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BackgroundThe significance of detection of Trypanosoma cruzi DNA in blood of antibody-positive patients for risk of development of Chagas heart disease is not well established. The objective of this study was to compare detection of T. cruzi DNA with known clinical and laboratory markers of Chagas cardiomyopathy (CC) severity.MethodsThis is a case-control study nested within a retrospective cohort developed in Brazil to understand the natural history of Chagas disease. The study enrolled 499 T. cruzi seropositive blood donors (SP-BD) and 488 frequency matched seronegative control donors (SN-BD) who had donated between 1996 and 2002, and 101 patients with clinically diagnosed CC. In 2008-2010 all enrolled subjects underwent a health questionnaire, medical examination, electrocardiograms and echocardiograms and polymerase chain reaction (PCR) analyses. A blinded panel of three cardiologists adjudicated the outcome of CC. Trypanosoma cruzi kinetoplast minicircle sequences were amplified by real-time PCR using an assay with a sensitivity of one parasite per 20 mL of blood. All testing was performed on coded samples.ResultsRates of PCR detection of T. cruzi DNA were significantly (P = 0.003) higher in CC patients and SP-BD diagnosed with CC (79/105 [75.2 %]) compared with SP-BD without CC (143/279 [51.3%]). The presence of parasitaemia was significantly associated with known markers of disease progression such as QRS and QT interval duration, lower left ventricular ejection fraction, higher left ventricular index mass, and elevated troponin and NTpro-BNP levels.ConclusionTrypanosoma cruzi PCR positivity is associated with presence and severity of cardiomyopathy, suggesting a direct role of parasite persistence in disease pathogenesis.

Purpose: To evaluate myocardial T1 mapping and extracellular volume (ECV) parameters in different stages of Chagas cardiomyopathy and determine whether they are predictive of disease severity and prognosis., Materials and Methods: Prospectively enrolled participants (July 2013 to September 2016) underwent cine and late gadolinium enhancement (LGE) cardiac MRI and T1 mapping with a precontrast (native) or postcontrast modified Look-Locker sequence. The native T1 and ECV values were measured among subgroups that were based on disease severity (indeterminate, Chagas cardiomyopathy with preserved ejection fraction [CCpEF], Chagas cardiomyopathy with midrange ejection fraction [CCmrEF], and Chagas cardiomyopathy with reduced ejection fraction [CCrEF]). Cox proportional hazards regression and the Akaike information criterion were used to determine predictors of major cardiovascular events (cardioverter defibrillator implant, heart transplant, or death)., Results: In 107 participants (90 participants with Chagas disease [mean age ± SD, 55 years ± 11; 49 men] and 17 age- and sex-matched control participants), the left ventricular (LV) ejection fraction and the extent of focal and diffuse or interstitial fibrosis were correlated with disease severity. Participants with CCmrEF and participants with CCrEF showed significantly higher global native T1 and ECV values than participants in the indeterminate, CCpEF, and control groups (T1: 1072 msec ± 34 and 1073 msec ± 63 vs 1010 msec ± 41, 1005 msec ± 69, and 999 msec ± 46; ECV: 35.5% ± 3.6 and 35.0% ± 5.4 vs 25.3% ± 3.5, 28.2% ± 4.9, and 25.2% ± 2.2; both P < .001). Remote (LGE-negative areas) native T1 and ECV values were also higher (T1: 1056 msec ± 32 and 1071 msec ± 55 vs 1008 msec ± 41, 989 msec ± 96, and 999 msec ± 46; ECV: 30.2% ± 4.7 and 30.8% ± 7.4 vs 25.1% ± 3.5, 25.1% ± 3.7, and 25.0% ± 2.2; both P < .001). Abnormal remote ECV values (>30%) occurred in 12% of participants in the indeterminate group, which increased with disease severity. Nineteen combined outcomes were observed (median follow-up time: 43 months), and a remote native T1 value greater than 1100 msec was independently predictive of combined outcomes (hazard ratio, 12 [95% CI: 4.1, 34.2]; P < .001)., Conclusion: Myocardial native T1 and ECV values were correlated with Chagas disease severity and may serve as markers of myocardial involvement in Chagas cardiomyopathy that precede LGE and LV dysfunction. Keywords: MRI, Cardiac, Heart, Imaging Sequences, Chagas Cardiomyopathy Supplemental material is available for this article. © RSNA, 2023., Competing Interests: Disclosures of conflicts of interest: R.J.L.M. No relevant relationships. A.N.A. No relevant relationships. T.C.M. No relevant relationships. C.H.N. No relevant relationships. M.I.S. No relevant relationships. M.M.F. No relevant relationships. F.J.A.R. No relevant relationships. F.F. No relevant relationships. B.M.I. No relevant relationships. C.M. No relevant relationships. C.E.R. Secretary-treasurer and board member of the Society for Cardiovascular Magnetic Resonance., (© 2023 by the Radiological Society of North America, Inc.)

Background: Heart failure (HF) is one of the leading causes of death worldwide. Studies show that women have better survival rates than men despite higher hospitalizations. However, little is known about differences in mortality and predictors of death in women and men with HF with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF)., Methods: From February 2017 to September 2020, mortality and predictors of death were analyzed in women and men with HF. Baseline data included clinical characteristics and echocardiographic findings., Results: A total of 11,282 patients, 63.9 ± 14.4 years, including 6256 (55.4%) males, were studied. Females were older, had a higher baseline mean left ventricular ejection fraction (LVEF) and lower left ventricular diastolic diameter. During follow-ups, 1375 (22%) men and 925 (18.4%) women died. Cumulative incidence of death was higher in men with HFrEF but similar for HFmrEF and HFpEF. Cox regression for death showed renal dysfunction, stroke, diabetes, atrial fibrillation, age, LVEF, valve disease, MI, and hypertensive CMP as independent death predictors for all HF patients., Conclusions: Women had a better prognosis than men in HFrEF and similar mortality for HFmrEF and HFpEF, but sex was not an independent predictor of death for all HF subtypes.

Chagas disease, caused by the protozoan Trypanosoma cruzi , is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brochet, Ianni, Laugier, Frade, Silva Nunes, Teixeira, Mady, Ferreira, Ferré, Santos, Kuramoto, Cabantous, Steffen, Stolf, Pomerantzeff, Fiorelli, Bocchi, Pissetti, Saba, Cândido, Dias, Sampaio, Gaiotto, Marin-Neto, Fragata, Zaniratto, Siqueira, Peixoto, Rigaud, Bacal, Buck, Almeida, Lin-Wang, Schmidt, Martinelli, Hirata, Donadi, Costa Pereira, Rodrigues Junior, Puthier, Kalil, Spinelli, Cunha-Neto and Chevillard.)

Background: Chagas disease is characterized by intense myocardial fibrosis stimulated by the exacerbated production of inflammatory cytokines, oxidative stress, and apoptosis. Air pollution is a serious public health problem and also follows this same path. Therefore, air pollution might amplify the inflammatory response of Chagas disease and increase myocardial fibrosis., Methods: We studied groups of Trypanosoma cruzi infected Sirius hamsters (Chagas=CH and Chagas exposed to pollution=CH+P) and 2 control groups (control healthy animals=CT and control exposed to pollution=CT+P). We evaluated acute phase (60 days post infection) and chronic phase (10 months). Echocardiograms were performed to assess left ventricular systolic and diastolic diameter, in addition to ejection fraction. Interstitial collagen was measured by morphometry in picrosirius red staining tissue. The evaluation of inflammation was performed by gene and protein expression of cytokines IL10, IFN-γ, and TNF; oxidative stress was quantified by gene expression of NOX1, MnSOD, and iNOS and by analysis of reactive oxygen species; and apoptosis was performed by gene expression of BCL2 and Capsase3, in addition to TUNEL analysis., Results: Chagas groups had increased collagen deposition mainly in the acute phase, but air pollution did not increase this deposition. Also, Chagas groups had lower ejection fraction in the acute phase (p = 0.002) and again air pollution did not worsen ventricular function or dilation. The analysis of the inflammation and oxidative stress pathways were also not amplified by air pollution. Apoptosis analysis showed increased expression of BCL2 and Caspase3 genes in chagasic groups in the acute phase, with a marginal p of 0.054 in BCL2 expression among infected groups, and TUNEL technique showed amplified of apoptotic cells by pollution among infected groups., Conclusions: A possible modulation of the apoptotic pathway was observed, inferring interference from air pollution in this pathway. However, it was not enough to promote a greater collagen deposition, or worsening ventricular function or dilation caused by air pollution in this model of Chagas cardiomyopathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fonseca, Pessoa, Ribeiro, Hotta, Ianni, Fernandes, Ferreira Rivero, Saldiva, Mady and Ramires.)

Extracellular vesicles (EVs) are lipid bilayer envelopes that encase several types of molecules. Their contents mostly reflect their cell origin and possible targets at other locations in the organism and can be modified in pathological conditions to interfere with intercellular communication, thus promoting disease establishment and development. These characteristics, in addition to their presence in virtually all body fluids, make such vesicles ideal for biomarker discovery in human diseases. Here, we describe the effect of different anticoagulants and the combination of two purification methods for isolation and characterization of circulating EVs from blood of chronic Chagas disease (CCD) patients. We illustrated this procedure by studying a population of patients with Chagas disease at the indeterminate chronic stage, in which the Trypanosoma cruzi is very scarce in circulation. EVs were harvested from blood collected without or with different anticoagulants. Protein and nanoparticle tracking analysis was used to measure EVs size and concentration. The EVs were purified by ultracentrifugation, followed by size-exclusion chromatography and characterized by chemiluminescent enzyme-linked immunosorbent assay and dot blot using antibodies that recognized parasite-derived EVs, such as hyperimmune sera, polyclonal and monoclonal antibodies against trans-sialidase and mucins. In parallel, antibodies against classical human EV markers CD9, CD63, CD81, and CD82, were also analyzed. The results showed that anticoagulants did not interfere with the analyzed parameters and circulating EVs from CCD patients contain T. cruzi antigens and classical human exosomal markers. Overall, our protocol is adequate for the isolation of the total circulating EVs and can serve as an important basis for further studies on biomarker discovery in Chagas' disease., (© 2022 International Federation for Cell Biology.)

Purpose: Patients with chronic chagasic cardiomyopathy with preserved ventricular function present with autonomic imbalance. This study evaluated the effects of exercise training (ET) in restoring peripheral and cardiac autonomic control and skeletal muscle phenotype in patients with subclinical chronic chagasic cardiomyopathy., Methods: This controlled trial (NCT02295215) included 24 chronic chagasic cardiomyopathy patients who were randomized www.random.org/lists/ into two groups: those who underwent exercise training (n = 12) and those who continued their usual activities (n = 12). Eight patients completed the exercise training protocol, and 10 patients were clinically followed up for 4 months. Muscular sympathetic nerve activity was measured by microneurography and muscle blood flow (MBF) using venous occlusion plethysmography. The low-frequency component of heart rate variability in normalized units (LFnuHR) reflects sympathetic activity in the heart, and the low-frequency component of systolic blood pressure variability in normalized units reflects sympathetic activity in the vessels. The infusion of vasoactive drugs (phenylephrine and sodium nitroprusside) was used to evaluate cardiac baroreflex sensitivity, and a vastus lateralis muscle biopsy was performed to evaluate atrogin-1 and MuRF-1 gene expression., Results: The baroreflex sensitivity for increases (p = 0.002) and decreases (p = 0.02) in systolic blood pressure increased in the ET group. Muscle blood flow also increased only in the ET group (p = 0.004). Only the ET group had reduced resting muscular sympathetic nerve activity levels (p = 0.008) and sympathetic activity in the heart (LFnu; p = 0.004) and vessels (p = 0.04) after 4 months. Regarding skeletal muscle, after 4 months, participants in the exercise training group presented with lower atrogin-1 gene expression than participants who continued their activities as usual (p = 0.001). The reduction in muscular sympathetic nerve activity was positively associated with reduced atrogin-1 (r = 0.86; p = 0.02) and MuRF-1 gene expression (r = 0.64; p = 0.06); it was negatively associated with improved baroreflex sensitivity both for increases (r = -0.72; p = 0.020) and decreases (r = -0.82; p = 0.001) in blood pressure., Conclusions: ET improved cardiac and peripheral autonomic function in patients with subclinical chagasic cardiomyopathy. ET reduced MSNA and sympathetic activity in the heart and vessels and increased cardiac parasympathetic tone and baroreflex sensitivity. Regarding peripheral muscle, after 4 months, patients who underwent exercise training had an increased cross-sectional area of type I fibers and oxidative metabolism of muscle fibers, and decreased atrogin-1 gene expression, compared to participants who continued their activities as usual. In addition, the reduction in MSNA was associated with improved cardiac baroreflex sensitivity, reduced sympathetic cardiovascular tone, and reduced atrogin-1 and MuRF-1 gene expression., Trial Registration: ID: NCT02295215. Registered in June 2013.

Background: The histopathological characteristics of Chagas disease (ChD) are: presence of myocarditis, destruction of heart fibers, and myocardial fibrosis. Galectin-3 (Gal-3) is a biomarker involved in the mechanism of fibrosis and inflammation that may be useful for risk stratification of individuals with ChD., Objectives: We sought to evaluate whether high Gal-3 levels are associated with severe forms of Chagas cardiomyopathy (CC) and whether they are predictive of mortality., Methods: We studied anti-T. cruzi positive blood donors (BD): Non-CC-BD (187 BD without CC with normal electrocardiogram [ECG] and left ventricular ejection fraction [LVEF]); CC-Non-Dys-BD (46 BD with CC with abnormal ECG but normal LVEF); and 153 matched serum-negative controls. This cohort was composed of 97 patients with severe CC (CC-Dys). We used Kruskall-Wallis and Spearman's correlation to test hypothesis of associations, assuming a two-tailed p<0.05 as significant., Results: The Gal-3 level was 12.3 ng/mL for Non-CC-BD, 12.0 ng/mL for CC-Non-Dys-BD, 13.8 ng/mL for controls, and 15.4 ng/mL for CC-Dys. LVEF<50 was associated with higher Gal-3 levels (p=0.0001). In our linear regression adjusted model, we found association between Gal-3 levels and echocardiogram parameters in T. cruzi-seropositive subjects. In CC-Dys patients, we found a significant association of higher Gal-3 levels (≥15.3 ng/mL) and subsequent death or heart transplantation in a 5-year follow-up (Hazard ratio - HR 3.11; 95%CI 1.21-8.04; p=0.019)., Conclusions: In ChD patients, higher Gal-3 levels were significantly associated with severe forms of the disease and more long-term mortality, which means it may be a useful means to identify high-risk patients. (Arq Bras Cardiol. 2021; 116(2):248-256).

Chagas disease, a neglected tropical disease (NTD) caused by the flagellated protozoan Trypanosoma cruzi ( T. cruzi ), is a major public health problem. It was initially restricted to Latin America, but it is now expanding globally. Host and pathogen interactions are crucial in the establishment of disease, and since 1970, it has been known that eukaryotic cells release extracellular vesicles (EVs), which in turn have an important role in intercellular communication in physiological and pathological conditions. Our study proposed to characterize and compare circulating EVs isolated from the plasma of chronic Chagas disease (CCD) patients and controls. For this, peripheral blood was collected from patients and controls, and mononuclear cells (PBMCs) were isolated and stimulated with parasite EVs, showing that patient cells released fewer EVs than control cells. Then, after plasma separation followed by EV total shedding enrichment, the samples were subjected to ultracentrifugation to isolate the circulating EVs, which then had their size and concentration characterized by nanoparticle tracking analysis (NTA). This showed that patients had a lower concentration of circulating EVs while there were no differences in size, corroborating the in vitro data. Additionally, circulating EVs were incubated with THP-1 cells (macrophages) that, after the interaction, had their supernatant analyzed by ELISA for cytokine detection. In relation to their ability to induce cytokine production, the CCD patient EVs were able to induce a differential production of IFN- γ and IL-17 in relation to controls, with differences being more evident in earlier/less severe stages of the disease. In summary, a decreased concentration of circulating EVs associated with differential activation of the immunological system in patients with CCD is related to parasite persistence and the establishment of chronic disease. It is also a potential biomarker for monitoring disease progression., Competing Interests: No potential conflict of interest was reported by the authors., (Copyright © 2021 Rafael Pedro Madeira et al.)

Background: Chagas disease, caused by the protozoan Trypanosoma cruzi , is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is the most important clinical consequence of T. cruzi infection, while the others remain asymptomatic (ASY). IFN-γ and IFN-γ-producing Th1-type T cells are increased in peripheral blood and CCC myocardium as compared to ASY patients, while the Th1-antagonizing cytokine IL-10 is more expressed in ASY patients. Importantly IFN-γ-producing Th1-type T cells are the most frequent cytokine-producing T cell subset in CCC myocardium, while expression of Th1-antagonizing cytokines IL-10 and IL-4 is unaltered. The control of IFN-γ production by Th1-type T cells may be a key event for progression toward CCC. A genetic component to disease progression was suggested by the familial aggregation of cases and the association of gene polymorphisms with CCC development. We here investigate the role of gene polymorphisms (SNPs) in several genes involved in the control of IFN-γ production and Th1 T cell differentiation in CCC development. Methods: We studied a Brazilian population including 315 CCC cases and 118 ASY subjects. We assessed 35 Tag SNPs designed to represent all the genetic information contained in the IL12B, IL10, IFNG , and IL4 genes. Results: We found 2 IL12 SNPs (rs2546893, rs919766) and a trend of association for a IL10 SNP (rs3024496) to be significantly associated with the ASY group. these associations were confirmed by multivariate analysis and allele tests. The rs919766C, 12rs2546893G, and rs3024496C alleles were associated to an increase risk to CCC development. Conclusions: Our data show that novel polymorphisms affecting IL12B and IL10 , but not IFNG or IL4 genes play a role in genetic susceptibility to CCC development. This might indicate that the increased Th1 differentiation and IFN-γ production associated with CCC is genetically controlled., (Copyright © 2020 Frade-Barros, Ianni, Cabantous, Pissetti, Saba, Lin-Wang, Buck, Marin-Neto, Schmidt, Dias, Hirata, Sampaio, Fragata, Pereira, Donadi, Rodrigues, Kalil, Chevillard and Cunha-Neto.)

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.

Background: Myocardial fibrosis (MF) according to cardiac magnetic resonance (CMR) is a frequent finding in Chagas cardiomyopathy and has been associated with risk factors of poor outcome., Objectives: The goal of this study was to determine the prognostic value of MF in predicting combined hard events or all-cause mortality., Methods: Patients with Chagas cardiomyopathy who had a previous CMR evaluation were included, and clinical follow-up was retrospectively obtained. The primary outcome was a combination of all-cause mortality, heart transplantation, antitachycardia pacing or appropriate shock from an implantable cardioverter-defibrillator, and aborted sudden cardiac death; the secondary outcome was all-cause mortality., Results: A total of 130 patients were included; mean age was 53.6 ± 11.5 years, and 53.9% were female. The majority of patients reported no symptoms of heart failure or arrhythmia, but electrocardiographic and echocardiographic abnormalities were common. On CMR, left ventricular dilatation and dysfunction were frequent, and MF was found in 76.1%, with a mean mass of 15.2 ± 16.5 g. Over a median follow-up of 5.05 years, 58 (44.6%) patients reached the combined endpoint, and 45 (34.6%) patients died. MF was associated with the primary outcome as a continuous variable (adjusted hazard ratio: 1.031; 95% CI: 1.013 to 1.049; p = 0.001) and as a categorical variable (MF ≥12.3 g) (adjusted hazard ratio: 2.107; 95% CI: 1.111 to 3.994; p = 0.022), independently from the Rassi risk score. MF expressed as a continuous variable was also associated with all-cause mortality (adjusted hazard ratio: 1.028; 95% CI: 1.005 to 1.051; p = 0.017) independently from the Rassi risk score., Conclusions: MF is an independent predictor of adverse outcome in Chagas cardiomyopathy. Our data may support the use of CMR in better risk-stratifying this population and possibly guiding therapy., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Archaeal genes present in Trypanosoma cruzi may represent symbionts that would explain development of heart failure in 30% of Chagas disease patients. Extracellular vesicles in peripheral blood, called exosomes (< 0.1 μm) or microvesicles (>0.1 μm), present in larger numbers in heart failure, were analyzed to determine whether they are derived from archaea in heart failure Chagas disease. Methods: Exosomes and microvesicles in serum supernatant from 3 groups were analyzed: heart failure Chagas disease ( N = 26), asymptomatic indeterminate form ( N = 21) and healthy non-chagasic control ( N = 16). Samples were quantified with transmission electron microscopy, flow cytometer immunolabeled with anti-archaemetzincin-1 antibody (AMZ 1, archaea collagenase) and probe anti-archaeal DNA and zymography to determine AMZ1 (Archaeal metalloproteinase) activity. Results: Indeterminate form patients had higher median numbers of exosomes/case vs. heart failure patients (58.5 vs. 25.5, P < 0.001), higher exosome content of AMZ1 antigens (2.0 vs. 0.0; P < 0.001), and lower archaeal DNA content (0.2 vs. 1.5, P = 0.02). A positive correlation between exosomes and AMZ1 content was seen in indeterminate form ( r = 0.5, P < 0.001), but not in heart failure patients (r = 0.002, P = 0.98). Higher free archaeal DNA (63.0 vs. 11.1, P < 0.001) in correlation with exosome numbers ( r = 0.66, P = 0.01) was seen in heart failure but not in indeterminate form ( r = 0.29, P = 0.10). Flow cytometer showed higher numbers of AMZ1 microvesicles in indeterminate form (64 vs. 36, P = 0.02) and higher archaeal DNA microvesicles in heart failure (8.1 vs. 0.9, P < 0.001). Zymography showed strong% collagenase activity in HF group, mild activity in IF compared to non-chagasic healthy group (121 ± 14, 106 ± 13 and 100; P < 0.001). Conclusions: Numerous exosomes, possibly removing and degrading abnormal AMZ1 collagenase, are associated with indeterminate form. Archaeal microvesicles and their exosomes, possibly associated with release of archaeal AMZ1 in heart failure, are future candidates of heart failure biomarkers if confirmed in larger series, and the therapeutic focus in the treatment of Chagas disease.

Background: Since a male-related higher cardiovascular morbidity and mortality in patients with Chagas' heart disease has been reported, we aimed to investigate gender differences in myocardial damage assessed by cardiovascular magnetic resonance (CMR)., Methods and Results: Retrospectively, 62 seropositive Chagas' heart disease patients referred to CMR (1.5 T) and with low probability of having significant coronary artery disease were included in this analysis. Amongst both sexes, there was a strong negative correlation between LV ejection fraction and myocardial fibrosis (male r = 0.64, female r = 0.73, both P < 0.001), with males showing significantly greater myocardial fibrosis (P = 0.002) and lower LV ejection fraction (P < 0.001) than females. After adjustment for potential confounders, gender remained associated with myocardial dysfunction, and 53% of the effect was mediated by myocardial fibrosis (P for mediation = 0.004). Also, the transmural pattern was more prevalent among male patients (23.7 vs. 9.9%, P < 0.001) as well as the myocardial heterogeneity or gray zone (2.2 vs. 1.3 g, P = 0.003)., Conclusions: We observed gender-related differences in myocardial damage assessed by CMR in patients with Chagas' heart disease. As myocardial fibrosis and myocardial dysfunction are associated to cardiovascular outcomes, our findings might help to understand the poorer prognosis observed in males in Chagas' disease.

Background: Chagas' heart disease is an important public health problem in South America. Several aspects of the pathogenesis are not fully understood, especially in its subclinical phases. On pathology Chagas' heart disease is characterized by chronic myocardial inflammation and extensive myocardial fibrosis. The latter has also been demonstrated by late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR). In three clinical phases of this disease, we sought to investigate the presence of LGE, myocardial increase in signal intensity in T2-weighted images (T2W) and in T1-weighted myocardial early gadolinium enhancement (MEGE), previously described CMR surrogates for myocardial fibrosis, myocardial edema and hyperemia, respectively., Methods: Fifty-four patients were analyzed. Sixteen patients with the indeterminate phase (IND), seventeen patients with the cardiac phase with no left ventricular systolic dysfunction (CPND), and twenty-one patients with the cardiac phase with left ventricular systolic dysfunction (CPD). All patients underwent 1.5 T CMR scan including LGE, T2W and MEGE image sequences to evaluate myocardial abnormalities., Results: Late gadolinium enhancement was present in 72.2 % of all patients, in 12.5 % of IND, 94.1 % of the CPND and 100 % of the CPD patients (p < 0.0001). Myocardial increase in signal intensity in T2-weighted images (T2W) was present in 77.8 % of all patients, in 31.3 % of the IND, 94.1 % of the CPND and 100 % of the CPD patients (p < 0.0001). T1-weighted myocardial early gadolinium enhancement (MEGE) was present in 73.8 % of all patients, in 25.0 % of the IND, 92.3 % of the CPND and 94.1 % of the CPD (p < 0.0001). A good correlation between LGE and T2W was observed (r = 0.72, and p < 0.001)., Conclusions: Increase in T2-weighted (T2W) myocardial signal intensity and T1-weighted myocardial early gadolinium enhancement (MEGE) can be detected by CMR in patients throughout all phases of Chagas' heart disease, including its subclinical presentation (IND). Moreover, those findings were parallel to myocardial fibrosis (LGE) in extent and location and also correlated with the degree of Chagas' heart disease clinical severity. These findings contribute to further the knowledge on pathophysiology of Chagas' heart disease, and might have therapeutic and prognostic usefulness in the future.

Background: Chagas disease (CD) induces autonomic dysfunction and inflammatory activity, which may promote metabolic abnormalities. We studied metabolism and his correlation with Autonomic Nervous System (ANS) and inflammation in CD., Methods and Results: Sixty subjects were divided into 4 groups: control group (CG), IF (indeterminate form) group; ECG group (ECG abnormalities and normal left ventricular systolic function), and LVD group (left ventricular sistolic dysfunction). Levels of adiponectin, leptin, insulin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were assayed in serum samples by ELISA. ANS was assessed by heart rate variability in frequency domain in 24-hour Holter and postural tilt test (rest and orthostatic position). High frequency (HFr) component values were used to estimate parasympathetic activity and low frequency (LFr) component, sympathetic activity. Analyzes were made of the correlations of each of the metabolic parameters (leptin and adiponectin) with the inflammatory cytokines (interleukin-6 and TNF- alpha) and with the ANS assessment measurements. No significant differences were observed in leptin and insulin levels. Adiponectin was higher in ECG and LVD groups: [CG = 4766.5 (5529.5), IF = 4003.5 (2482.5), ECG = 8376.5 (8388.5), LVD = 8798 (4188.0) ng/mL, p<0.001)]. IL-6 and TNF-alpha were higher in LVD group: [IL-6: CG = 1.85 (6.41); IF = 1.58 (1.91); ECG = 1.0 (1.57); LVD= 31.44 (72.19) pg/ml; p = 0.001. TNF-alpha: CG = 22.57 (88.2); IF = 19.31 (33.16); ECG = 12.45 (3.07); LVD = 75.15 (278.57) pg/ml; p = 0.04]. Adiponectin levels had a positive association with the HFr component (r = 0.539; p = 0.038) and an inverse association with the LFr component (r = - 0.539; p = 0.038) in ECG group. Leptin levels had a negative association with the HFr component (r= - 0.632; p = 0.011) and a positive association with the LFr component (r = 0.632; p = 0.011) in LVD group., Conclusions: We found increased adiponectin levels in Chagas' heart disease with systolic dysfunction and in patients with ECG abnormalities and normal systolic function at rest. Adipocytokines levels (adiponectin and leptin) were associated with ANS parameters in Chagas' heart disease.

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.

Background: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the rest of the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described. IL-18 could potentially amplify the process by inducing increased expression of IFN-γ which in turn can increase the production of IL-18, thereby creating a positive feedback mechanism. In order to assess the contribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the association between a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developing Chagas cardiomyopathy., Methods and Results: We analyzed the rs2043055 marker in the IL18 gene in a cohort of Chagas disease cardiomyopathy patients (n=849) and asymptomatic subjects (n=202). We found a significant difference in genotype frequencies among moderate and severe CCC patients with ventricular dysfunction., Conclusions: Our analysis suggests that the IL18 rs2043055 polymorphism- or a SNP in tight linkage disequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)