Combination of Tele-Cardiology Tools for Cardiovascular Risk Stratification in Primary Care: Data from the PROVAR+ Study. / Combinação de Ferramentas de Telecardiologia para Estratificação de Risco Cardiovascular na Atenção Primária: Dados do Estudo PROVAR.

BACKGROUND: Tele-cardiology tools are valuable strategies to improve risk stratification. OBJECTIVE: We aimed to evaluate the accuracy of tele-electrocardiography (ECG) to predict abnormalities in screening echocardiography (echo) in primary care (PC). METHODS: In 17 months, 6 health providers at 16 PC units were trained on simplified handheld echo protocols. Tele-ECGs were recorded for final diagnosis by a cardiologist. Consented patients with major ECG abnormalities by the Minnesota code, and a 1:5 sample of normal individuals underwent clinical questionnaire and screening echo interpreted remotely. Major heart disease was defined as moderate/severe valve disease, ventricular dysfunction/hypertrophy, pericardial effusion, or wall-motion abnormalities. Association between major ECG and echo abnormalities was assessed by logistic regression as follows: 1) unadjusted model; 2) model 1 adjusted for age/sex; 3) model 2 plus risk factors (hypertension/diabetes); 4) model 3 plus history of cardiovascular disease (Chagas/rheumatic heart disease/ischemic heart disease/stroke/heart failure). P-values < 0.05 were considered significant. RESULTS: A total 1,411 patients underwent echo; 1,149 (81%) had major ECG abnormalities. Median age was 67 (IQR 60 to 74) years, and 51.4% were male. Major ECG abnormalities were associated with a 2.4-fold chance of major heart disease on echo in bivariate analysis (OR = 2.42 [95% CI 1.76 to 3.39]), and remained significant after adjustments in models (p < 0.001) 2 (OR = 2.57 [95% CI 1.84 to 3.65]), model 3 (OR = 2.52 [95% CI 1.80 to3.58]), and model 4 (OR = 2.23 [95%CI 1.59 to 3.19]). Age, male sex, heart failure, and ischemic heart disease were also independent predictors of major heart disease on echo. CONCLUSIONS: Tele-ECG abnormalities increased the likelihood of major heart disease on screening echo, even after adjustments for demographic and clinical variables.

FUNDAMENTO: As ferramentas de telecardiologia são estratégias valiosas para melhorar a estratificação de risco. OBJETIVO: Objetivamos avaliar a acurácia da tele-eletrocardiografia (ECG) para predizer anormalidades no ecocardiograma de rastreamento na atenção primária. MÉTODOS: Em 17 meses, 6 profissionais de saúde em 16 unidades de atenção primária foram treinados em protocolos simplificados de ecocardiografia portátil. Tele-ECGs foram registrados para diagnóstico final por um cardiologista. Pacientes consentidos com anormalidades maiores no ECG pelo código de Minnesota e uma amostra 1:5 de indivíduos normais foram submetidos a um questionário clínico e ecocardiograma de rastreamento interpretado remotamente. A doença cardíaca grave foi definida como doença valvular moderada/grave, disfunção/hipertrofia ventricular, derrame pericárdico ou anormalidade da motilidade. A associação entre alterações maiores do ECG e anormalidades ecocardiográficas foi avaliada por regressão logística da seguinte forma: 1) modelo não ajustado; 2) modelo 1 ajustado por idade/sexo; 3) modelo 2 mais fatores de risco (hipertensão/diabetes); 4) modelo 3 mais história de doença cardiovascular (Chagas/cardiopatia reumática/cardiopatia isquêmica/AVC/insuficiência cardíaca). Foram considerados significativos valores de p < 0,05. RESULTADOS: No total, 1.411 pacientes realizaram ecocardiograma, sendo 1.149 (81%) com anormalidades maiores no ECG. A idade mediana foi de 67 anos (intervalo interquartil de 60 a 74) e 51,4% eram do sexo masculino. As anormalidades maiores no ECG se associaram a uma chance 2,4 vezes maior de doença cardíaca grave no ecocardiograma de rastreamento na análise bivariada (OR = 2,42 [IC 95% 1,76 a 3,39]) e permaneceram significativas (p < 0,001) após ajustes no modelo 2 (OR = 2,57 [IC 95% 1,84 a 3,65]), modelo 3 (OR = 2,52 [IC 95% 1,80 a 3,58]) e modelo 4 (OR = 2,23 [IC 95% 1,59 a 3,19]). Idade, sexo masculino, insuficiência cardíaca e doença cardíaca isquêmica também foram preditores independentes de doença cardíaca grave no ecocardiograma. CONCLUSÕES: As anormalidades do tele-ECG aumentaram a probabilidade de doença cardíaca grave no ecocardiograma de rastreamento, mesmo após ajustes para variáveis demográficas e clínicas.

Agreement between Handheld and Standard Echocardiography for Diagnosis of Latent Rheumatic Heart Disease in Brazilian Schoolchildren from High-Prevalence Settings (Agreement between Screening and Standard Echo for RHD).

Introduction: Handheld echocardiography (echo) is the tool of choice for rheumatic heart disease (RHD) screening. We aimed to assess the agreement between screening and standard echo for latent RHD diagnosis in schoolchildren from an endemic setting. Methods: Over 14 months, 3 nonphysicians used handheld machines and the 2012 WHF Criteria to determine RHD prevalence in consented schoolchildren from Brazilian low-income public schools. Studies were interpreted by telemedicine by 3 experts (Brazil, US). RHD-positive children (borderline/definite) and those with congenital heart disease (CHD) were referred for standard echo, acquired and interpreted by a cardiologist. Agreement between screening and standard echo, by WHF subgroups, was assessed. Results: 1390 students were screened in 6 schools, with 110 (7.9%, 95% CI 6.5-9.5) being screen positive (14 ± 2 years, 72% women). Among 16 cases initially diagnosed as definite RHD, 11 (69%) were confirmed, 4 (25%) reclassified to borderline, and 1 to normal. Among 79 cases flagged as borderline RHD, 19 (24%) were confirmed, 50 (63%) reclassified to normal, 8 (10%) reclassified as definite RHD, and 2 had mild CHD. Considering the 4 diagnostic categories, kappa was 0.18. In patients with borderline RHD reclassified to non-RHD, the most frequent WHF criterion was B (isolated mitral regurgitation, 64%), followed by A (2 mitral valve morphological features, 31%). In 1 patient with definite RHD reclassified to normal, the WHF criterion was D (borderline RHD in aortic and mitral valves). After standard echo, RHD prevalence was 3.2% (95% CI 2.3-4.2). Conclusions: Although practical, RHD screening with handheld devices tends to overestimate prevalence.

Combinação de Ferramentas de Telecardiologia para Estratificação de Risco Cardiovascular na Atenção Primária: Dados do Estudo PROVAR+ / Combination of Tele-Cardiology Tools for Cardiovascular Risk Stratification in Primary Care: Data from the PROVAR+ Study

Resumo Fundamento: As ferramentas de telecardiologia são estratégias valiosas para melhorar a estratificação de risco. Objetivo: Objetivamos avaliar a acurácia da tele-eletrocardiografia (ECG) para predizer anormalidades no ecocardiograma de rastreamento na atenção primária. Métodos: Em 17 meses, 6 profissionais de saúde em 16 unidades de atenção primária foram treinados em protocolos simplificados de ecocardiografia portátil. Tele-ECGs foram registrados para diagnóstico final por um cardiologista. Pacientes consentidos com anormalidades maiores no ECG pelo código de Minnesota e uma amostra 1:5 de indivíduos normais foram submetidos a um questionário clínico e ecocardiograma de rastreamento interpretado remotamente. A doença cardíaca grave foi definida como doença valvular moderada/grave, disfunção/hipertrofia ventricular, derrame pericárdico ou anormalidade da motilidade. A associação entre alterações maiores do ECG e anormalidades ecocardiográficas foi avaliada por regressão logística da seguinte forma: 1) modelo não ajustado; 2) modelo 1 ajustado por idade/sexo; 3) modelo 2 mais fatores de risco (hipertensão/diabetes); 4) modelo 3 mais história de doença cardiovascular (Chagas/cardiopatia reumática/cardiopatia isquêmica/AVC/insuficiência cardíaca). Foram considerados significativos valores de p < 0,05. Resultados: No total, 1.411 pacientes realizaram ecocardiograma, sendo 1.149 (81%) com anormalidades maiores no ECG. A idade mediana foi de 67 anos (intervalo interquartil de 60 a 74) e 51,4% eram do sexo masculino. As anormalidades maiores no ECG se associaram a uma chance 2,4 vezes maior de doença cardíaca grave no ecocardiograma de rastreamento na análise bivariada (OR = 2,42 [IC 95% 1,76 a 3,39]) e permaneceram significativas (p < 0,001) após ajustes no modelo 2 (OR = 2,57 [IC 95% 1,84 a 3,65]), modelo 3 (OR = 2,52 [IC 95% 1,80 a 3,58]) e modelo 4 (OR = 2,23 [IC 95% 1,59 a 3,19]). Idade, sexo masculino, insuficiência cardíaca e doença cardíaca isquêmica também foram preditores independentes de doença cardíaca grave no ecocardiograma. Conclusões: As anormalidades do tele-ECG aumentaram a probabilidade de doença cardíaca grave no ecocardiograma de rastreamento, mesmo após ajustes para variáveis demográficas e clínicas.

Abstract Background: Tele-cardiology tools are valuable strategies to improve risk stratification. Objective: We aimed to evaluate the accuracy of tele-electrocardiography (ECG) to predict abnormalities in screening echocardiography (echo) in primary care (PC). Methods: In 17 months, 6 health providers at 16 PC units were trained on simplified handheld echo protocols. Tele-ECGs were recorded for final diagnosis by a cardiologist. Consented patients with major ECG abnormalities by the Minnesota code, and a 1:5 sample of normal individuals underwent clinical questionnaire and screening echo interpreted remotely. Major heart disease was defined as moderate/severe valve disease, ventricular dysfunction/hypertrophy, pericardial effusion, or wall-motion abnormalities. Association between major ECG and echo abnormalities was assessed by logistic regression as follows: 1) unadjusted model; 2) model 1 adjusted for age/sex; 3) model 2 plus risk factors (hypertension/diabetes); 4) model 3 plus history of cardiovascular disease (Chagas/rheumatic heart disease/ischemic heart disease/stroke/heart failure). P-values < 0.05 were considered significant. Results: A total 1,411 patients underwent echo; 1,149 (81%) had major ECG abnormalities. Median age was 67 (IQR 60 to 74) years, and 51.4% were male. Major ECG abnormalities were associated with a 2.4-fold chance of major heart disease on echo in bivariate analysis (OR = 2.42 [95% CI 1.76 to 3.39]), and remained significant after adjustments in models (p < 0.001) 2 (OR = 2.57 [95% CI 1.84 to 3.65]), model 3 (OR = 2.52 [95% CI 1.80 to3.58]), and model 4 (OR = 2.23 [95%CI 1.59 to 3.19]). Age, male sex, heart failure, and ischemic heart disease were also independent predictors of major heart disease on echo. Conclusions: Tele-ECG abnormalities increased the likelihood of major heart disease on screening echo, even after adjustments for demographic and clinical variables.

Outcomes of latent rheumatic heart disease: External validation of a simplified score in patients with and without secondary prophylaxis.

BACKGROUND: Secondary antibiotic prophylaxis reduces progression of latent rheumatic heart disease (RHD) but not all children benefit. Improved risk stratification could refine recommendations following positive screening. We aimed to evaluate the performance of a previously developed echocardiographic risk score to predict mid-term outcomes among children with latent RHD. METHODS: We included children who completed the GOAL, a randomized trial of secondary antibiotic prophylaxis among children with latent RHD in Uganda. Outcomes were determined by a 4-member adjudication panel. We applied the point-based score, consisting of 5 variables (mitral valve (MV) anterior leaflet thickening (3 points), MV excessive leaflet tip motion (3 points), MV regurgitation jet length ≥ 2 cm (6 points), aortic valve focal thickening (4 points) and any aortic regurgitation (5 points)), to panel results. Unfavorable outcome was defined as progression of diagnostic category (borderline to definite, mild definite to moderate/severe definite), worsening valve involvement or remaining with mild definite RHD. RESULTS: 799 patients (625 borderline and 174 definite RHD) were included, with median follow-up of 24 months. At total 116 patients (14.5%) had unfavorable outcome per study criteria, 57.8% not under prophylaxis. The score was strongly associated with unfavorable outcome (HR = 1.26, 95% CI 1.16-1.37, p < 0.001). Unfavorable outcome rates in low (≤6 points), intermediate (7-9 points) and high-risk (≥10 points) children at follow-up were 11.8%, 30.4%, and 42.2%, (p < 0.001) respectively (C-statistic = 0.64 (95% CI 0.59-0.69)). CONCLUSIONS: The simple risk score provided an accurate prediction of RHD status at 2-years, showing a good performance in a population with milder RHD phenotypes.

Reasons for disagreement between screening and standard echocardiography in primary care: data from the PROVAR + study : Disagreement between screening and standard echo.

We aimed to evaluate the reasons for disagreement between screening echocardiography (echo), acquired by nonexperts, and standard echo in the Brazilian primary care (PC). Over 20 months, 22 PC workers 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 remotelyinterpreted in US and Brazil, and those diagnosed with major or severe HD were referred for standard echoperformed by an expert. Major HD was defined as moderate to severe valve disease, ventriculardysfunction/hypertrophy, pericardial effusion or wall-motion abnormalities. A random sample of exams wasselected for evaluation of variables accounting for disagreement. A sample of 768 patients was analyzed, 651(85%) in the referred group. Quality issues were reported in 5.8%, and the random Kappa for major HD between screening and standard echo was 0.51. The most frequent reasons for disagreement 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 mitral and aortic morphological abnormalities was observed in 12.4% and 3.0%, and underestimation of AR and MR occurred in 4.6% and 11.1%. Among 257 patients with suspected mild/moderate MR, 129 were reclassified to normal. In conclusion, although screening echo with task-shifting in PC is a promising tool in low-income areas, estimation of valve regurgitation and LV function and size account for considerable disagreement with standard exams.

Investigation of the Familial Risk of Rheumatic Heart Disease with Systematic Echocardiographic Screening: Data from the PROVAR+ Family Study.

We aimed to use echocardiographic (echo) screening to evaluate the risk of Rheumatic Heart Disease (RHD) among the relatives of patients with advanced RHD, who were enrolled in the University Hospital's outpatient clinics from February 2020 to September 2021. Consenting first-degree relatives were invited for echo screening using handheld devices (GE VSCAN) by non-physicians, with remote interpretation. Matched controls (spouses, neighbors) living in the same household were enrolled in a 1:5 fashion. A standard echo (GE Vivid-IQ) was scheduled if abnormalities were observed. In 16 months, 226 relatives and 47 controls of 121 patients were screened, including 129 children, 77 siblings and 20 parents. The mean age was 40 ± 17 years, 67% of the patients were women, and 239 (88%) lived with the index case for >10 years. Echo findings suggestive of RHD were confirmed in zero controls and 14 (7.5%) relatives (p = 0.05): 11 patients had mild/moderate mitral regurgitation, and four were associated with mitral stenosis and abnormal morphology. Two patients had mild aortic regurgitation and abnormal morphology, which were associated with mild aortic and mitral stenosis, and two patients with advanced RHD had bioprostheses in the mitral (2) and aortic (1) positions. In conclusion, first-degree relatives of individuals with clinical RHD are at greater risk of having RHD, on top of socioeconomic conditions.

Outcomes of Echocardiography-Detected Rheumatic Heart Disease: Validating a Simplified Score in Cohorts From Different Countries.

Background The natural history of latent rheumatic heart disease (RHD) detected by echocardiography remains unclear. We aimed to assess the accuracy of a simplified score based on the 2012 World Heart Federation criteria in predicting mid-term RHD echocardiography outcomes in children from 4 different countries. Methods and Results Patient-level baseline and follow-up data of children with latent RHD from 4 countries (Australia, n=62; Brazil, n=197; Malawi, n=40; New Zealand, n=94) were combined. A simplified echocardiographic scoring system previously developed from Brazilian and Ugandan cohorts, consisting of 5 point-based variables with respective weights, was applied: mitral valveanterior leaflet thickening (weight=3), excessive leaflettip motion (3), regurgitation jet length ≥2 cm (6), aortic valvefocal thickening (4), and any regurgitation (5). Unfavorable outcome was defined as worsening diagnostic category, persistent definite RHD or development/worsening of valve regurgitation/stenosis. The score model was updated using methods for recalibration. 393 patients (314 borderline, 79 definite RHD) with median follow-up of 36 (interquartile range, 25-48) months were included. Median age was 14 (interquartile range, 11-16) years and secondary prophylaxis was prescribed to 16%. The echocardiographic score model applied to this external population showed significant association with unfavorable outcome (hazard ratio, 1.10; 95% CI, 1.04-1.16; P=0.001). Unfavorable outcome rates in low (≤5 points), intermediate (6-9), and high-risk (≥10) children at 3-year follow-up were 14.3%, 20.8%, and 38.5% respectively (P<0.001). The updated score model showed good performance in predicting unfavorable outcome. Conclusions The echocardiographic score model for predicting RHD outcome was updated and validated for different latent RHD populations. It has potential utility in the clinical and screening setting for risk stratification of latent RHD.

Bedside echocardiography to predict mortality of COVID-19 patients beyond clinical data: Data from the PROVAR-COVID study.

INTRODUCTION: Cardiac involvement seems to impact prognosis of COVID-19, being more frequent in critically ill patients. We aimed to assess the prognostic value of right ventricular (RV) and left ventricular (LV) dysfunction, evaluated by bedside echocardiography (echo), in patients hospitalized with COVID-19. METHODS: Patients admitted in 2 reference hospitals in Brazil from Jul to Sept/2020 with confirmed COVID-19 and moderate/severe presentations underwent clinical and laboratory evaluation, and focused bedside echo (GE Vivid-IQ), at the earliest convenience, with remote interpretation. The association between demographics, clinical comorbidities and echo variables with all-cause hospital mortality was assessed, and factors significant at p<0.10 were put into multivariable models. RESULTS: Total 163 patients were enrolled, 59% were men, mean age 64±16 years, and 107 (66%) were admitted to intensive care. Comorbidities were present in 144 (88%) patients: hypertension 115 (71%), diabetes 61 (37%) and heart failure 22 (14%). In-hospital mortality was 34% (N=56). In univariate analysis, echo variables significantly associated with death were: LV ejection fraction (LVEF, OR=0.94), RV fractional area change (OR=0.96), tricuspid annular plane systolic excursion (TAPSE, OR=0.83) and RV dysfunction (OR=5.3). In multivariate analysis, after adjustment for clinical and demographic variables, independent predictors of mortality were age≥63 years (OR=5.53, 95%CI 1.52-20.17), LVEF<64% (OR=7.37, 95%CI 2.10-25.94) and TAPSE<18.5 mm (OR=9.43, 95% CI 2.57-35.03), and the final model had good discrimination, with C-statistic=0.83 (95%CI 0.75-0.91). CONCLUSION: Markers of RV and LV dysfunction assessed by bedside echo are independent predictors of mortality in hospitalized COVID-19 patients, after adjustment for clinical variables.

Towards automatic diagnosis of rheumatic heart disease on echocardiographic exams through video-based deep learning.

OBJECTIVE: Rheumatic heart disease (RHD) affects an estimated 39 million people worldwide and is the most common acquired heart disease in children and young adults. Echocardiograms are the gold standard for diagnosis of RHD, but there is a shortage of skilled experts to allow widespread screenings for early detection and prevention of the disease progress. We propose an automated RHD diagnosis system that can help bridge this gap. MATERIALS AND METHODS: Experiments were conducted on a dataset with 11 646 echocardiography videos from 912 exams, obtained during screenings in underdeveloped areas of Brazil and Uganda. We address the challenges of RHD identification with a 3D convolutional neural network (C3D), comparing its performance with a 2D convolutional neural network (VGG16) that is commonly used in the echocardiogram literature. We also propose a supervised aggregation technique to combine video predictions into a single exam diagnosis. RESULTS: The proposed approach obtained an accuracy of 72.77% for exam diagnosis. The results for the C3D were significantly better than the ones obtained by the VGG16 network for videos, showing the importance of considering the temporal information during the diagnostic. The proposed aggregation model showed significantly better accuracy than the majority voting strategy and also appears to be capable of capturing underlying biases in the neural network output distribution, balancing them for a more correct diagnosis. CONCLUSION: Automatic diagnosis of echo-detected RHD is feasible and, with further research, has the potential to reduce the workload of experts, enabling the implementation of more widespread screening programs worldwide.

Echocardiographic screening of pregnant women by non-physicians with remote interpretation in primary care.

BACKGROUND: Impact of heart disease (HD) on pregnancy is significant. OBJECTIVE: We aimed to evaluate the feasibility of integrating screening echocardiography (echo) into the Brazilian prenatal primary care to assess HD prevalence. METHODS: Over 13 months, 20 healthcare workers acquired simplified echo protocols, utilizing hand-held machines (GE-VSCAN), in 22 primary care centres. Consecutive pregnant women unaware of HD underwent focused echo, remotely interpreted in USA and Brazil. Major HD was defined as structural valve abnormalities, more than mild valve dysfunction, ventricular systolic dysfunction/hypertrophy, or other major abnormalities. Screen-positive women were referred for standard echo. RESULTS: At total, 1 112 women underwent screening. Mean age was 27 ± 8 years, mean gestational age 22 ± 9 weeks. Major HD was found in 100 (9.0%) patients. More than mild mitral regurgitation was observed in 47 (4.2%), tricuspid regurgitation in 11 (1.0%), mild left ventricular dysfunction in 4 (0.4%), left ventricular hypertrophy in 2 (0.2%) and suspected rheumatic heart disease in 36 (3.2%): all, with mitral valve and two 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 mitral valve and two with AV disease), mitral regurgitation in 40 (14 with morphological changes, 10 suggestive of rheumatic heart disease), other AV disease in two (mild/moderate regurgitation). CONCLUSIONS: Integration of echo screening into primary prenatal care is feasible in Brazil. However, the low prevalence of severe disease urges further investigations about the effectiveness of the strategy.

Impact of incorporating echocardiographic screening into a clinical prediction model to optimise utilisation of echocardiography in primary care.

INTRODUCTION: Access to public subspecialty healthcare is limited in underserved areas of Brazil, including echocardiography (echo). Long waiting lines and lack of a prioritisation system lead to diagnostic lag and may contribute to poor outcomes. We developed a prioritisation tool for use in primary care, aimed at improving resource utilisation, by predicting those at highest risk of having an abnormal echo, and thus in highest need of referral. METHODS: All patients in the existing primary care waiting list for echo were invited for participation and underwent a clinical questionnaire, simplified 7-view echo screening by non-physicians with handheld devices, and standard echo by experts. Two derivation models were developed, one including only clinical variables and a second including clinical variables and findings of major heart disease (HD) on echo screening (cut point for high/low-risk). For validation, patients were risk-classified according to the clinical score. High-risk patients and a sample of low-risk underwent standard echo. Intermediate-risk patients first had screening echo, with a standard echo if HD was suspected. Discrimination and calibration of the two models were assessed to predict HD in standard echo. RESULTS: In derivation (N = 603), clinical variables associated with HD were female gender, body mass index, Chagas disease, prior cardiac surgery, coronary disease, valve disease, hypertension and heart failure, and this model was well calibrated with C-statistic = 0.781. Performance was improved with the addition of echo screening, with C-statistic = 0.871 after cross-validation. For validation (N = 1526), 227 (14.9%) patients were classified as low risk, 1082 (70.9%) as intermediate risk and 217 (14.2%) as high risk by the clinical model. The final model with two categories had high sensitivity (99%) and negative predictive value (97%) for HD in standard echo. Model performance was good with C-statistic = 0.720. CONCLUSION: The addition of screening echo to clinical variables significantly improves the performance of a score to predict major HD.

Cytokine gene functional polymorphisms and phenotypic expression as predictors of evolution from latent to clinical rheumatic heart disease.

INTRODUCTION: Inflammation associated with rheumatic heart disease (RHD) is influenced by gene polymorphisms and inflammatory cytokines. There are currently no immunologic and genetic markers to discriminate latent versus clinical patients, critical to predict disease evolution. Employing machine-learning, we searched for predictors that could discriminate latent versus clinical RHD, and eventually identify latent patients that may progress to clinical disease. METHODS: A total of 212 individuals were included, 77 with latent, 100 with clinical RHD, and 35 healthy controls. Circulating levels of 27 soluble factors were evaluated using Bio-Plex ProTM® Human Cytokine Standard 27-plex assay. Gene polymorphism analyses were performed using RT-PCR for the following genes: IL2, IL4, IL6, IL10, IL17A, TNF and IL23. RESULTS: Serum levels of all cytokines were higher in clinical as compared to latent RHD patients, and in those groups than in controls. IL-4, IL-8, IL-1RA, IL-9, CCL5 and PDGF emerged in the final multivariate model as predictive factors for clinical, compared with latent RHD. IL-4, IL-8 and IL1RA had the greater power to predict clinical RHD. In univariate analysis, polymorphisms in IL2 and IL4 were associated with clinical RHD and in the logistic analysis, IL6 (GG + CG), IL10 (CT + TT), IL2 (CA + AA) and IL4 (CC) genotypes were associated with RHD. CONCLUSION: Despite higher levels of all cytokines in clinical RHD patients, IL-4, IL-8 and IL-1RA were the best predictors of clinical disease. An association of polymorphisms in IL2, IL4, IL6 and IL10 genes and clinical RHD was observed. Gene polymorphism and phenotypic expression of IL-4 accurately discriminate latent versus clinical RHD, potentially instructing clinical management.

Bedside echocardiography to predict mortality of COVID-19 patients beyond clinical data: Data from the PROVAR-COVID study

Abstract INTRODUCTION: Cardiac involvement seems to impact prognosis of COVID-19, being more frequent in critically ill patients. We aimed to assess the prognostic value of right ventricular (RV) and left ventricular (LV) dysfunction, evaluated by bedside echocardiography (echo), in patients hospitalized with COVID-19. METHODS: Patients admitted in 2 reference hospitals in Brazil from Jul to Sept/2020 with confirmed COVID-19 and moderate/severe presentations underwent clinical and laboratory evaluation, and focused bedside echo (GE Vivid-IQ), at the earliest convenience, with remote interpretation. The association between demographics, clinical comorbidities and echo variables with all-cause hospital mortality was assessed, and factors significant at p<0.10 were put into multivariable models. RESULTS: Total 163 patients were enrolled, 59% were men, mean age 64±16 years, and 107 (66%) were admitted to intensive care. Comorbidities were present in 144 (88%) patients: hypertension 115 (71%), diabetes 61 (37%) and heart failure 22 (14%). In-hospital mortality was 34% (N=56). In univariate analysis, echo variables significantly associated with death were: LV ejection fraction (LVEF, OR=0.94), RV fractional area change (OR=0.96), tricuspid annular plane systolic excursion (TAPSE, OR=0.83) and RV dysfunction (OR=5.3). In multivariate analysis, after adjustment for clinical and demographic variables, independent predictors of mortality were age≥63 years (OR=5.53, 95%CI 1.52-20.17), LVEF<64% (OR=7.37, 95%CI 2.10-25.94) and TAPSE<18.5 mm (OR=9.43, 95% CI 2.57-35.03), and the final model had good discrimination, with C-statistic=0.83 (95%CI 0.75-0.91). CONCLUSION: Markers of RV and LV dysfunction assessed by bedside echo are independent predictors of mortality in hospitalized COVID-19 patients, after adjustment for clinical variables.

Health Education about Rheumatic Heart Disease: A Community-Based Cluster Randomized Trial: Rheumatic Heart Disease Educational Strategies.

Introduction: The burden of rheumatic heart disease (RHD) is still high in Brazil. Lack of population awareness about the disease limits the efficacy of prevention programs. We aimed to evaluate the effectiveness of education on RHD in schools, comparing the conventional expository teaching method with tablet-based worked examples. Method: A prospective, cluster randomized trial was conducted over eight months in six randomly selected low-income Brazilian public schools. Each class was considered a cluster (total: 90), being randomized 1:1 to receive one of the educational methods. Pre-test evaluated students' prior knowledge on RHD. Post-tests, 10 days, and three months later, evaluated retention of knowledge. Results: At total 1,301 students (52% female) completed the study, being 63% from high school. Baseline knowledge about RHD was universally low (average score expository classes [G1] 33.9% vs. worked examples [G2] 32.5%, p = 0.23). A significant but similar improvement was observed in both groups in the immediate post-test (pre- vs. post: p < 0.001): G1 57.5% vs. G2 56.7%, p = 0.69. In the late post-test, a significant 20% worsening was observed in both groups and the final scores were again similar: G1 45.0% vs. G2 45.9%, p = 0.87. Highschool students had higher scores (p < 0.001), and girls had better overall performances than boys (p < 0.001). Conclusion: The novel technology of tablet-based worked examples had similar results compared with expository classes for RHD education in schools. Both educational processes resulted in modest gains in knowledge, with low retention. More studies are needed to determine if increased knowledge leads to behavioral changes that could reduce RHD burden. Highlights: In a cluster-randomized trial, two different educational strategies about Rheumatic Heart Disease (RHD) for children - standard expository classes and worked examples based on interactive modules in tablet computers - were compared in public schools of underserved Brazilian neighborhoods.Baseline knowledge was low, and the novel tablet-based technology had similar results compared with traditional teaching for RHD education in schools, with no differences in acquisition and mid-term retention of knowledge.Both educational interventions resulted in similar 71% improvement in the immediate post-test, although with suboptimal retention, with over 20% worsening in three months in both groups.Our data suggests that the optimal strategy for RHD education is yet to be determined, and future studies should be warranted to determine if increased knowledge leads to behavioral changes that could reduce disease burden in endemic areas.

Cost-Effectiveness of Rheumatic Heart Disease Echocardiographic Screening in Brazil: Data from the PROVAR+ Study: Cost-effectiveness of RHD screening in Brazil.

Introduction: In recent years, new technologies - noticeably ultra-portable echocardiographic machines - have emerged, allowing for Rheumatic Heart Disease (RHD) early diagnosis. We aimed to perform a cost-utility analysis to assess the cost-effectiveness of RHD screening with handheld devices in the Brazilian context. Methods: A Markov model was created to assess the cost-effectiveness of one-time screening for RHD in a hypothetical cohort of 11-year-old socioeconomically disadvantaged children, comparing the intervention to standard care using a public perspective and a 30-year time horizon. The model consisted of 13 states: No RHD, Undiagnosed Asymptomatic Borderline RHD, Diagnosed Asymptomatic Borderline RHD, Untreated Asymptomatic Definite RHD, Treated Asymptomatic Definite RHD, Untreated Mild Clinical RHD, Treated Mild Clinical RHD, Untreated Severe Clinical RHD, Treated Severe Clinical RHD, Surgery, Post-Surgery and Death. The initial distribution of the population over the different states was derived from primary echo screening data. Costs of the different states were derived from the Brazilian public health system database. Transition probabilities and utilities were derived from published studies. A discount rate of 3%/year was used. A cost-effectiveness threshold of $25,949.85 per Disability Adjusted Life Year (DALY) averted is used in concordance with the 3x GDP per capita threshold in 2015. Results: RHD echo screening is cost-effective with an Incremental Cost-Effectiveness Ratio of $10,148.38 per DALY averted. Probabilistic modelling shows that the intervention could be considered cost-effective in 70% of the iterations. Conclusion: Screening for RHD with hand held echocardiographic machines in 11-year-old children in the target population is cost-effective in the Brazilian context. Highlights: A cost-effectiveness analysis showed that Rheumatic Heart Disease (RHD) echocardiographic screening utilizing handheld devices, performed by non-physicians with remote interpretation by telemedicine is cost-effective in a 30-year time horizon in Brazil.The model included primary data from the first large-scale RHD screening program in Brazilian underserved populations and costs from the Unified Health System (SUS), and suggests that the Incremental Cost-Effectiveness Ratio of the intervention is considerably below the acceptable threshold for Brazil, even after a detailed sensitivity analysis.Considering the high prevalence of subclinical RHD in Brazil, and the significant economic burden posed by advanced disease, these data are important for the formulation of public policies and surveillance approaches.Cost-saving strategies first implemented in Brazil by the PROVAR study, such as task-shifting to non-physicians, computer-based training, routine use of affordable devices and telemedicine for remote diagnosis may help planning RHD control programs in endemic areas worldwide.

Validation of a simplified score for predicting latent rheumatic heart disease progression using a prospective cohort of Brazilian schoolchildren.

OBJECTIVES: Echocardiographic (echo) screening is an important tool to estimate rheumatic heart disease (RHD) prevalence, but the natural history of screen-detected RHD remains unclear. The PROVAR+ (Programa de RastreamentO da VAlvopatia Reumática) study, which uses non-experts, telemedicine and portable echo, pioneered RHD screening in Brazil. We aimed to assess the mid-term evolution of Brazilian schoolchildren (5-18 years) with echocardiography-detected subclinical RHD and to assess the performance of a simplified score consisting of five components of the World Heart Federation criteria, as a predictor of unfavourable echo outcomes. SETTING: Public schools of underserved areas and private schools in Minas Gerais, southeast Brazil. PARTICIPANTS: A total of 197 patients (170 borderline and 27 definite RHD) with follow-up of 29±9 months were included. Median age was 14 (12-16) years, and 130 (66%) were woman. Only four patients in the definite group were regularly receiving penicillin. PRIMARY AND SECONDARY OUTCOME MEASURES: Unfavourable outcome was based on the 2-year follow-up echo, defined as worsening diagnostic category, remaining with mild definite RHD or development/worsening of valve regurgitation/stenosis. RESULTS: Among patients with borderline RHD, 29 (17.1%) progressed to definite, 49 (28.8%) remained stable, 86 (50.6%) regressed to normal and 6 (3.5%) were reclassified as other heart diseases. Among those with definite RHD, 13 (48.1%) remained in the category, while 5 (18.5%) regressed to borderline, 5 (18.5%) regressed to normal and 4 (14.8%) were reclassified as other heart diseases. The simplified echo score was a significant predictor of RHD unfavourable outcome (HR 1.197, 95% CI 1.098 to 1.305, p<0.001). CONCLUSION: The simple risk score provided an accurate prediction of RHD status at 2-year follow-up, showing a good performance in Brazilian schoolchildren, with a potential value for risk stratification and monitoring of echocardiography-detected RHD.

Atrial fibrillation detection with a portable device during cardiovascular screening in primary care.

INTRODUCTION: A novel handheld dual-electrode stick is a portable atrial fibrillation (AF) screening device (AFSD). We evaluated AFSD performance in primary care patients referred for echocardiogram (echo). METHODS: The AFSD has a light indication of irregular rhythm and single-lead ECG recording. Patients were instructed to hold the device for 1 min, and AF indication was recorded. A 12-lead ECG was performed for all AFSD-positive patients and 250 patients with negative AFSD screen. Echos were performed based on a clinical risk score: all high-risk patients and a sampling of low-risk patients underwent complete echo. Intermediate risk patients first had a screening echocardiogram, with a follow-up complete study if abnormality was suspected. RESULTS: In 5 days, 1518 patients underwent clinical evaluation and cardiovascular risk stratification: mean age 58±16 years, 66% women. The AFSD was positive in 6.4%: 12.6% high risk, 6.1% intermediate risk and 2.2% low risk. Older age was a risk factor (9.3% vs 4.8% in those more than and less than 65 years, p=0.001). AFSD positive was independently associated with heart disease in echo (OR=3.9, 95% CI 2.1 to 7.2, p<0.001). Compared with 12-lead ECG, the AFSD had sensitivity of 90.2% (95% CI 77.0% to 97.3%) and specificity of 84.0% (95% CI 79.3% to 88.0%) for AF detection. CONCLUSION: AFSD demonstrated high sensitivity for AF detection in primary care patients referred for echo. AF prevalence was substantial and independently associated with structural or functional heart disease, suggesting that AFSD screening could be a useful primary care tool to stratify risk and prioritise echo.

Circulating cytokines predict severity of rheumatic heart disease.

BACKGROUND: Rheumatic heart disease (RHD) is associated with inflammation that damages cardiac valves, often requiring surgical interventions. The underlying mechanisms involved in the disease progression are not completely understood. This study aimed to evaluate cytokine plasma levels in patients with RHD as possible markers of disease severity. METHODS AND RESULTS: Eighty-nine patients with RHD, age of 41 years ±11.5 years, were prospectively enrolled. RHD severity was defined as valve dysfunction that required invasive intervention, either valve repair or replacement. Peripheral blood samples were collected from all patients for cytokine measurements. The patients were followed up to look at adverse clinical events defined as either the need for valve intervention or death. At baseline, 64 (71.9%) patients had previously undergone valve intervention, whereas 25 patients had stable clinical presentation. Patients with severe RHD displayed higher levels of inflammatory cytokines than patients with stable disease. Cluster analysis showed segregation of severe and stable RHD based on IL-6/TNF-α and IL-6/IL-17A, respectively. IL-6 and TNF-α expression were positively correlated in severe but not in stable RHD patients. During a median follow-up of 23 months, 16 patients (18%) had an adverse outcome. IL-10 at baseline (HR 1.24, 95% CI 1.08-1.43, p = 0.003), and IL-4 (HR 1.12, 95% CI 1.01-1.24, p = 0.041) were predictors of events during the follow-up. CONCLUSIONS: High levels of cytokines are associated with severity of RHD. The co-regulated expression of IL-6 and TNF-α is associated with severe valve dysfunction, whereas high IL-10 and IL-4 levels predicted subsequently adverse outcome.

Integration of echocardiographic screening by non-physicians with remote reading in primary care.

INTRODUCTION: Heart disease (HD) accounts for high morbidity and mortality in Brazil. Underserved populations often suffer long delays in diagnosis. We aimed to evaluate the feasibility of integrating screening echocardiography (echo) with remote interpretation in the established primary care system (PC) in Brazil and to assess HD prevalence. METHODS: Over 11 months, 20 healthcare workers (four physicians, four nurses, and 12 technicians) at 16 PC centres were trained on simplified handheld echo protocols. Three screening (SC) groups, including all consented patients aged 17-20, 35-40 and 60-65 years, and patients referred (RF) for clinical indications underwent focused echo. Studies were remotely interpreted through telemedicine. Significant HD was defined as moderate/severe valve disease, ventricular dysfunction/hypertrophy, pericardial effusion, wall-motion abnormalities and congenital heart disease. RESULTS: Total 1004 patients underwent echo; 299 (29.8%) in the SC group. Median age was 51±18 years, 63.9% females; 42.7% had cardiovascular symptoms. Significant HD was found in 354 (35.3%) patients (23.4% in SC vs 40.3% in RF group, p<0.001). Prevalence was higher in patients in the SC group aged >60 years (29.2%), compared with 35-40 (14.9%) and under 20 (16.5%), p=0.012. Comparing SC to RF groups, moderate/severe left ventricular dysfunction was observed in 4.1% vs 8.1%, p=0.03, mitral regurgitation in 8.9% vs 20.3%, p<0.001 and aortic stenosis in 5.4% vs 4.3%, p=0.51. CONCLUSIONS: Integration focused echo into PC is feasible in Brazil as a strategy to deliver cardiovascular care to low-resourced areas through task shifting. The burden of HD observed suggests this tool may improve early diagnosis and referral.