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ABSTRACTCD4−CD8−(double-negative [DN]) T cells have recently been shown to display important immunological functions in human diseases. They express γδ or αβ T-cell receptors that recognize lipid/glycolipid antigens presented via the nonclassical major histocompatibility complex molecules of the CD1 family. We recently demonstrated that while αβ DN T cells serve primarily to express inflammatory cytokines, γδ DN T cells express mainly interleukin-10 (IL-10) in patients with cutaneous leishmaniasis. We also demonstrated a correlation between DN T cells and the expression of gamma interferon in the acute phase of Trypanosoma cruziexperimental infection. In this work, we sought to investigate whether αβ or γδ DN T cells display distinct immunoregulatory potentials in patients with polar forms of human Chagas' disease. Our data showed that in vitroinfection with T. cruzileads to expansion of DN T cells in patients with the indeterminate and severe cardiac clinical forms of the disease. However, while αβ DN T cells primarily produce inflammatory cytokines in both forms of the disease, γδ DN T cells display a marked, significant increase in antigen-specific IL-10 expression in indeterminate patients relative to cardiac patients. Finally, higher frequencies of the IL-10-producing γδ DN T cells were correlated with improved clinical measures of cardiac function in the patients, suggesting a protective role for these cells in Chagas' disease. Taken together, these data show distinct functional characteristics for αβ and γδ DN T cells associated with distinct morbidity rates and clinical forms in human Chagas' disease.

CD4–CD8–(double-negative [DN]) T cells have recently been shown to display important immunological functions in human diseases. They express or β T-cell receptors that recognize lipid/glycolipid antigens presented via the nonclassical major histocompatibility complex molecules of the CD1 family. We recently demonstrated that while β DN T cells serve primarily to express inflammatory cytokines, DN T cells express mainly interleukin-10 (IL-10) in patients with cutaneous leishmaniasis. We also demonstrated a correlation between DN T cells and the expression of gamma interferon in the acute phase of Trypanosoma cruzi experimental infection. In this work, we sought to investigate whether β or DN T cells display distinct immunoregulatory potentials in patients with polar forms of human Chagas' disease. Our data showed that in vitro infection with T. cruzi leads to expansion of DN T cells in patients with the indeterminate and severe cardiac clinical forms of the disease. However, while β DN T cells primarily produce inflammatory cytokines in both forms of the disease, DN T cells display a marked, significant increase in antigen-specific IL-10 expression in indeterminate patients relative to cardiac patients. Finally, higher frequencies of the IL-10-producing DN T cells were correlated with improved clinical measures of cardiac function in the patients, suggesting a protective role for these cells in Chagas' disease. Taken together, these data show distinct functional characteristics for β and DN T cells associated with distinct morbidity rates and clinical forms in human Chagas' disease.

Los estudios previos en los que se ha abordado la influencia de la enfermedad de Chagas en la mortalidad de pacientes con insuficiencia cardiaca han tenido la limitación de la heterogeneidad de la población estudiada. Existen pocos datos sobre la asociación entre la causa subyacente de la miocardiopatía dilatada y el pronóstico a largo plazo. El objetivo de este estudio es identificar los factores de riesgo de mortalidad en pacientes con miocardiopatía dilatada secundaria a enfermedad de Chagas o idiopática, y determinar el valor pronóstico de la identificación de la enfermedad de Chagas como etiología subyacente de la miocardiopatía dilatada.

Introduction:Delays in diagnosis of heart disease (HD) associated with pregnancy may impact clinical outcomes. We aimed to evaluate the feasibility of integrating screening echocardiography (echo) with remote interpretation into the Brazilian pre-natal primary care (PC), and to assess HD prevalence.Methods:Over 12 months, 20 healthcare workers were trained to provide simplified echo protocols, utilizing handheld machines (GE VSCAN), in 22 PC centers. Health agents provided house-to house education. Consecutive pregnant women without history of HD underwent focused echo. Studies were interpreted remotely in US and Brazil by telemedicine. Major HD was defined as moderate to severe valve disease, ventricular dysfunction/hypertrophy, pericardial effusion or wall-motion abnormalities. Screen-positive women were referred for follow-up standard echo.Results:From Jan/2018 to Jan/2019, 1,112 women underwent echo. Quality issues were reported in 1.5%, not precluding interpretation. Mean age was 27?8 years, mean gestational age 22?9 weeks, 48% were primiparous, 4.5% had hypertension, and 4.6% family history of valve disease. The most frequent symptoms were dyspnea (37.7%) and palpitations (20%). Major HD was found in 100 (9.0%) patients (9.1% in 1st/ 2ndtrimesters vs. 7.5% in 3rd, p=0.35). Moderate mitral regurgitation (MR) was observed in 47 (4.2%), tricuspid regurgitation in 11 (1.0%), mild left ventricular (LV) dysfunction in 4 (0.4%), LV hypertrophy in 2 (0.2%) and suspected rheumatic heart disease (RHD) in 36 (3.2%): all with mitral valve (MV) and 2 with aortic valve (AV) involvement. Other AV disease was observed in 11 (10%). In 56 screen-positive women undergoing standard echo, major HD was confirmed in 45 (80.4%): RHD findings in 12 patients (all with MV and 2 with AV disease, being 1 AV stenosis), MR in 40 (14 with morphological findings, 10 suggestive of RHD), other AV disease in 2 (mild/moderate regurgitation). Mild LV dysfunction was confirmed in 1 case.Conclusions:Integration of screening echo into primary pre-natal care is feasible in Brazil. Although the echocardiographic HD burden was considerable, the low prevalence of severe disease requiring clinical attention urges further investigations about the effectiveness of the strategy.

Introduction:Screening echocardiography (echo) may be a tool for early diagnosis and rationalization of referrals in primary care (PC), organizing waiting lines. We aimed to evaluate the role of screening echo integrated with the Brazilian PC for prioritization of referrals and risk stratification.Methods:Over 24 months, 22 healthcare workers at 21 PC centers were trained on simplified handheld (GE VSCAN) echo protocols. Screening (SC) groups, including consented patients aged 17-20, 35-40 and 60-65 years, and patients referred (RF) for clinical indications, in waiting lines, answered a clinical questionnaire and underwent focused echo, interpreted remotely in US and Brazil by telemedicine. Significant HD was defined as moderate/severe valve disease, ventricular dysfunction/hypertrophy, pericardial effusion or wall-motion abnormalities. A study-derived score including clinical variables (sex, body mass, history of hypertension, coronary disease, heart failure, heart surgery, valve disease and Chagas disease) was applied, and the reclassification rates from intermediate (13% to 69%) to high (?70%) and low (<13%) risk after screening echo were assessed, as well as the accuracy of the final risk classification to predict HD in standard echo.Results:Total 3252 patients underwent screening echo; 1114 (34%) from SC groups, and 489 underwent standard echo. Mean age was 53?17 years, 66% were women; 43.1% had hypertension, 20.4% diabetes. In screening, significant HD was found in 28.1% in SC vs. 32.1% in RF group, p=0.02. Previously to screening echo, 2396 (74%) patients were classified as moderate risk and 856 (26%) as high risk. Screening echo reclassified 28% of moderate-risk patients to low-risk, and 3.9% to high-risk, and 54.3% of those of high risk to moderate risk. A final high-risk score (>70%) had an overall sensitivity of 73% (95% CI 64 - 80) and specificity of 99% (95% CI 96 - 100) to predict HD in standard echo. Screening echo significantly improved overall score accuracy from 63% (95% CI 59 - 68) to 90% (95% CI 87 - 93).Conclusions:Screening echo in PC is a promising prioritization strategy in low resourced areas, through task-shifting. It?s utilization in combination with clinical variables has good accuracy to predict high risk of significant HD.

Background:In 2012, the World Heart Federation (WHF) published guidelines for the echocardiographic diagnosis of rheumatic heart disease (RHD). This study assesses the reliability of the 2012 WHF criteria in the context of a randomized clinical trial (ClinicalTrials.gov: NCT03346525).Methods:Four cardiologists with experience in the WHF criteria were selected to review echocardiograms and to participate in a blinded adjudication panel. Echocardiograms were systematically assigned to two members of the panel for pre-review. All echocardiograms subsequently underwent in-person panel adjudication with consensus determination. The panel decision was considered the ?gold standard? for diagnosis. Sensitivity and specificity analyses were used to compare the performance of independent reviewers to the panel adjudication.Results:Echocardiograms from 784 children had both double pre-review and panel adjudication (1568 independent reviews). The overall diagnostic breakdown reflected mild RHD with panel determination of 78 normal/other, 578 borderline RHD, 132 mild definite RHD, and 5 moderate/severe RHD. Independent reviewers had high sensitivity (94%; 95% CI 93-95%) but lower specificity (62%; 95% CI 53-70%) for overall diagnosis (RHD vs. normal). Similarly, for diagnosis of pathological mitral regurgitation, independent reviewers showed high sensitivity (94%; 95% CI 93-95%) but lower specificity (78%, 95% CI 72-82%). In contrast, across all four morphological mitral valve abnormalities in the WHF guidelines, independent reviewers showed lower sensitivity and higher specificity (range 42-64% and 91-97%, respectively). Independent reviewers were quite consistent with the panel on pathological aortic insufficiency (sensitivity 93%, specificity 99%) and abnormal aortic valve morphology (sensitivity 96%, specificity 97%).Conclusions:Compared to the gold standard of panel adjudication of echocardiograms, independent reviewers were more likely to over-diagnose RHD and pathological mitral regurgitation and under-diagnose morphological mitral valve abnormalities. Further work is needed to increase the reliability of the 2012 WHF criteria in order to facilitate consistent implementation for RHD diagnosis around the world.

Introduction:Clinical progression of rheumatic mitral stenosis (MS) typically spans several decades. It is characterized by progressive narrowing of the mitral orifice, with eventual hemodynamic deterioration. Although mitral valve (MV) intervention has changed the natural course of this disease, MS remains a progressive disease. This study aimed to assess the predictors of clinical outcome in a contemporary cohort of patients with MS on optimized guideline based therapy.Methods:A total of 590 patients with MS (valve area of 1.1 ? 0.4, range, 0.3 to 2.9 cm2), were prospectively enrolled between 2011 and 2019. The patients were divided into two groups according to MS severity. Group 1 comprised 321 patients with symptomatic severe MS who underwent percutaneous mitral valvuloplasty (PMV) at the time of enrollment, whereas group 2 included 269 with progressive or asymptomatic MS, without initial indication for valve intervention. The patients were followed for a mean of 3 years. The endpoint was a composite of cardiovascular death or MV intervention.Results:The mean age was 46 ? 12 years, and 499 were women (85%). In group 1, the endpoint was reached in 72 patients, with an incidence of 6.2 events per 100 patient-years (pt/y). The predictors of events were NYHA class pre procedure (HR 1.87, 95% CI 1.317-2.65), and postprocedural MV area (HR 0.13, 95% CI 0.04-0.38), mean gradient (HR 1.12, 95% CI 1.12-1.57), and degree of mitral regurgitation (MR; HR 3.13 95% CI 1.92-5.09). In group 2, 37 events occurred with an incidence of 5.5 events per 100 pt/y, similar to group 1. The predictors of events were age (HR 1.03 95% CI 1.01-1.05), NYHA class (HR 1.53, 95% CI 1.17-2.01), degree of MR (HR 2.99 95% CI 1.52-5.89) and tricuspid regurgitation (TR; HR 2.15 95% CI 1.31-3.53), and interaction between MV area and net atrioventricular compliance (Cn).Conclusions:In this large cohort representative of a wide spectrum of disease severity, the predictors of outcome depended on the stages of MS. In patients with progressive MS, the baseline variables including functional status, MR and TR severity, MV area and Cnwere predictors of adverse outcome. Conversely, in the patients with severe MS who required intervention, postprocedural parameters were the main determinants of prognosis.

Introduction:Heart disease (HD) exerts high morbidity and mortality in Brazil. Screening echocardiography (echo) may be a useful tool in the primary care (PC) setting. We aimed to evaluate the reasons for disagreement between screening echo, acquired by non-experts, and standard echo in the Brazilian PC system.Methods:Over 20 months, 22 healthcare workers at 20 PC centers were trained on simplified handheld (GE VSCAN) echo protocols. Screening groups, consisting of patients aged 17-20, 35-40 and 60-65 years, and patients referred for clinical indications underwent focused echo. Studies were interpreted in US and Brazil by telemedicine, and those diagnosed with major or severe HD were referred for standard echo performed by an expert. Major HD was defined as moderate to severe valve disease, ventricular dysfunction/hypertrophy, pericardial effusion or wall-motion abnormalities. A random sample of exams was selected for evaluation of variables accounting for disagreement.Results:From 2237 patients screened, a sample of 768 was analyzed, 651 (85%) from the referred group. Mean age was 58?15 years, 62.5% were women; 68.4% had hypertension and 23% diabetes. Quality issues were reported in 5.8%, and the random Kappa for major and severe HD between screening and standard echo was 0.51 and 0.45. The most frequent reasons for disagreement in screening were: overestimation of mitral regurgitation (MR) (17.9%, N=138), left ventricular (LV) dysfunction (15.7%, N=121), aortic regurgitation (AR) (15.2%, N=117), LV hypertrophy (13.5%, N=104) and tricuspid regurgitation (12.7%, N=98). Misdiagnosis of morphological abnormalities of the aortic and mitral valves were observed in 12.4% and 3.0% of the cases. Underestimation of AR and MR occurred in 4.6% and 11.1%. Of note, among 257 patients with initial diagnosis of mild/moderate MR, 129 (50.2%) were reclassified to normal, as well as 101 (80.8%) among 125 initially flagged with mild/moderate LV dysfunction.Conclusion:Although screening echo with task-shifting in PC may be a promising tool in low-income areas, estimation of valve regurgitation and LV function and size account for considerable disagreement with standard exams. Training and quality-assurance strategies must be implemented to improve accuracy.

Introduction:Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity. Portable devices such as MyDiagnostick? (MDS) allow for AF screening. We aimed to evaluate the sensitivity and specificity of MDS for AF diagnosis in patients in the waiting list for echocardiogram (ECHO) in primary care and to assess the prevalence of AF by this method.Methods:In 5 days, 1,518 patients from low-income areas of Brazil underwent clinical evaluation and cardiovascular (CV) risk stratification using a study-derived score based on demographics and CV comorbidities. Patients were then screened for AF with MDS, holding the device with both hands for 1-minute. The test was considered positive when the device indicated the presence of AF. The gold-standard for AF diagnosis was the 12-lead ECG interpreted by a cardiologist. Patients with intermediate CV risk were submitted to ECHO screening with ultraportable device. Individuals with abnormalities in screening or those with high CV risk, in addition to a low-risk sample, underwent standard ECHO. Major heart disease (HD) was defined as moderate to severe valve disease, ventricular dysfunction/hypertrophy, pericardial effusion or wall-motion abnormalities.Results:Mean age was 58 ? 16 years, 66% were women. Prevalence of AF by MDS was 6.4% (N=97): higher in patients with high CV risk (12.6%), compared with moderate (6.1%) and low risk (2.2 %), p<0.001. Prevalence was also higher in >65-year-olds (9.3%) than in those aged 40-64 years (4.2%) and <40 years (6.9%), p=0.001. Of 1,063 patients undergoing ECHO screening, 45% (N=481) had HD, whereas among 64 patients with AF in MDS undergoing ECHO, 55% had HD (p=0.12). Positive AF screening was independently associated with the presence of HD on standard ECHO (OR = 3.9, 95%CI 2.1 - 7.2, p <0.001) after adjusting for sex, age and clinical variables. Compared to the ECG, the MDS had sensitivity of 97% (95%CI 86 - 100) and specificity of 69% (95%CI 61 - 76.) for AF detection.Conclusion:Screening with the MDS portable device demonstrated high sensitivity for early detection of AF in primary care. Prevalence in a population referred for ECHO was high and associated with age and higher CV risk. AF at screening was independently associated with HD detected by ECHO.