody deposition, and serum cardiac troponin I as a measure of cardiac damage. We also performed a serum transfer experiment in which sera from T. cruzi‐infected and T. cruzi‐immunized mice (and controls) were transferred into naïve recipients, which were then analysed for the presence of antibodies and serum troponin. Unlike T. cruzi‐infected mice, T. cruzi‐immunized mice did not show significant antibody deposition in the myocardium. These results indicate that antibody deposition does not precede cardiac damage and inflammation in mice immunized with or infected with T. cruzi. Serum adoptive transfer did not induce cardiac damage in any recipients. Based on these findings, we conclude that the cardiac damage induced by immunization with HKTC is not mediated by antibodies.     

Echocardiographic Parameters and Survival in Chagas Heart Disease with Severe Systolic Dysfunction

Background

Echocardiography provides important information on the cardiac evaluation of patients with heart failure. The identification of echocardiographic parameters in severe Chagas heart disease would help implement treatment and assess prognosis.

Objective

To correlate echocardiographic parameters with the endpoint cardiovascular mortality in patients with ejection fraction < 35%.

Methods

Study with retrospective analysis of pre-specified echocardiographic parameters prospectively collected from 60 patients included in the Multicenter Randomized Trial of Cell Therapy in Patients with Heart Diseases (Estudo Multicêntrico Randomizado de Terapia Celular em Cardiopatias) - Chagas heart disease arm. The following parameters were collected: left ventricular systolic and diastolic diameters and volumes; ejection fraction; left atrial diameter; left atrial volume; indexed left atrial volume; systolic pulmonary artery pressure; integral of the aortic flow velocity; myocardial performance index; rate of increase of left ventricular pressure; isovolumic relaxation time; E, A, Em, Am and Sm wave velocities; E wave deceleration time; E/A and E/Em ratios; and mitral regurgitation.

Results

In the mean 24.18-month follow-up, 27 patients died. The mean ejection fraction was 26.6 ± 5.34%. In the multivariate analysis, the parameters ejection fraction (HR = 1.114; p = 0.3704), indexed left atrial volume (HR = 1.033; p < 0.0001) and E/Em ratio (HR = 0.95; p = 0.1261) were excluded. The indexed left atrial volume was an independent predictor in relation to the endpoint, and values > 70.71 mL/m² were associated with a significant increase in mortality (log rank p < 0.0001).

Conclusion

The indexed left atrial volume was the only independent predictor of mortality in this population of Chagasic patients with severe systolic dysfunction.     

Assessment of Galectin-3 Polymorphism in Subjects with Chronic Chagas Disease

Background

Galectin-3, a β-galactoside binding lectin, has been described as a mediator of cardiac fibrosis in experimental studies and as a risk factor associated with cardiovascular events in subjects with heart failure. Previous studies have evaluated the genetic susceptibility to Chagas disease in humans, including the polymorphisms of cytokine genes, demonstrating correlations between the genetic polymorphism and cardiomyopathy development in the chronic phase. However, the relationship between the galectin-3 single nucleotide polymorphism (SNP) and phenotypic variations in Chagas disease has not been evaluated.

Objective

The present study aimed to determine whether genetic polymorphisms of galectin-3 may predispose to the development of cardiac forms of Chagas disease.

Methods

Fifty-five subjects with Chagas disease were enrolled in this observational study. Real-time polymerase chain reaction (PCR) was used for genotyping the variants rs4644 and rs4652 of the galectin-3 gene.

Results

For the SNP rs4644, the relative risk for the cardiac form was not associated with the genotypes AA (OR = 0.79, p = 0.759), AC (OR = 4.38, p = 0.058), or CC (OR = 0.39, p = 0.127). Similarly, for the SNP rs4652, no association was found between the genotypes AA (OR = 0.64, p = 0.571), AC (OR = 2.85, p = 0.105), or CC (OR = 0.49, p = 0.227) and the cardiac form of the disease.

Conclusion

Our results showed no association between the different genotypes for both SNPs of the galectin-3 gene and the cardiac form of Chagas disease.     

Left Atrial Function in Patients with Chronic Chagasic Cardiomyopathy

Background

Chagas disease is a cause of dilated cardiomyopathy, and information about left atrial (LA) function in this disease still lacks.

Objective

To assess the different LA functions (reservoir, conduit and pump functions) and their correlation with the echocardiographic parameters of left ventricular (LV) systolic and diastolic functions.

Methods

10 control subjects (CG), and patients with Chagas disease as follows: 26 with the indeterminate form (GI); 30 with ECG alterations (GII); and 19 with LV dysfunction (GIII). All patients underwent M-mode and two-dimensional echocardiography, pulsed-wave Doppler and tissue Doppler imaging.

Results

Reservoir function (Total Emptying Fraction: TEF): (p <0.0001), lower in GIII as compared to CG (p = 0.003), GI (p <0.001) and GII (p <0.001). Conduit function (Passive Emptying Fraction: PEF): (p = 0.004), lower in GIII (GIII and CG, p = 0.06; GI and GII, p = 0.06; and GII and GIII, p = 0.07). Pump function (Active Emptying Fraction: AEF): (p = 0.0001), lower in GIII as compared to CG (p = 0.05), GI (p<0.0001) and GII (p = 0.002). There was a negative correlation of E/e’_average with the reservoir and pump functions (TEF and AEF), and a positive correlation of e’_average with s’ wave (both septal and lateral walls) and the reservoir, conduit and pump LA functions.

Conclusion

An impairment of LA functions in Chagas cardiomyopathy was observed.     

PREVALENCE OF CHAGAS DISEASE AMONG BLOOD DONOR CANDIDATES IN TRIANGULO MINEIRO,MINAS GERAIS STATE,BRAZIL

Despite public health campaigns and epidemiological surveillance activities, Chagas disease remains a major health problem in Latin America. According to data from the World Health Organization, there are approximately 7-8 million people infected with Trypanosoma cruzi worldwide, a large percentage of which in Latin America. This study aims to examine the serological profile of blood donors in blood banks of Hemominas hematology center, in the town of Ituiutaba, Minas Gerais State, Brazil. The study sample consisted of 53,941 blood donors, which were grouped according to gender and age. Sample collections were performed from January 1991 to December 2011, and 277 donors (0.5%) were considered serologically ineligible due to Chagas disease. Analysis of data showed no significant difference between genders. As for age, the highest proportion of ineligible donors was from 40 to 49 years (30%), and there was a positive correlation between increasing age and the percentage of patients seropositive for Chagas disease. Therefore, adopting strategies that allow the safe identification of donors with positive serology for Chagas disease is essential to reduce or eliminate indeterminate serological results.     

ECG Manifestations of the Biggest Outbreak of Chagas Disease due to Oral Infection in Latin-America

Background

Chagas disease affects more than 15 million people worldwide. Although vector-borne transmission has decreased, oral transmission has become important. Recently, our group published the clinical and epidemiological characteristics of the largest outbreak of orally transmitted Chagas disease reported till date. Objective: To describe electrocardiographic changes occurring in the study population during the outbreak caused by ingestion of contaminated guava juice.

Methods

We evaluated 103 positive cases, of which 76 (74%) were aged ≤ 18 years (average age: 9.1 ± 3.1 years) and 27 (26%) were aged > 18 years (average age: 46 ± 11.8 years). All patients underwent clinical evaluations and ECG. If the patients had palpitations or evident alterations of rhythm at baseline, ambulatory ECG monitoring was performed.

Results

A total of 68 cases (66%; 53 children and 15 adults) had ECG abnormalities. Further, 69.7% (53/76) of those aged ≤ 18 years and 56% (15/27) of those aged >18 years showed some ECG alteration (p = ns). ST-T abnormalities were observed in 37.86% cases (39/103) and arrhythmias were evident in 28.16% cases (29/103). ST alterations occurred in 72% of those aged ≤18 years compared with 19% of th ose aged >18 years (p < 0.0001).

Conclusion

This study reports the largest number of cases in the same outbreak of acute Chagas disease caused by oral contamination, with recorded ECGs. ECG changes suggestive of acute myocarditis and arrhythmias were the most frequent abnormalities found.     

Effects of Exercise Training on Heart Rate Variability in Chagas Heart Disease

Background:

Heart rate variability (HRV) is a marker of autonomic dysfunction severity. The effects of physical training on HRV indexes in Chagas heart disease (CHD) are not well established.

Objective:

To evaluate the changes in HRV indexes in response to physical training in CHD.

Methods:

Patients with CHD and left ventricular (LV) dysfunction, physically inactive, were randomized either to the intervention (IG, N = 18) or control group (CG, N = 19). The IG participated in a 12-week exercise program consisting of 3 sessions/week.

Results:

Mean age was 49.5 ± 8 years, 59% males, mean LVEF was 36.3 ± 7.8%. Baseline HRV indexes were similar between groups. From baseline to follow-up, total power (TP): 1653 (IQ 625 - 3418) to 2794 (1617 - 4452) ms, p = 0.02) and very low frequency power: 586 (290 - 1565) to 815 (610 - 1425) ms, p = 0.047) increased in the IG, but not in the CG. The delta (post - pre) HRV indexes were similar: SDNN 11.5 ± 30.0 vs. 3.7 ± 25.1 ms. p = 0.10; rMSSD 2 (6 - 17) vs. 1 (21 - 9) ms. p = 0.43; TP 943 (731 - 3130) vs. 1780 (921 - 2743) Hz. p = 0.46; low frequency power (LFP) 1.0 (150 - 197) vs. 60 (111 - 146) Hz. p = 0.85; except for high frequency power, which tended to increase in the IG: 42 (133 - 92) vs. 79 (61 - 328) Hz. p = 0.08).

Conclusion:

In the studied population, the variation of HRV indexes was similar between the active and inactive groups. Clinical improvement with physical activity seems to be independent from autonomic dysfunction markers in CHD.