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.

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.

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.

Simplified Echocardiography Screening Criteria for Diagnosing and Predicting Progression of Latent Rheumatic Heart Disease.

BACKGROUND: The 2012 World Heart Federation Criteria are the current gold standard for the diagnosis of latent rheumatic heart disease (RHD). Because data and experience using these criteria have grown, there is opportunity to simplify and develop outcome prediction tools. We aimed to develop a simple echocardiographic score applicable for RHD screening with potential to predict disease progression. METHODS: This study included 3 cohorts used for score derivation (n=9501), score validation (n=7312), and assessment of outcomes prediction (n=227). In the derivation cohort, variables independently associated with definite RHD were assigned point values proportional to their regression coefficients. The sum of these values was stratified into low (0-6), intermediate (7-9), and high (≥10) risk. RESULTS: Five components were selected for score development, including mitral valve anterior leaflet thickening, excessive leaflet tip motion, and regurgitation jet length ≥2 cm, and aortic valve focal thickening and any regurgitation. The score showed optimal discrimination and calibration for RHD diagnosis in the derivation and validation cohorts (C statistic, 0.998 and 0.994, respectively), with good discrimination for predicting disease progression (C statistic, 0.811). Progression-free survival rate in the low-risk children at 1-, 2-, and 3-year follow-up was 100%, 100%, and 93%, respectively, compared with 90%, 60%, and 47% in high-risk group. The point-based score was strongly associated with disease progression (hazard ratio, 1.270; 95% CI, 1.188-1.358; P<0.001). CONCLUSIONS: This simplified score, based on components of the World Heart Federation criteria, is highly accurate to recognize definite RHD and provides the first tool for risk stratification, assigning children with latent RHD to low, intermediate, or high risk based on echocardiographic features at diagnosis.

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.

Telehealth solutions to enable global collaboration in rheumatic heart disease screening.

Background The global burden of rheumatic heart disease is nearly 33 million people. Telemedicine, using cloud-server technology, provides an ideal solution for sharing images performed by non-physicians with cardiologists who are experts in rheumatic heart disease. Objective We describe our experience in using telemedicine to support a large rheumatic heart disease outreach screening programme in the Brazilian state of Minas Gerais. Methods The Programa de Rastreamento da Valvopatia Reumática (PROVAR) is a prospective cross-sectional study aimed at gathering epidemiological data on the burden of rheumatic heart disease in Minas Gerais and testing of a non-expert, telemedicine-supported model of outreach rheumatic heart disease screening. The primary goal is to enable expert support of remote rheumatic heart disease outreach through cloud-based sharing of echocardiographic images between Minas Gerais and Washington. Secondary goals include (a) developing and sharing online training modules for non-physicians in echocardiography performance and interpretation and (b) utilising a secure web-based system to share clinical and research data. Results PROVAR included 4615 studies that were performed by non-experts at 21 schools and shared via cloud-telemedicine technology. Latent rheumatic heart disease was found in 251 subjects (4.2% of subjects: 3.7% borderline and 0.5% definite disease). Of the studies, 50% were preformed on full functional echocardiography machines and transmitted via Digital Imaging and Communications in Medicine (DICOM) and 50% were performed on handheld echocardiography machines and transferred via a secure Dropbox connection. The average time between study performance date and interpretation was 10 days. There was 100% success in initial image transfer. Less than 1% of studies performed by non-experts could not be interpreted. Discussion A sustainable, low-cost telehealth model, using task-shifting with non-medical personal in low and middle income countries can improve access to echocardiography for rheumatic heart disease.

Comparison Between Different Strategies of Rheumatic Heart Disease Echocardiographic Screening in Brazil: Data From the PROVAR (Rheumatic Valve Disease Screening Program) Study.

BACKGROUND: Considering the limited accuracy of clinical examination for early diagnosis of rheumatic heart disease (RHD), echocardiography has emerged as an important epidemiological tool. The ideal setting for screening is yet to be defined. We aimed to evaluate the prevalence and pattern of latent RHD in schoolchildren (aged 5-18 years) and to compare effectiveness of screening between public schools, private schools, and primary care centers in Minas Gerais, Brazil. METHODS AND RESULTS: The PROVAR (Rheumatic Valve Disease Screening Program) study uses nonexperts and portable and handheld devices for RHD echocardiographic screening, with remote interpretation by telemedicine, according to the 2012 World Heart Federation criteria. Compliance with study consent and prevalence were compared between different screening settings, and variables associated with RHD were analyzed. In 26 months, 12 048 students were screened in 52 public schools (n=10 901), 2 private schools (n=589), and 3 primary care centers (n=558). Median age was 12.9 years, and 55.4% were girls. Overall RHD prevalence was 4.0% borderline (n=486) and 0.5% definite (n=63), with statistically similar rates between public schools (4.6%), private schools (3.5%), and primary care centers (4.8%) (P=0.24). The percentage of informed consents signed was higher in primary care centers (84.4%) and private schools (66.9%) compared with public schools (38.7%) (P<0.001). Prevalence was higher in children ≥12 years (5.3% versus 3.1%; P<0.001) and girls (4.9% versus 4.0%; P=0.02). Only age (odds ratio, 1.12; 95% confidence interval, 1.09-1.17; P<0.001) was independently associated with RHD. CONCLUSIONS: RHD screening in primary care centers seems to achieve higher coverage rates. Prevalence among schoolchildren is significantly high, with rates higher than expected in private schools of high-income areas. These data are important for the formulation of public policies to confront RHD.

Echocardiographic prevalence of rheumatic heart disease in Brazilian schoolchildren: Data from the PROVAR study.

BACKGROUND: Accurate estimates of Rheumatic Heart Disease (RHD) burden are needed to justify improved integration of RHD prevention and screening into the public health systems, but data from Latin America are still sparse. OBJECTIVE: To determine the prevalence of RHD among socioeconomically disadvantaged youth (5-18years) in Brazil and examine risk factors for the disease. METHODS: The PROVAR program utilizes non-expert screeners, telemedicine, and handheld and standard portable echocardiography to conduct echocardiographic screening in socioeconomically disadvantaged schools in Minas Gerais, Brazil. Cardiologists in the US and Brazil provide expert interpretation according to the 2012 World Heart Federation Guidelines. Here we report prevalence data from the first 14months of screening, and examine risk factors for RHD. RESULTS: 5996 students were screened across 21 schools. Median age was 11.9 [9.0/15.0] years, 59% females. RHD prevalence was 42/1000 (n=251): 37/1000 borderline (n=221) and 5/1000 definite (n=30). Pathologic mitral regurgitation was observed in 203 (80.9%), pathologic aortic regurgitation in 38 (15.1%), and mixed mitral/aortic valve disease in 10 (4.0%) children. Older children had higher prevalence (50/1000 vs. 28/1000, p<0.001), but no difference was observed between northern (lower resourced) and central areas (34/1000 vs. 44/1000, p=0.31). Females had higher prevalence (48/1000 vs. 35/1000, p=0.016). Age (OR=1.15, 95% CI:1.10-1.21, p<0.001) was the only variable independently associated with RHD findings. CONCLUSIONS: RHD continues to be an important and under recognized condition among socioeconomically disadvantaged Brazilian schoolchildren. Our data adds to the compelling case for renewed investment in RHD prevention and early detection in Latin America.

Efficacy of a Standardized Computer-Based Training Curriculum to Teach Echocardiographic Identification of Rheumatic Heart Disease to Nonexpert Users.

The ability to integrate echocardiographic for rheumatic heart disease (RHD) into RHD prevention programs is limited because of lack of financial and expert human resources in endemic areas. Task shifting to nonexperts is promising; but investigations into workforce composition and training schemes are needed. The objective of this study was to test nonexperts' ability to interpret RHD screening echocardiograms after a brief, standardized, computer-based training course. Six nonexperts completed a 3-week curriculum on image interpretation. Participant performance was tested in a school-screening environment in comparison to the reference approach (cardiologists, standard portable echocardiography machines, and 2012 World Heart Federation criteria). All participants successfully completed the curriculum, and feedback was universally positive. Screening was performed in 1,381 children (5 to 18 years, 60% female), with 397 (47 borderline RHD, 6 definite RHD, 336 normal, and 8 other) referred for handheld echo. Overall sensitivity of the simplified approach was 83% (95% CI 76% to 89%), with an overall specificity of 85% (95% CI 82% to 87%). The most common reasons for false-negative screens (n = 16) were missed mitral regurgitation (MR; 44%) and MR ≤1.5 cm (29%). The most common reasons for false-positive screens (n = 179) included identification of erroneous color jets (25%), incorrect MR measurement (24%), and appropriate application of simplified guidelines (39.4%). In conclusion, a short, independent computer-based curriculum can be successfully used to train a heterogeneous group of nonexperts to interpret RHD screening echocardiograms. This approach helps address prohibitive financial and workforce barriers to widespread RHD screening.