Correlation of blood-based immune molecules with cardiac gene expression profiles reveals insights into Chagas cardiomyopathy pathogenesis.

Introduction: Understanding compartmentalized immune responses in target organs is crucial for elucidating the pathogenesis of various diseases. However, obtaining samples from affected vital organs often poses safety challenges. In this study, we aimed to investigate potential correlations between the levels of disease-associated immune molecules in the bloodstream with their gene expression profiles in the hearts of patients suffering from Chagas Cardiomyopathy (CCC). This debilitating and often fatal condition is caused by infection with the protozoan Trypanosoma cruzi. Methods: Blood samples were analyzed using the Bio-Plex platform. Gene Expression Omnibus (GEO) database was used to determine gene expression profile in heart tissue from CCC and non-Chagas controls (CTRL). Results: Elevated levels of inflammatory cytokines were detected in the plasma of CCC patients, and these levels correlated with clinical indicators of deteriorating cardiac function. Notably, 75% of the soluble factors assessed in the plasma exhibited a consistent relationship with their gene expression levels in the cardiac tissue of CCC patients. Analysis of interactions and signaling pathways related to these molecules revealed an overrepresentation of inflammatory pathways in both blood and heart compartments. Moreover, we identified that differentially expressed genes in CCC cardiac tissue were primarily associated with T-cell signaling pathways and correlated with the presence of CD8+ T cells in the myocardium. Discussion: Our findings establish a strong correlation between relevant immune molecules and their signaling pathways in both the blood and heart tissue in CCC. This validates the use of blood as a non-invasive medium for understanding immunopathology and identifying markers for cardiac dysfunction in Chagas disease.

Accuracy of Transthoracic Echocardiogram as a Screening Method in the Clinical Practice of Pulmonary Hypertension Investigation. / Acurácia do Ecocardiograma Transtorácico como Método de Triagem na Prática Clínica da Investigação da Hipertensão Pulmonar.

BACKGROUND: The transthoracic echocardiogram (TTE) plays a screening role in the diagnostic algorithm of pulmonary hypertension (PH). Studies have shown a significant disagreement between TTE measurements of the systolic pulmonary artery pressure (sPAP) and right atrial pressure (RAP) and those obtained by right heart catheterization (RHC). OBJECTIVE: To compare TTE measurements of sPAP and RAP with those obtained by RHC in patients being investigated for PH. METHODS: Patients referred to a PH reference center with a high or intermediate TTE probability of PH upon admission were submitted to RHC. The agreement between sPAP and RAP from both procedures was assessed through the Bland-Altman test. Differences of up to 10 mmHg for sPAP and 5 mmHg for RAP were considered within the variability of the test. Receiver Operating Characteristic (ROC) curve was constructed to determine the most accurate sPAP and Tricuspid regurgitation maximal velocity (TRV)values associated with the diagnosis of PH by RHC. The adopted level of statistical significance was 5%. RESULTS: Ninety-five patients were included. The Bland-Altman analysis showed a bias of 8.03 mmHg (95% CI:-34.9-50.9) for sPAP and -3.30 mmHg (95% CI:-15.9-9.3) for RAP. AUC for sPAP and TRV measured by TTE for discrimination of probable PH were 0.936 (95% CI: 0.836-1.0) and 0.919 (95% CI: 0.837-1.0), respectively. However, only 33.4% of the echocardiographic estimate of sPAP and 55.1% of RAP were accurate, as compared to the measurements obtained by RHC. CONCLUSION: TTE has a high discriminatory power as a screening diagnostic method for PH despite presenting disagreements between sPAP and RAP absolute values when compared to RHC measurements.

FUNDAMENTO: O ecocardiograma transtorácico (ETT) tem um papel de triagem no algoritmo diagnóstico da hipertensão pulmonar (HP). Estudos demonstraram uma discordância significativa entre as medições do ETT da pressão arterial pulmonar sistólica (PAPs) e da pressão atrial direita (PAD) e as obtidas pelo cateterismo do coração direito (CCD). OBJETIVO: Comparar as medições do ETT da PAPs e da PAD com as obtidas pelo CCD em pacientes com suspeita de HP. MÉTODOS: Pacientes encaminhados a um centro de referência com probabilidade alta ou intermediária de PH ao ETT na admissão hospitalar passaram por CCD. A concordância entre a PAPs e a PAD em ambos os procedimentos foi avaliada pelo teste de Bland-Altman. Diferenças de até 10 mmHg na PAPs e de até 5 mmHg na PAD foram consideradas dentro da variabilidade do teste. A curva de característica de operação do receptor (ROC) foi construída para determinar os valores mais precisos de PAPs e VRT associados ao diagnóstico de HP pelo CCD. O nível de significância estatística adotado foi 5%. RESULTADOS: Foram incluídos noventa e cinco pacientes. A análise de Bland-Altman análise revelou um viés de 8,03 mmHg (IC 95%: -34,9 a 50,9) na PAPs e -3,30 mmHg (IC 95%: -15,9 a 9,3) na PAD. AUC da PAPs e VRT medidas pelo ETT para a discriminação de provável HP foram de 0,936 (IC 95%: 0,836 a 1,0) e 0,919 (IC 95%: 0,837 a 1,0), respectivamente. Entretanto, apenas 33,4% da estimativa ecocardiográfica da PAPs e 55,1% da PAD foram precisas, em comparação às medições obtidas pelo CCD. CONCLUSÃO: O ETT tem um alto poder discriminatório como método diagnóstico de triagem para HP, apesar de apresentar discordâncias entre os valores absolutos de PAPs e PAD, em comparação às medições por CCD.

Cardiac device-related infective endocarditis need for lead extraction whatever the device according to the ESC EORP EURO-ENDO registry.

Aims: Cardiac device-related infective endocarditis (CDRIE) is a severe complication of cardiac device (CD) implantation and is usually treated by antibiotic therapy and percutaneous device extraction. Few studies report the management and prognosis of CDRIE in real life. In particular, the rate of device extraction in clinical practice and the management of patients with left heart infective endocarditis (LHIE) and an apparently non-infected CD (LHIE+CDRIE-) are not well described. Methods and results: We sought to study in EURO-ENDO, the characteristics, prognosis, and management of 483 patients with a CD included in the European Society of Cardiology EurObservational Research Programme EURO-ENDO registry. Three populations were compared: 280 isolated CDRIE (66.7 ± 14.3 years), 157 patients with LHIE and an apparently non-infected CD (LHIE+CDRIE-) (71.1 ± 13.6), and 46 patients with both LHIE and CDRIE (LHIE+CDRIE+) (70.2 ± 10.1). Echocardiography was not always transoesophageal echography (TOE); it was transthoracic echography (TTE) for isolated CDRIE in 88.4% (TOE = 67.6%), for LHIE+CDRIE- TTE = 93.0% (TOE = 58.6%), and for CDRIE+LHIE+ TTE = 87.0% (TOE = 63.0%). Nuclear imaging was performed in 135 patients (positive for 75.6%). In-hospital mortality was lower in isolated CDRIE 13.2% vs. 22.3% and 30.4% for LHIE+CDRIE- and LHIE+CDRIE+ (P = 0004). Device extraction was performed in 62.1% patients with isolated CDRIE, 10.2% of LHIE+CDRIE- patients, and 45.7% of CDRIE+LHIE+ patients. Device extraction was associated with a better prognosis [hazard ratio 0.59 (0.40-0.87), P = 0.0068] even in the LHIE+CDRIE- group (P = 0.047). Conclusion: Prognosis of endocarditis in patients with a CD remains poor, particularly in the presence of an associated LHIE. Although recommended by guidelines, device extraction is not always performed. Device removal was associated with better prognosis, even in the LHIE+CDRIE- group.

Blocking activation of CD4-CD8- T cells modulates their cytotoxic potential and decreases the expression of inflammatory and chemotactic receptors.

CD4-CD8- (double negative - DN) T cells represent a small fraction of circulating T lymphocytes but are a major source of pro-inflammatory cytokines in patients with infectious diseases, including chronic Chagas cardiomyopathy (CCC), one of the deadliest cardiopathies known. Chagas disease is caused by an infection with the protozoan parasite Trypanosoma cruzi and can lead to either an asymptomatic form or a high-mortality cardiac disease. While circulating DN T cells represent a major inflammatory cytokine-expressing cell population in Chagas disease, their potential to be recruited to the heart and to perform cytotoxicity has not been determined. Our previous studies showed that blocking DN T cell activation decreases the expression of IFN-gamma, a cytokine involved in the severity of CCC. Here, studying a well-characterized cohort of Chagas patients with CCC or the asymptomatic form of Chagas disease (indeterminate form, IND), we evaluated the expression of cytotoxic molecules, cytokine and chemokine receptors in γδ+ and αß+ DN T cells by multiparameter flow cytometry, and investigated whether blocking the activation of DN T cells influences the expression of these molecules. We observed that DN T cells from CCC display a higher expression of granzyme A, perforin, inflammatory molecules, and inflammatory chemokine receptors than cells from IND. Messenger RNA coding for these molecules is also upregulated in the heart of CCC patients. Importantly, blocking the activation of DN T cells from CCC modulates their cytotoxic potential and the expression of inflammatory and of chemokine receptors, suggesting that targeting DN T cell activation may be a valid strategy to reduce recruitment to the heart, inflammation, cytotoxicity and, thereby diminish CCC progression and severity.

Parasite DNA and Markers of Decreased Immune Activation Associate Prospectively with Cardiac Functional Decline over 10 Years among Trypanosoma cruzi Seropositive Individuals in Brazil.

Parasitemia and inflammatory markers are cross-sectionally associated with chronic Chagas cardiomyopathy (CCC) among patients with Trypanosoma cruzi. However, the prospective association of the parasite load and host immune response-related characteristics with CCC (that is, progressors) among T. cruzi seropositive individuals has only been partially defined. In a cohort of T. cruzi seropositive patients in Montes Claros and São Paulo, Brazil who were followed over 10 years, we identified the association of a baseline T. cruzi parasite load and systemic markers of inflammation with a decline in cardiac function and/or the presence of cardiac congestion 10 years later. The progressors (n = 21) were individuals with a significant decline in the left ventricular ejection fraction and/or elevated markers of cardiac congestion after 10 years. The controls (n = 31) had normal markers of cardiac function and congestion at the baseline and at the follow-up. They were matched with the progressors on age, sex, and genetic ancestry. The progressors had higher mean parasite loads at the baseline than the controls (18.3 vs. 0.605 DNA parasite equivalents/20 mL, p < 0.05). Of the 384 inflammation-related proteins analyzed, 47 differed significantly at a false discovery rate- (FDR-) corrected p < 0.05 between the groups. There were 44 of these 47 proteins that were significantly higher in the controls compared to in the progressors, including the immune activation markers CCL21, CXCL12, and HCLS1 and several of the tumor necrosis factor superfamily of proteins. Among the individuals who were seropositive for T. cruzi at the baseline and who were followed over 10 years, those with incident CCC at the 10-year marker had a comparatively higher baseline of T. cruzi parasitemia and lower baseline markers of immune activation and chemotaxis. These findings generate the hypothesis that the early impairment of pathogen-killing immune responses predisposes individuals to CCC, which merits further study.

Acurácia do Ecocardiograma Transtorácico como Método de Triagem na Prática Clínica da Investigação da Hipertensão Pulmonar / Accuracy of Transthoracic Echocardiogram as a Screening Method in the Clinical Practice of Pulmonary Hypertension Investigation

Resumo Fundamento O ecocardiograma transtorácico (ETT) tem um papel de triagem no algoritmo diagnóstico da hipertensão pulmonar (HP). Estudos demonstraram uma discordância significativa entre as medições do ETT da pressão arterial pulmonar sistólica (PAPs) e da pressão atrial direita (PAD) e as obtidas pelo cateterismo do coração direito (CCD). Objetivo Comparar as medições do ETT da PAPs e da PAD com as obtidas pelo CCD em pacientes com suspeita de HP. Métodos Pacientes encaminhados a um centro de referência com probabilidade alta ou intermediária de PH ao ETT na admissão hospitalar passaram por CCD. A concordância entre a PAPs e a PAD em ambos os procedimentos foi avaliada pelo teste de Bland-Altman. Diferenças de até 10 mmHg na PAPs e de até 5 mmHg na PAD foram consideradas dentro da variabilidade do teste. A curva de característica de operação do receptor (ROC) foi construída para determinar os valores mais precisos de PAPs e VRT associados ao diagnóstico de HP pelo CCD. O nível de significância estatística adotado foi 5%. Resultados Foram incluídos noventa e cinco pacientes. A análise de Bland-Altman análise revelou um viés de 8,03 mmHg (IC 95%: -34,9 a 50,9) na PAPs e -3,30 mmHg (IC 95%: -15,9 a 9,3) na PAD. AUC da PAPs e VRT medidas pelo ETT para a discriminação de provável HP foram de 0,936 (IC 95%: 0,836 a 1,0) e 0,919 (IC 95%: 0,837 a 1,0), respectivamente. Entretanto, apenas 33,4% da estimativa ecocardiográfica da PAPs e 55,1% da PAD foram precisas, em comparação às medições obtidas pelo CCD. Conclusão O ETT tem um alto poder discriminatório como método diagnóstico de triagem para HP, apesar de apresentar discordâncias entre os valores absolutos de PAPs e PAD, em comparação às medições por CCD.

Abstract Background The transthoracic echocardiogram (TTE) plays a screening role in the diagnostic algorithm of pulmonary hypertension (PH). Studies have shown a significant disagreement between TTE measurements of the systolic pulmonary artery pressure (sPAP) and right atrial pressure (RAP) and those obtained by right heart catheterization (RHC). Objective To compare TTE measurements of sPAP and RAP with those obtained by RHC in patients being investigated for PH. Methods Patients referred to a PH reference center with a high or intermediate TTE probability of PH upon admission were submitted to RHC. The agreement between sPAP and RAP from both procedures was assessed through the Bland-Altman test. Differences of up to 10 mmHg for sPAP and 5 mmHg for RAP were considered within the variability of the test. Receiver Operating Characteristic (ROC) curve was constructed to determine the most accurate sPAP and Tricuspid regurgitation maximal velocity (TRV)values associated with the diagnosis of PH by RHC. The adopted level of statistical significance was 5%. Results Ninety-five patients were included. The Bland-Altman analysis showed a bias of 8.03 mmHg (95% CI:-34.9-50.9) for sPAP and -3.30 mmHg (95% CI:-15.9-9.3) for RAP. AUC for sPAP and TRV measured by TTE for discrimination of probable PH were 0.936 (95% CI: 0.836-1.0) and 0.919 (95% CI: 0.837-1.0), respectively. However, only 33.4% of the echocardiographic estimate of sPAP and 55.1% of RAP were accurate, as compared to the measurements obtained by RHC. Conclusion TTE has a high discriminatory power as a screening diagnostic method for PH despite presenting disagreements between sPAP and RAP absolute values when compared to RHC measurements.

Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature.

BACKGROUND: Chronic Chagas Cardiomyopathy (CCC) usually develops between 10 and 20 years after the first parasitic infection and is one of the leading causes of end-stage heart failure in Latin America. Despite the great inter-individual variability in CCC susceptibility (only 30% of infected individuals ever present CCC), there are no known predictors for disease development in those chronically infected. METHODOLOGY/PRINCIPAL FINDINGS: We describe a new susceptibility locus for CCC through a GWAS analysis in the SaMi-Trop cohort, a population-based study conducted in a Chagas endemic region from Brazil. This locus was also associated with CCC in the REDS II Study. The newly identified locus (rs34238187, OR 0.73, p-value 2.03 x 10-9) spans a haplotype of approximately 30Kb on chromosome 18 (chr18: 5028302-5057621) and is also associated with 80 different traits, most of them blood protein traits significantly enriched for immune-related biological pathways. Hi-C data show that the newly associated locus is able to interact with chromatin sites as far as 10Mb on chromosome 18 in a number of different cell types and tissues. Finally, we were able to confirm, at the tissue transcriptional level, the immune-associated blood protein signature using a multi-tissue differential gene expression and enrichment analysis. CONCLUSIONS/SIGNIFICANCE: We suggest that the newly identified locus impacts CCC risk among T cruzi infected individuals through the modulation of a downstream transcriptional and protein signature associated with host-parasite immune response. Functional characterization of the novel risk locus is warranted.

Guideline of the Brazilian Society of Cardiology on Diagnosis and Treatment of Patients with Chagas Disease Cardiomyopathy / Diretriz da Sociedade Brasileira de Cardiologia sobre Diagnóstico e Tratamento de Pacientes com Cardiomiopatia da Doença de Chagas

This guideline aimed to update the concepts and formulate the standards of conduct and scientific evidence that support them, regarding the diagnosis and treatment of the Cardiomyopathy of Chagas disease, with special emphasis on the rationality base that supported it.  Chagas disease in the 21st century maintains an epidemiological pattern of endemicity in 21 Latin American countries. Researchers and managers from endemic and non-endemic countries point to the need to adopt comprehensive public health policies to effectively control the interhuman transmission of T. cruzi infection, and to obtain an optimized level of care for already infected individuals, focusing on diagnostic and therapeutic opportunistic opportunities.   Pathogenic and pathophysiological mechanisms of the Cardiomyopathy of Chagas disease were revisited after in-depth updating and the notion that necrosis and fibrosis are stimulated by tissue parasitic persistence and adverse immune reaction, as fundamental mechanisms, assisted by autonomic and microvascular disorders, was well established. Some of them have recently formed potential targets of therapies.  The natural history of the acute and chronic phases was reviewed, with enhancement for oral transmission, indeterminate form and chronic syndromes. Recent meta-analyses of observational studies have estimated the risk of evolution from acute and indeterminate forms and mortality after chronic cardiomyopathy. Therapeutic approaches applicable to individuals with Indeterminate form of Chagas disease were specifically addressed. All methods to detect structural and/or functional alterations with various cardiac imaging techniques were also reviewed, with recommendations for use in various clinical scenarios. Mortality risk stratification based on the Rassi score, with recent studies of its application, was complemented by methods that detect myocardial fibrosis.  The current methodology for etiological diagnosis and the consequent implications of trypanonomic treatment deserved a comprehensive and in-depth approach. Also the treatment of patients at risk or with heart failure, arrhythmias and thromboembolic events, based on pharmacological and complementary resources, received special attention. Additional chapters supported the conducts applicable to several special contexts, including t. cruzi/HIV co-infection, risk during surgeries, in pregnant women, in the reactivation of infection after heart transplantation, and others.     Finally, two chapters of great social significance, addressing the structuring of specialized services to care for individuals with the Cardiomyopathy of Chagas disease, and reviewing the concepts of severe heart disease and its medical-labor implications completed this guideline.

Esta diretriz teve como objetivo principal atualizar os conceitos e formular as normas de conduta e evidências científicas que as suportam, quanto ao diagnóstico e tratamento da CDC, com especial ênfase na base de racionalidade que a embasou. A DC no século XXI mantém padrão epidemiológico de endemicidade em 21 países da América Latina. Investigadores e gestores de países endêmicos e não endêmicos indigitam a necessidade de se adotarem políticas abrangentes, de saúde pública, para controle eficaz da transmissão inter-humanos da infecção pelo T. cruzi, e obter-se nível otimizado de atendimento aos indivíduos já infectados, com foco em oportunização diagnóstica e terapêutica. Mecanismos patogênicos e fisiopatológicos da CDC foram revisitados após atualização aprofundada e ficou bem consolidada a noção de que necrose e fibrose sejam estimuladas pela persistência parasitária tissular e reação imune adversa, como mecanismos fundamentais, coadjuvados por distúrbios autonômicos e microvasculares. Alguns deles recentemente constituíram alvos potenciais de terapêuticas. A história natural das fases aguda e crônica foi revista, com realce para a transmissão oral, a forma indeterminada e as síndromes crônicas. Metanálises recentes de estudos observacionais estimaram o risco de evolução a partir das formas aguda e indeterminada e de mortalidade após instalação da cardiomiopatia crônica. Condutas terapêuticas aplicáveis aos indivíduos com a FIDC foram abordadas especificamente. Todos os métodos para detectar alterações estruturais e/ou funcionais com variadas técnicas de imageamento cardíaco também foram revisados, com recomendações de uso nos vários cenários clínicos. Estratificação de risco de mortalidade fundamentada no escore de Rassi, com estudos recentes de sua aplicação, foi complementada por métodos que detectam fibrose miocárdica. A metodologia atual para diagnóstico etiológico e as consequentes implicações do tratamento tripanossomicida mereceram enfoque abrangente e aprofundado. Também o tratamento de pacientes em risco ou com insuficiência cardíaca, arritmias e eventos tromboembólicos, baseado em recursos farmacológicos e complementares, recebeu especial atenção. Capítulos suplementares subsidiaram as condutas aplicáveis a diversos contextos especiais, entre eles o da co-infecção por T. cruzi/HIV, risco durante cirurgias, em grávidas, na reativação da infecção após transplante cardíacos, e outros.    Por fim, dois capítulos de grande significado social, abordando a estruturação de serviços especializados para atendimento aos indivíduos com a CDC, e revisando os conceitos de cardiopatia grave e suas implicações médico-trabalhistas completaram esta diretriz. 

Hospitalizations due to gastrointestinal Chagas disease: National registry.

OBJECTIVES: Analyze the hospitalizations of patients admitted for Chagas disease with gastro-intestinal involvement (CD-GI) in the Brazilian Unified Health System, describe the epidemiological profile, mortality and costs. METHODS: This is an observational study that uses secondary data from the National Hospital Information System (SIH-SUS) for the years 2017-2019. CD-GI admissions were defined by specific ICD-10 codes that identify the main diagnosis. RESULTS: From 2017 to 2019, there were 4,407 hospitalizations for CD-GI in Brazil, considering only public hospitals and those associated with the SUS. This corresponds to an average of 1,470 hospitalizations per year, or 0.6 per 100,000 inhabitants, with significant regional variation. Hospitalizations increased with age and were slightly higher in men. More than 60% were emergencies and in 50% the procedure performed was surgical. The most used code was the one for megaesophagus followed by megacolon. In-hospital mortality was 5.8% and 17.2% went to intensive care units. The median cost was USD$ 553.15 per hospitalization, and an overall cost of USD$ 812,579.98 per year to the SUS budget. CONCLUSION: The numbers, rates and costs presented here are possibly underestimated but they give us an idea of the overall profile of hospitalizations due to CD-GI, which are not rare and are related to significant in-hospital mortality. CD-GI is a neglected manifestation of a neglected disease.

Biomakers in Chronic Chagas Cardiomyopathy.

The primary objective was to observe the relationship between serum levels of BNP, Ca-125, C-reactive protein and uric acid as prognostic and functional markers in patients with chronic Chagas cardiomyopathy (CCC). Circulating levels of cytokines: IL-1ß, TNFα, IL-10, IL6, IL-8 and IL-12 were determined and investigated regarding their association with hemodynamic parameters, clinical signs of heart failure and outcome. Chagas is still a neglected disease that affects numerous individuals, many of them in their most productive years. CCC with left ventricular dysfunction is the most severe presentation of Chagas Disease. BNP is a well-recognized prognostic and clinical biomarker, not only in chronic heart failure patients but also in patients with CCC. Previous studies have shown Ca-125, C-reactive protein, and uric acid to be potentially good prognostic markers in heart failure (HF). Fifty patients with left ventricular fraction less (LVEF) than 55% were selected and followed for a mean period of 18 ± 8.3 months. Patient's mean age was 43.42 ± 10.3 years (32 male), their BNP was 293 (160-530) pg/mL, Ca-125 8.5 (5.5-16.75) U/mL, uric acid 6.2 ± 2 mg/dL, and C- reactive protein 4.5 (4.5-7.3) mg/L. Patients who had LVEF less than 35% had higher BNP (p = 0.0023), Ca-125 (p = 0.027) and uric acid (p = 0.01) serum levels. Patients who died also showed higher BNP (p = 0.01), uric acid (p = 0.05) and a trend towards higher Ca-125 serum levels (p = 0.056). All markers: BNP, Ca-125, uric acid and C-reactive had good predictability of death in Cox-regression univariate analysis, however, not on the final multivariate model. Of the inflammatory cytokines, IL-8 and IL-12 showed a relation to LVEF of less than 35%. IL-12 was related to adverse cardiovascular events and non-survival. IL-1ß was a good predictor of mortality in the final Cox regression model. Determination of Ca-125, uric acid levels and C-reactive protein may add useful clinical and prognostic information and may help clinical decision making for patients with 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.

Contextual influence on poor self-rated health in patients with Chagas disease: multilevel study.

Chagas disease (CD) is recognized by the World Health Organization as one of the thirteen most neglected tropical diseases in the world. Self-perceived health is considered a better predictor of mortality than objective measures of health status, and the context in which one lives influences this predictor. This study aimed to evaluate the prevalence and individual and contextual factors associated with poor self-rated health among CD patients from an endemic region in Brazil. It is a multilevel cross-sectional study. The individual data come from a cross-section of a cohort study named SaMi-Trop. Contextual data was collected from publicly accessible institutional information systems and platforms. The dependent variable was self-perceived health. The analysis was performed using multilevel binary logistic regression. The study included 1,513 patients with CD, where 335 (22.1%) had Poor self-rated health. This study revealed the influence of the organization/offer of the Brazilian public health service and of individual characteristics on the self-perceived health of patients with CD.

Two-year death prediction models among patients with Chagas Disease using machine learning-based methods.

Chagas disease (CD) is recognized by the World Health Organization as one of the thirteen most neglected tropical diseases. More than 80% of people affected by CD will not have access to diagnosis and continued treatment, which partly supports the high morbidity and mortality rate. Machine Learning (ML) can identify patterns in data that can be used to increase our understanding of a specific problem or make predictions about the future. Thus, the aim of this study was to evaluate different models of ML to predict death in two years of patients with CD. ML models were developed using different techniques and configurations. The techniques used were: Random Forests, Adaptive Boosting, Decision Tree, Support Vector Machine, and Artificial Neural Networks. The adopted settings considered only interview variables, only complementary exam variables, and finally, both mixed. Data from a cohort study with CD patients called SaMi-Trop were analyzed. The predictor variables came from the baseline; and the outcome, which was death, came from the first follow-up. All models were evaluated in terms of Sensitivity, Specificity and G-mean. Among the 1694 individuals with CD considered, 134 (7.9%) died within two years of follow-up. Using only the predictor variables from the interview, the different techniques achieved a maximum G-mean of 0.64 in predicting death. Using only the variables from complementary exams, the G-mean was up to 0.77. In this configuration, the protagonism of NT-proBNP was evident, where it was possible to observe that an ML model using only this single variable reached G-mean of 0.76. The configuration that mixed interview variables and complementary exams achieved G-mean of 0.75. ML can be used as a useful tool with the potential to contribute to the management of patients with CD, by identifying patients with the highest probability of death. Trial Registration: This trial is registered with ClinicalTrials.gov, Trial ID: NCT02646943.

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies.

Chronic Chagas cardiomyopathy (CCC) is one of the deadliest cardiomyopathies known and the most severe manifestation of Chagas disease, which is caused by infection with the parasite Trypanosoma cruzi. Idiopathic dilated cardiomyopathies (IDC) are a diverse group of inflammatory heart diseases that affect the myocardium and are clinically similar to CCC, often causing heart failure and death. While T-cells are critical for mediating cardiac pathology in CCC and IDC, the mechanisms underlying T-cell function in these cardiomyopathies are not well-defined. In this study, we sought to investigate the phenotypic and functional characteristics of T-cell subpopulations in CCC and IDC, aiming to clarify whether the inflammatory response is similar or distinct in these cardiomyopathies. We evaluated the expression of systemic cytokines, determined the sources of the different cytokines, the expression of their receptors, of cytotoxic molecules, and of molecules associated with recruitment to the heart by circulating CD4+, CD8+, and CD4-CD8- T-cells from CCC and IDC patients, using multiparameter flow cytometry combined with conventional and unsupervised machine-learning strategies. We also used an in silico approach to identify the expression of genes that code for key molecules related to T-cell function in hearts of patient with CCC and IDC. Our data demonstrated that CCC patients displayed a more robust systemic inflammatory cytokine production as compared to IDC. While CD8+ T-cells were highly activated in CCC as compared to IDC, CD4+ T-cells were more activated in IDC. In addition to differential expression of functional molecules, these cells also displayed distinct expression of molecules associated with recruitment to the heart. In silico analysis of gene transcripts in the cardiac tissue demonstrated a significant correlation between CD8 and inflammatory, cytotoxic and cardiotropic molecules in CCC transcripts, while no correlation with CD4 was observed. A positive correlation was observed between CD4 and perforin transcripts in hearts from IDC but not CCC, as compared to normal tissue. These data show a clearly distinct systemic and local cellular response in CCC and IDC, despite their similar cardiac impairment, which may contribute to identifying specific immunotherapeutic targets in these diseases.

"Subclinical atherosclerosis in acromegaly: Possible association with cardiovascular risk factors rather than disease activity".

OBJECTIVE: Cardiovascular (CV) disease is still a major cause of excessive morbidity and mortality in patients with active acromegaly, which may be attributed to a high prevalence of associated pro-atherosclerotic risk factors. However, a direct effect of GH/IGF-1 excess on the vasculature has been previously suggested, warranting further investigation. The present study was designed to investigate whether chronic GH/IGF-1 excess is associated with an increased prevalence of subclinical atherosclerosis in patients with acromegaly. DESIGN: We measured carotid intima-media thickness (cIMT) and assessed carotid plaques by ultrasonography along with classical CV risk factors in 54 acromegaly patients (34 females, 50 ± 12 years and compared those with 62 (42 females, 53 ± 13 years) age-, sex- and CV risk factors- matched controls. In order to compare cIMT measurements between patients and controls we analyzed common carotid artery far wall data as well as a combined measurement result, which consisted of the mean value of the six different measurements, three at each side. RESULTS: mean ± SD serum GH and IGF-1 levels were 2.76 ± 4.65 ng/mL and 1.7 ± 1.25 x ULN, respectively, in all acromegaly patients. Age, body mass index, blood pressure, lipid levels, fasting glucose and Framingham's global cardiovascular risk score classification were similar comparing patients and controls. Combined median [IQR] cIMT measurements were similar in acromegaly patients and matched controls (0.59 [0.52-0.66] mm vs. 0.59 [0.52-0.69] mm; P = 0.872) as well as in acromegaly patients with active and controlled disease (0.59 [0.51-0.68] mm vs. 0.60 [0.54-0.68] mm; P = 0.385). No significant correlations were observed between cIMT measurements and GH (Spearman r = 0.1, P = 0.49) or IGF-1 (Spearman r = 0.13, P = 0.37) levels in patients with acromegaly. Carotid atherosclerotic plaques prevalence was similar in patients and controls (26% vs. 32%; P = 0.54) as well as in patients with active and controlled acromegaly (22% vs. 30%; P = 0.537). CONCLUSIONS: Our data suggest that GH/IGF-1 excess itself is not one of the main drivers of subclinical morphological atherosclerosis changes in patients with acromegaly and that optimal control of acromegaly-associated CV risk factors may preserve vasculature structure even when strict biochemical control is not achieved.

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.