Severe Chagas Research Articles

TNF blockers alone and associated with Benznidazole impact in vitro cytokine dynamics in chronic Chagas disease.

Studies involving the immune response in Chagas disease suggest an imbalance in the immune response of symptomatic patients, with an inflammatory profile dominating in Chagas heart disease, mainly by tumour necrosis factor (TNF). TNF is considered a key cytokine in immunopathology in chronic carriers in several processes during the immune response. Our work aimed to evaluate regulatory (interleukin [IL]-4 and IL-10) and inflammatory (TNF, interferon-gamma [IFN-γ], IL-2 and IL-6) cytokines in peripheral blood mononuclear cells culture supernatants. of affected patients with undetermined clinical forms-IND (n = 13) mild heart form-CARD1 (n = 13) and severe cardiac form-CARD2 (n = 16), treated in vitro with two TNF blockers, Adalimumab (ADA) and Etanercept (ETA) alone or in association with Benznidazole (BZ). The results indicate that ADA was more competent in blocking TNF (compared to ETA) in all groups but with much lower levels in the CARD2 group. ETA statistically decreased TNF levels only in the CARD2 group. IFN-γ increased in the CARD2 group after treatment with ETA relative to ADA. IL-4 had its levels decreased when treated by both drugs. IL-2 was detected in cells from CARD2 carriers compared to the NEG group after treatment with both drugs. The association with BZ decreased levels of IL-2/TNF and increased IL-4. These data reinforce the participation of TNF in severe Chagas heart disease and bring perspectives on using these blockers in the immunological treatment of Chagas disease since the use of BZ is extremely limited in these patients.

Severe Chagas disease in Ecuador: a countrywide geodemographic epidemiological analysis from 2011 to 2021.

Chagas disease is a neglected and often forgotten tropical disease caused by the Trypanosoma cruzi. This parasite can be transmitted through the direct contact of human skin with feces and urine of the triatomine insect. According to the World Health Organization (WHO), an estimated 6-7 million people are infected worldwide, killing at least 14,000 every year. The disease has been reported in 20 of the 24 provinces of Ecuador, with El Oro, Guayas, and Loja being the most affected. We analyzed the morbidity and mortality rates of severe Chagas disease in Ecuador on a nationwide, population-based level. Hospitalization cases and deaths were also examined based on altitude, including low (< 2,500 m) and high (> 2,500 m) altitudes, according to the International Society. Data was retrieved from the National Institute of Statistics and Census hospital admissions and in-hospital mortality databases from 2011 to 2021. A total of 118 patients have been hospitalized in Ecuador since 2011 due to Chagas disease. The overall in-hospital mortality rate was 69.4% (N = 82). Men have a higher incidence rate (4.8/1,000,000) than women, although women have a significantly higher mortality rate than men (6.9/1,000,000). Chagas disease is a severe parasitic condition that primarily affects rural and poorer areas of Ecuador. Men are more likely to be infected due to differences in work and sociocultural activities. Using average elevation data, we conducted a geodemographic analysis to assess incidence rates by altitude. Our findings indicate that the disease is more common at low and moderate altitudes, but recent increases in cases at higher altitudes suggest that environmental changes, such as global warming, could be driving the proliferation of disease-carrying vectors in previously unaffected areas.

Correlation of TcII discrete typing units with severe chronic Chagas cardiomyopathy in patients from various Brazilian geographic regions.

Chagas disease (ChD) is caused by Trypanosoma cruzi. The genetic structure of the species is divided into seven distinct genetic groups, TcI to TcVI, and Tcbat, which have shown differences in terms of geographic distribution, biological properties, and susceptibility to drugs. However, the association between genetic variability and clinical forms of ChD has not yet been fully elucidated. The predominance of TcII and TcVI discrete typing units (DTUs) (genetic groups) is known to occur in several Brazilian regions and is associated with both the domestic and the wild cycles of ChD. Thus, this study aimed to verify the genotypes of the parasites present in 330 patients with chronic Chagas cardiomyopathy (CCC) from different Brazilian states attended at the Clinical Hospital of the Ribeirão Preto Medical School and to assess the existence of a correlation between the clinical forms with the main cardiovascular risk factors and the genetics of the parasite. All patients with CCC were clinically evaluated through anamnesis, physical examination, biochemical tests, 12-lead electrocardiogram, echocardiogram and chest X-ray. Peripheral blood (5 mL) was collected in guanidine/ethylenediaminetetraacetic acid from each patient for DNA extraction and real-time polymerase chain reaction (PCR) for Chagas disease and genotyping of the parasite in the 7 DTUs. Parasite genotyping was performed using conventional multilocus PCR. Samples of only 175 patients were positive after amplification of the specific genes contained in the T. cruzi genotyping criteria. TcII (64/175), TcVI (9/175), and TcI (3/175) DTUs were predominant, followed by TcII/TcV/TcVI (74/175), and TcII/TcVI (23/175). The TcIII and TcIV DTU´s was detected in only one sample of CCC patients. Our data corroborate previous findings, indicating the predominance of the TcII genotype in patients with CCC of Brazilian origin. Moreover, this study pioneered disclosing a direct correlation between the TcII DTU and severe CCC.

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.

Fatal acute Chagas disease by Trypanosoma cruzi DTU TcI, Ecuador

BackgroundChagas disease is caused by the haemoflagellate protozoan Trypanosoma cruzi. Currently, T. cruzi recognizes seven discrete typing units (DTUs): TcI to TcVI and Tcbat. The genetic diversity of T. cruzi is suspected to influence the clinical outcome. Acute clinical manifestations, which include myocarditis and meningoencephalitis, are sometimes fatal; occur most frequently in children and in immunocompromised individuals. Acute disease is often overlooked, leading to a poor prognosis.Case presentationA 38-year-old man from a subtropical area of the Andes mountains of Ecuador was hospitalized after 3 weeks of evolution with high fever, chills, an enlarged liver, spleen, and lymph nodes, as well as facial edema. ECG changes were also observed. T. cruzi was identified in blood smears, culture and amplification of DNA by PCR. Tests for anti-T. cruzi IgG and IgM and HIV were negative. Molecular typing by restriction fragment length polymorphism (PCR-RFLP) determined the parasite to DTU TcI. In the absence of a timely anti-T. cruzi medication, the patient died.ConclusionsThis is a case of severe pathogenicity and the virulence of a DTU TcI strain in an adult patient. The severe acute Chagas disease was probably overlooked due to limited awareness and its low incidence. Our findings suggest that T. cruzi DTU TcI strains circulating in Ecuador are capable of causing fatal acute disease. Early diagnosis and prompt treatment is of paramount importance to avoid fatalities in acute infections.

A cardiac rehabilitation exercise program potentially inhibits progressive inflammation in patients with severe Chagas cardiomyopathy: A pilot single-arm clinical trial.

Background:Cardiac rehabilitation exerts anti-inflammatory effect on several cardiovascular diseases; however, these effects were not described for Chagas cardiomyopathy, which is associated with pro-inflammatory imbalance.Materials and Methods:Ten patients with severe Chagas cardiomyopathy performed 8 months of exercise training in a cardiac rehabilitation program. Interleukin-1 beta (IL-1β), IL-8, IL-10, interferon gamma (IF-γ), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) serum levels were measured using enzyme-linked immunosorbent assay at baseline, 4, and 8 months. The influence of exercise on cytokine levels was evaluated using the one-way analysis of variance for repeated measurements, with Bonferroni posttest for multiple comparisons.Results:Levels of pro-inflammatory (TNF-α, IL-1β, IL-8, IF-γ, and (MCP-1) and anti-inflammatory (IL-10) cytokines did not vary significantly during the observation period.Conclusion:Exercise may benefit patients with severe Chagas cardiomyopathy by curbing the production of pro-inflammatory cytokines in this disease characterized by a continuous state of inflammation.

Polyfunctional CD4+ T cells specific for Trypanosoma cruzi can be restored after in vitro treatment with IL-7 and IL-27

Abstract Chronically Trypanosoma cruzi-infected subjects bear several features associated with immune exhaustion, including an impairment in the polyfunctionality of T cells over time and alterations in the IL-7/IL-7R and IL-27/IL-27R axis. Since IL-7 and IL-27 have several functions on different immune cells, gene expression analysis was conducted in total PBMCs in response to rhIL-7 and rhIL-27 in vitro. TBX21, EOMES, GZMB and MIG-cytokine-induced gene expression was low in patients with severe Chagas disease compared with those without cardiac involvement. IL-7-induced TBX21 expression positively correlated with the magnitude of T. cruzi-specific T-cell responses. We also assessed whether treatment of PBMCs of chronically T. cruzi infected subjects with IL-7/IL-27 could improve the quality of T. cruzi-specific T-cell responses. Polyfunctionality of CD4+ T cells was improved after treatment with IL-7 and IL-27, by increasing the production of IL-2 on CD4+ T cells producing two or three functions in response to T. cruzi antigens in patients with mild cardiac disease. These findings support that alterations in IL-7/IL-27 pathways in chronic Chagas disease are not only at the signal-transduction level but also at the transcriptional regulation level. In vitro treatment of PBMCs of patients in early clinical stages of chronic Chagas disease can restore T-cell function.

CCR5 Expression is Lower in Women, and Mediates Sex-Based Differences in Post-LVAD Right Ventricular Failure

Purpose Women have increased risk of right ventricular failure (RVF) after LVAD implant, however the underlying pathophysiology is unknown. Chemokines are inflammatory signaling molecules, and fundamental to cardiac homeostasis and stress adaptation. Prior studies have demonstrated a cardio-protective role for chemokine receptor-5 (CCR5) in viral myocarditis and severe Chagas cardiomyopathy, and that sex hormones modulate CCR5 gene expression. We have previously shown that CCR 3-8 down-regulation is predictive of RVF and 1-year survival after implant. We hypothesized that CCR5 expression mediates sex-based differences in post-LVAD RVF. Methods CCR expression was examined in patient's peripheral blood 24 hours pre-LVAD. RNA was isolated using PAXgene protocol. Gene expression was assessed using a targeted microarray (RT2 Profiler PCR array, Qiagen). Results were expressed as PCR cycles to threshold (CT). ΔCT was calculated as (CCR gene CT) - (HPRT1 control gene CT), and log2 transformed for analysis. Log-fold differences in expression were reported using 2−ΔΔCT method. RVF was defined as both planned and unplanned RVAD requirement. Multivariable logistic regression was used to determine the association of sex with RVF, adjusting for significantly different covariates (p Results We analyzed 111 LVAD patients (mean age: 53.57 ± 13 years, 18% female, 17.1% black). The criteria for RVF was met in 35 (31.5%) patients. Women had increased incidence of RVF (50% vs. 27.5%, p=0.047), and under-expressed CCR5 (1.41 fold decrease, p=0.012) compared to men. After controlling for age, heart failure etiology, albumin, BUN, creatinine and cardiac output, women had a higher risk of RVF (HR: 3.18, 95% CI: 1.04-9.8, p=0.043). Addition of CCR5 as a covariate to the model attenuated the association of female sex with RVF (HR: 2.86, 95% CI: 0.91-8.97, p=0.071). Conclusion Pre-implant CCR5 expression is lower in women than in men and may mediate sex disparities in post-LVAD RVF.

Complete Resolution of Electrocardiographic Changes Induced by Acute Chagas Myocarditis

Abstract We present a case of a female adolescent with severe acute Chagas myocarditis, acquired by oral transmission in an endemic area in the Brazilian western Amazon, who had electrocardiographic changes normalized after empirical treatment with the antiparasitic drug benznidazole combined with conventional treatment for severe heart failure.

Rescue Therapy with Nifurtimox and Dipyridamole for Severe Acute Chagas Myocarditis with Congestive Heart Failure in NMRI Albino Mice

Abstract Background: Chagas disease is a global health problem; therefore, the development of new therapeutic protocols is necessary. Our group recently demonstrated that nifurtimox associated with dipyridamole has curative effects in mice with acute Chagas disease. In this study, we assess the effect of this therapeutic protocol in chagasic mice with heart failure. Objective: To evaluate whether nifurtimox and dipyridamole are useful to rescue mice with severe acute chagasic myocarditis with heart failure. Methods: 42 mice with acute chagasic myocarditis and congestive heart failure were divided into three groups: control chagas (n = 11), Nif-Dip treated with nifurtimox and dipyridamole (n = 14) and Nif-Dip-heart failure treated with nifurtimox and dipyridamole associated with digoxin, furosemide, and captopril (n = 17). Nifurtimox and dipyridamole doses were 40 and 30 mg/kg/day, respectively, for 6 weeks. Mice underwent clinical, electrocardiographic, hemoparasitological and histopathological assessments. Results: Lower mortality in Nif-Dip (28.57%; n = 4) compared to control chagas (54.54%; n = 6) and Nif-Dip-heart failure (52.9%; n = 9) was observed. Clinically, nifurtimox and dipyridamole-treated mice increased body weight and improved heart failure without splenomegaly. In these groups, parasitemia and tissue parasites were eradicated; fibrosis, myocytolysis, inflammatory cell infiltrate and mast cells decreased. Repolarization disorders, prolonged QRS and QT intervals, increase of S wave amplitude and atrioventricular dissociation were reversed by the treatment. Conclusion: Nifurtimox with dipyridamole can rescue NMRI mice from severe acute chagas disease, as nifurtimox showed trypanocidal activity and dipyridamole potentiated its effect. Dipyridamole would be useful in chagasic heart failure.

Lineage-specific serology confirms Brazilian Atlantic forest lion tamarins, Leontopithecus chrysomelas and Leontopithecus rosalia, as reservoir hosts of Trypanosoma cruzi II (TcII).

Background Trypanosoma cruzi, the agent of Chagas disease in humans, has a vast reservoir of mammalian hosts in the Americas, and is classified into six genetic lineages, TcI-TcVI, with a possible seventh, TcBat. Elucidating enzootic cycles of the different lineages is important for understanding the ecology of this parasite, the emergence of new outbreaks of Chagas disease and for guiding control strategies. Direct lineage identification by genotyping is hampered by limitations of parasite isolation and culture. An indirect method is to identify lineage-specific serological reactions in infected individuals; here we describe its application with sylvatic Brazilian primates.MethodsSynthetic peptides representing lineage-specific epitopes of the T. cruzi surface protein TSSA were used in ELISA with sera from Atlantic Forest Leontopithecus chrysomelas (golden-headed lion tamarin), L. rosalia (golden lion tamarin), Amazonian Sapajus libidinosus (black-striped capuchin) and Alouatta belzebul (red-handed howler monkey).ResultsThe epitope common to lineages TcII, TcV and TcVI was recognised by sera from 15 of 26 L. chrysomelas and 8 of 13 L. rosalia. For 12 of these serologically identified TcII infections, the identity of the lineage infection was confirmed by genotyping T. cruzi isolates. Of the TcII/TcV/TcVI positive sera 12 of the 15 L. chrysomelas and 2 of the 8 L. rosalia also reacted with the specific epitope restricted to TcV and TcVI. Sera from one of six S. libidinous recognised the TcIV/TcIII epitopes.ConclusionsThis lineage-specific serological surveillance has verified that Atlantic Forest primates are reservoir hosts of at least TcII, and probably TcV and TcVI, commonly associated with severe Chagas disease in the southern cone region of South America. With appropriate reagents, this novel methodology is readily applicable to a wide range of mammal species and reservoir host discovery.

Impact of the Use of Benznidazole Followed by Antioxidant Supplementation in the Prevalence of Ventricular Arrhythmias in Patients With Chronic Chagas Disease: Pilot Study.

Patients with chronic Chagas disease have a higher prevalence of premature ventricular contraction (PVC) because of immunoinflammatory response magnified by the increased oxidative stress. Thus, the sequential treatment with benznidazole (BZN) and antioxidants can reduce the prevalence of PVC. We wish to establish whether the etiological treatment of Chagas disease followed by supplementation with the antioxidant vitamins E and C decreases the prevalence of PVC in these patients. A sample of 41 patients with chronic Chagas disease at different stages of the heart disease was selected for the treatment against the causative agent using BZN (5 mg·kg·d, minimum dose 300 mg daily) for 2 months followed by supplementation with antioxidants such as vitamins E (800 UI/d) and C (500 mg/d) for 6 months. The prevalence of PVC was observed by conducting 24-hour Holter. To evaluate the oxidative status of the patients, serum markers of oxidative stress like glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase were measured, and also reduced glutathione, vitamin E, and markers of tissue damage like thiobarbituric acid reactive substances and protein carbonyl. A decrease in the prevalence of PVC in patients with advanced Chagas heart disease was observed (5391 vs. 1185, P = 0.0068). This reduction was followed by decrease of serum markers of oxidative stress. In patients with a lower degree of cardiac damage, the reduction on prevalence of PVC was not significant. The etiological treatment with BZN followed by supplementation with antioxidant vitamins E and C reduces episodes of PVC in patients with severe Chagas heart disease.

First report of Sapajus cay naturally infected by Trypanosoma cruzi in San Pedro Department, Paraguay.

To verify the occurrence of natural Trypanosoma cruzi infection in non-human primates from a rural endemic area of the east region of Paraguay, xenodiagnosis was performed in 35 animals belonging to two species. For genotyping and T. cruzi discrete typing unit (DTU) assignment, a combination of four markers was used, including amplification products of the small (18S) and large (24Sα) subunits of ribosomal ribonucleic acid gene, the intergenic region of mini-exon gene and the heat shock protein 60 Eco-RV polymerase chain reaction-restriction fragment length polymorphism (HSP60/EcoRV-PCR-RFLP). One specimen of Sapajus cay was found positive and infected by the DTU TcII. This result constitutes the first record of natural T. cruzi infection in a sylvatic monkey in Paraguay, harbouring a DTU associated with severe Chagas disease in humans.

Importation of Hybrid Human-Associated Trypanosoma cruzi Strains of Southern South American Origin, Colombia.

We report the characterization of Trypanosoma cruzi of southern South American origin among humans, domestic vectors, and peridomestic hosts in Colombia using high-resolution nuclear and mitochondrial genotyping. Expanding our understanding of the geographic range of lineage TcVI, which is associated with severe Chagas disease, will help clarify risk of human infection for improved disease control.

Longitudinal study of patients with chronic Chagas cardiomyopathy in Brazil (SaMi-Trop project): a cohort profile

PurposeWe have established a prospective cohort of 1959 patients with chronic Chagas cardiomyopathy to evaluate if a clinical prediction rule based on ECG, brain natriuretic peptide (BNP) levels, and other...

Biomarkers and mortality in severe Chagas cardiomyopathy.

Chagas cardiomyopathy is a chronic sequela of infection by the parasite, Trypanosoma cruzi. Advanced cardiomyopathy is associated with a high mortality rate, and clinical characteristics have been used to predict mortality risk. Though multiple biomarkers have been associated with Chagas cardiomyopathy, it is unknown how these are related to survival. This study aimed to identify biomarkers associated with mortality in individuals with severe Chagas cardiomyopathy in an urban Bolivian hospital. The population included individuals with and without T.cruzi infection recruited in an urbanhospital in Santa Cruz, Bolivia. Baseline characteristics, electrocardiogram findings, medications, and serum cardiac biomarker levels (B-type natriuretic peptide [BNP], N-terminal pro-B-type natriuretic peptide [NT-proBNP], creatine kinase-myocardial band [CK-MB], troponin I, matrix metalloproteinase [MMP]-2, MMP-9, tissue inhibitor of metalloproteinases [TIMP] 1 and 2, transforming growth factor [TGF] beta 1 and 2) were ascertained. Echocardiograms were performed on those with cardiac symptoms or electrocardiogram abnormalities at baseline. Participants were contacted approximately 1 year after initial evaluation; deaths were reported by family members. Receiver-operating characteristic curves (ROC) were used to optimize cutoff values for each marker. For markers with area under the curve (AUC) >0.55, Cox proportional hazards models were performed to determine the hazards ratio (HR) and 95% confidence interval (CI) for the association of each marker with mortality. The median follow-up time was 14.1 months (interquartile range 12.5, 16.7). Of 254 individuals with complete cardiac data, 220 (87%) had follow-up data. Of 50 patients with severe Chagas cardiomyopathy at baseline, 20 (40%) had died. Higher baseline levels of BNP (HR: 3.1, 95% CI: 1.2 to 8.4), NT-proBNP (HR: 4.4, 95% CI: 1.8 to 11.0), CK-MB (HR: 3.3, 95% CI: 1.3 to 8.0), and MMP-2 (HR: 4.2, 95% CI: 1.5 to 11.8) were significantly associated with subsequent mortality. Severe Chagas cardiomyopathy is associated with high short-term mortality. BNP, NT-proBNP, CK-MB, and MMP-2 have added predictive value for mortality, even in the presence of decreased ejection fraction and other clinical signs of congestive heart failure.

Reconstructing the Life of an Unknown (ca. 500 Years-Old South American Inca) Mummy – Multidisciplinary Study of a Peruvian Inca Mummy Suggests Severe Chagas Disease and Ritual Homicide

The paleopathological, paleoradiological, histological, molecular and forensic investigation of a female mummy (radiocarbon dated 1451–1642 AD) provides circumstantial evidence for massive skull trauma affecting a young adult female individual shortly before death along with chronic infection by Trypanosoma cruzi (Chagas disease). The mummy (initially assumed to be a German bog body) was localized by stable isotope analysis to South America at/near the Peruvian/Northern Chilean coast line. This is further supported by New World camelid fibers attached to her plaits, typical Inca-type skull deformation and the type of Wormian bone at her occiput. Despite an only small transverse wound of the supraorbital region computed tomography scans show an almost complete destruction of face and frontal skull bones with terrace-like margins, but without evidence for tissue reaction. The type of destruction indicates massive blunt force applied to the center of the face. Stable isotope analysis indicates South American origin: Nitrogen and hydrogen isotope patterns indicate an extraordinarily high marine diet along with C4-plant alimentation which fits best to the coastal area of Pacific South America. A hair strand over the last ten months of her life indicates a shift to a more “terrestric” nutrition pattern suggesting either a move from the coast or a change in her nutrition. Paleoradiology further shows extensive hypertrophy of the heart muscle and a distended large bowel/rectum. Histologically, in the rectum wall massive fibrosis alternates with residual smooth muscle. The latter contains multiple inclusions of small intracellular parasites as confirmed by immunohistochemical and molecular ancient DNA analysis to represent a chronic Trypanosoma cruzi infection. This case shows a unique paleopathological setting with massive blunt force trauma to the skull nurturing the hypothesis of a ritual homicide as previously described in South American mummies in an individual that suffered from severe chronic Chagas disease.

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

BackgroundEchocardiography 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. ObjectiveTo correlate echocardiographic parameters with the endpoint cardiovascular mortality in patients with ejection fraction < 35%. MethodsStudy 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. ResultsIn 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). ConclusionThe indexed left atrial volume was the only independent predictor of mortality in this population of Chagasic patients with severe systolic dysfunction.

Mode of Death on Chagas Heart Disease: Comparison with Other Etiologies. A Subanalysis of the REMADHE Prospective Trial

BackgroundSudden death has been considered the main cause of death in patients with Chagas heart disease. Nevertheless, this information comes from a period before the introduction of drugs that changed the natural history of heart failure. We sought to study the mode of death of patients with heart failure caused by Chagas heart disease, comparing with non-Chagas cardiomyopathy.Methods and resultsWe examined the REMADHE trial and grouped patients according to etiology (Chagas vs non-Chagas) and mode of death. The primary end-point was all-cause, heart failure and sudden death mortality; 342 patients were analyzed and 185 (54.1%) died. Death occurred in 56.4% Chagas patients and 53.7% non-Chagas patients. The cumulative incidence of all-cause mortality and heart failure mortality was significantly higher in Chagas patients compared to non-Chagas. There was no difference in the cumulative incidence of sudden death mortality between the two groups. In the Cox regression model, Chagas etiology (HR 2.76; CI 1.34–5.69; p = 0.006), LVEDD (left ventricular end diastolic diameter) (HR 1.07; CI 1.04–1.10; p<0.001), creatinine clearance (HR 0.98; CI 0.97–0.99; p = 0.006) and use of amiodarone (HR 3.05; CI 1.47–6.34; p = 0.003) were independently associated with heart failure mortality. LVEDD (HR 1.04; CI 1.01–1.07; p = 0.005) and use of beta-blocker (HR 0.52; CI 0.34–0.94; p = 0.014) were independently associated with sudden death mortality.ConclusionsIn severe Chagas heart disease, progressive heart failure is the most important mode of death. These data challenge the current understanding of Chagas heart disease and may have implications in the selection of treatment choices, considering the mode of death.Trial RegistrationClinicalTrails.gov NCT00505050 (REMADHE)

Elevated Serum Levels of Macrophage Migration Inhibitory Factor Are Associated with Progressive Chronic Cardiomyopathy in Patients with Chagas Disease

Clinical symptoms of chronic Chagas disease occur in around 30% of the individuals infected with Trypanosoma cruzi and are characterized by heart inflammation and dysfunction. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood yet, partially because disease evolution depends on complex host-parasite interactions. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that promotes numerous pathophysiological processes. In the current study, we investigated the link between MIF and CCC progression.Immunohistochemical analysis demonstrated MIF overexpression in the hearts from chronically T. cruzi-infected mice, particularly those showing intense inflammatory infiltration. We also found that MIF exogenously added to parasite-infected murine macrophage cultures is capable of enhancing the production of TNF-α and reactive oxygen species, both with pathogenic roles in CCC. Thus, the integrated action of MIF and other cytokines and chemokines may account for leukocyte influx to the infected myocardium, accompanied by enhanced local production of multiple inflammatory mediators. We further examined by ELISA the level of MIF in the sera from chronic indeterminate and cardiomyopathic chagasic patients, and healthy subjects. CCC patients displayed significantly higher MIF concentrations than those recorded in asymptomatic T. cruzi-infected and uninfected individuals. Interestingly, increased MIF levels were associated with severe progressive Chagas heart disease, in correlation with elevated serum concentration of high sensitivity C-reactive protein and also with several echocardiographic indicators of left ventricular dysfunction, one of the hallmarks of CCC. Our present findings represent the first evidence that enhanced MIF production is associated with progressive cardiac impairment in chronic human infection with T. cruzi, strengthening the relationship between inflammatory response and parasite-driven pathology. These observations contribute to unravel the elements involved in the pathogenesis of CCC and may also be helpful for the design of novel therapies aimed to control long-term morbidity in chagasic patients.