2023 World Heart Federation guidelines for the echocardiographic diagnosis of rheumatic heart disease.

Rheumatic heart disease (RHD) is an important and preventable cause of morbidity and mortality among children and young adults in low-income and middle-income countries, as well as among certain at-risk populations living in high-income countries. The 2012 World Heart Federation echocardiographic criteria provided a standardized approach for the identification of RHD and facilitated an improvement in early case detection. The 2012 criteria were used to define disease burden in numerous epidemiological studies, but researchers and clinicians have since highlighted limitations that have prompted a revision. In this updated version of the guidelines, we incorporate evidence from a scoping review, an expert panel and end-user feedback and present an approach for active case finding for RHD, including the use of screening and confirmatory criteria. These guidelines also introduce a new stage-based classification for RHD to identify the risk of disease progression. They describe the latest evidence and recommendations on population-based echocardiographic active case finding and risk stratification. Secondary antibiotic prophylaxis, echocardiography equipment and task sharing for RHD active case finding are also discussed. These World Heart Federation 2023 guidelines provide a concise and updated resource for clinical and research applications in RHD-endemic regions.

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.

Clinical Profile and Outcomes of Rheumatic Heart Disease Patients Undergoing Surgical Valve Procedures in Uganda.

Background: Chronic valvular heart disease is a well-known, long-term complication of acute rheumatic fever (ARF), which remains a major public health problem in low- and middle-income countries. Access to surgical management remains limited. Outcomes of the minority proportion of patients that access surgery have not been described in Uganda. Objectives: To describe the volume and type of rheumatic heart disease (RHD) valvular interventions and the outcomes of operated patients in the Uganda RHD registry. Methods: We performed a retrospective cohort study of all valve surgery procedures identified in the Uganda RHD registry through December 2021. Results: Three hundred and sixty-seven surgical procedures were performed among 359 patients. More than half were among young (55.9% were ≤20 years of age), female (59.9%) patients. All patients were censored at 15 years. The median (IQR) follow up period was 43 (22,79) months. Nearly half of surgeries (46.9%) included interventions on multiple valves, and most valvular operations were replacements with mechanical prostheses (96.6%). Over 70% of the procedures were sponsored by charity organizations. The overall mortality of patients who underwent surgery was 13% (47/359), with over half of the mortalities occurring within the first year following surgery (27/47; 57.4%). Fifteen-year survival or freedom from re-operation was not significantly different between those receiving valve replacements and those receiving valve repair (log-rank p = 0.76). Conclusions: There has been increasing access to valve surgery among Ugandan patients with RHD. Post-operative survival is similar to regionally reported rates. The growing cohort of patients living with prosthetic valves necessitates national expansion and decentralization of post-operative care services. Major reliance on charity funding of surgery is unsustainable, thus calling for locally generated and controlled support mechanisms such as a national health insurance scheme. The central illustration (Figure 1) provides a summary of our findings and recommendations.

Tertiary prevention and treatment of rheumatic heart disease: a National Heart, Lung, and Blood Institute working group summary.

Although entirely preventable, rheumatic heart disease (RHD), a disease of poverty and social disadvantage resulting in high morbidity and mortality, remains an ever-present burden in low-income and middle-income countries (LMICs) and rural, remote, marginalised and disenfranchised populations within high-income countries. In late 2021, the National Heart, Lung, and Blood Institute convened a workshop to explore the current state of science, to identify basic science and clinical research priorities to support RHD eradication efforts worldwide. This was done through the inclusion of multidisciplinary global experts, including cardiovascular and non-cardiovascular specialists as well as health policy and health economics experts, many of whom also represented or closely worked with patient-family organisations and local governments. This report summarises findings from one of the four working groups, the Tertiary Prevention Working Group, that was charged with assessing the management of late complications of RHD, including surgical interventions for patients with RHD. Due to the high prevalence of RHD in LMICs, particular emphasis was made on gaining a better understanding of needs in the field from the perspectives of the patient, community, provider, health system and policy-maker. We outline priorities to support the development, and implementation of accessible, affordable and sustainable interventions in low-resource settings to manage RHD and related complications. These priorities and other interventions need to be adapted to and driven by local contexts and integrated into health systems to best meet the needs of local communities.

Long COVID in Uganda: Electrographic findings among patients at risk.

Background: COVID-19 has a significant cardiovascular involvement. Electrocardiographic (ECG) abnormalities among people at a risk of Long COVID in Uganda was investigated. Methods: A cross-sectional study was conducted from February to June 2022 at the post COVID - 19 clinic in Mulago National Specialized Hospital, Kampala. A standard resting ECG was performed on individuals at least 2 months following acute COVID-19, with a negative SARS-CoV-2 reverse-transcription polymerase chain reaction. Sociodemographic and clinical characteristics as well as vital signs were recorded for all study participants. Results: Of the 244 study participants, 117 (47.9%) were female. The median age of all the participants was 33.0 (interquartile range: 26.0 - 43.5) years. Twenty-five (10.2%) participants had a history of smoking while 117 (48%) had a history of alcohol intake. In total, 46 (18.9%) had abnormal ECG findings (95% Confidence Interval (CI): 14.39 - 24.29) and non-specific T-wave inversion (n = 16, 34%) was the most frequent ECG abnormality. The proportion of participants with ECG abnormalities was 48% lower among females (adjusted prevalence ratio (aPR): 0.52, 95% CI: 0.28 - 0.96, p value < 0.05) and 2-fold greater for those with a history of smoking (aPR: 2.03, 95% CI:1.096 - 3.776, p value < 0.05). Conclusion: One in five Ugandans who were checked at the clinic at a risk of Long COVID showed ECG abnormalities. ECG screening is suggested to be integrated into the follow-up care of those at a risk of Long COVID.

The Use of Artificial Intelligence Guidance for Rheumatic Heart Disease Screening by Novices.

INTRODUCTION: A novel technology utilizing artificial intelligence (AI) to provide real-time image-acquisition guidance, enabling novices to obtain diagnostic echocardiographic images, holds promise to expand the reach of echo screening for rheumatic heart disease (RHD). We evaluated the ability of nonexperts to obtain diagnostic-quality images in patients with RHD using AI guidance with color Doppler. METHODS: Novice providers without prior ultrasound experience underwent a 1-day training curriculum to complete a 7-view screening protocol using AI guidance in Kampala, Uganda. All trainees then scanned 8 to 10 volunteer patients using AI guidance, half RHD and half normal. The same patients were scanned by 2 expert sonographers without the use of AI guidance. Images were evaluated by expert blinded cardiologists to assess (1) diagnostic quality to determine presence/absence of RHD and (2) valvular function and (3) to assign an American College of Emergency Physicians score of 1 to 5 for each view. RESULTS: Thirty-six novice participants scanned a total of 50 patients, resulting in a total of 462 echocardiogram studies, 362 obtained by nonexperts using AI guidance and 100 obtained by expert sonographers without AI guidance. Novice images enabled diagnostic interpretation in >90% of studies for presence/absence of RHD, abnormal MV morphology, and mitral regurgitation (vs 99% by experts, P ≤ .001). Images were less diagnostic for aortic valve disease (79% for aortic regurgitation, 50% for aortic stenosis, vs 99% and 91% by experts, P < .001). The American College of Emergency Physicians scores of nonexpert images were highest in the parasternal long-axis images (mean, 3.45; 81% ≥ 3) compared with lower scores for apical 4-chamber (mean, 3.20; 74% ≥ 3) and apical 5-chamber images (mean, 2.43; 38% ≥ 3). CONCLUSIONS: Artificial intelligence guidance with color Doppler is feasible to enable RHD screening by nonexperts, performing significantly better for assessment of the mitral than aortic valve. Further refinement is needed to optimize acquisition of color Doppler apical views.

Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†.

BACKGROUND: The genetics of rheumatic heart disease (RHDGen) Network was developed to assist the discovery and validation of genetic variations and biomarkers of risk for rheumatic heart disease (RHD) in continental Africans, as a part of the global fight to control and eradicate rheumatic fever/RHD. Thus, we describe the rationale and design of the RHDGen study, comprising participants from 8 African countries. METHODS: RHDGen screened potential participants using echocardiography, thereafter enrolling RHD cases and ethnically-matched controls for whom case characteristics were documented. Biological samples were collected for conducting genetic analyses, including a discovery case-control genome-wide association study (GWAS) and a replication trio family study. Additional biological samples were also collected, and processed, for the measurement of biomarker analytes and the biomarker analyses are underway. RESULTS: Participants were enrolled into RHDGen between December 2012 and March 2018. For GWAS, 2548 RHD cases and 2261 controls (3301 women [69%]; mean age [SD], 37 [16.3] years) were available. RHD cases were predominantly Black (66%), Admixed (24%), and other ethnicities (10%). Among RHD cases, 34% were asymptomatic, 26% had prior valve surgery, and 23% had atrial fibrillation. The trio family replication arm included 116 RHD trio probands and 232 parents. CONCLUSIONS: RHDGen presents a rare opportunity to identify relevant patterns of genetic factors and biomarkers in Africans that may be associated with differential RHD risk. Furthermore, the RHDGen Network provides a platform for further work on fully elucidating the causes and mechanisms associated with RHD susceptibility and development.

Positive impact of training rural health workers in identification and prevention of acute rheumatic fever in eastern Uganda.

BACKGROUND: Diagnosis of acute rheumatic fever (ARF) is mainly clinical. Delayed or missed diagnosis and failure to administer appropriate and timely treatment of ARF leads to rheumatic heart disease (RHD), which could necessitate expensive treatments such as open-heart surgery. Implementation of preventative guidelines depends on availability of trained healthcare workers. As part of the routine support supervision, the Uganda Heart Institute sent out a team to rural eastern Uganda to evaluate health workers' knowledge level regarding management of ARF. METHODS: Health workers from selected health facilities in Tororo district, eastern Uganda, were assessed for their knowledge on the clinical features and role of benzathine penicillin G (BPG) in the treatment and prevention of ARF recurrence. Using the RHD Action Needs assessment tool, we generated and administered a pre-test, then conducted training and re-administered a post-test. Eight months later, health workers were again assessed for knowledge retention and change in practices. Statistical analysis was done using Stata version 15. RESULTS: During the initial phase, 34 of the 109 (31%) health workers passed the pre-test, indicating familiarity with clinical features of ARF. The level of knowledge of BPG use in ARF was very poor in all the health units [25/109 (22.6%)] but improved after training to 80%, as shown by the chi-squared test ( χ2 = 0.000). However, retention of this knowledge waned after eight months and was not significantly different compared to pre-training (χ2 ≥ 0.2). CONCLUSIONS: A critical knowledge gap is evident among health workers, both in awareness and treatment of ARF, and calls for repetitive training as a priority strategy in prevention.

The role of conventional echocardiographic parameters on detecting subclinical anthracycline therapy related cardiac dysfunction-The SATRACD study.

Background: Subclinical anthracycline therapy related cardiac dysfunction (ATRCD) can be detected with speckle tracking echocardiographic image (STE), which is not widely available in Uganda. We aimed to investigate the role of the two conventional echocardiographic parameters [mitral annular plane systolic excursion (MAPSE) and mitral annular peak systolic tissue Doppler velocity (S')] on diagnosing subclinical ATRCD. Method and results: 207 cancer patients who underwent anthracycline based chemotherapy were recruited at baseline and followed up until 6 months after ending anthracycline therapy. Comprehensive echocardiographic data were collected at each visit. Global longitudinal strain (GLS) by STE was used as the gold standard diagnostic test to define the case of subclinical ATRCD. Data of the 200 patients who had no evidence of clinical ATRCD were analyzed. One hundred and seventy-two (86.0%) were female, with a median age of 42 years and 47 (23.5%) patients were diagnosed with subclinical ATRCD at the end of anthracycline therapy by GLS criteria. The area under the curve (AUC), cutoff point, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of reduction of MAPSE (ΔMAPSE) were 0.6736 (95% CI: 0.5885, 0.7587), ≥ 2 mm, 74.5% (95% CI: 59.7%, 86.1%), 54.9% (95% CI: 46.7%, 63.0%), 33.7% (95% CI: 24.7%, 43.6%), and 87.5% (95% CI: 79.2%, 93.4%). The AUC, cutoff point, sensitivity, specificity, PPV, and NPV of reduction of S' (ΔS') were 0.6018 (95% CI: 0.5084, 0.6953), ≥ 0.5 cm/s, 61.7% (95% CI: 46.4%, 75.5%), 52.7% (95% CI: 44.4%, 60.9%), 29.0% (95% CI: 20.4%, 38.9%), and 76.1% (95% CI: 72.4%, 88.6%). When ΔMAPSE and ΔS' are used as parallel test, the net sensitivity and specificity is 89.4% and 28.8%, respectively, the net PPV and NPV is 27.8% and 90.0%, respectively. Conclusion: The ΔMAPSE and ΔS' showed fairly good accuracy, sensitivity and NPV to detect subclinical ATRCD in Ugandan cancer patients. These conventional echocardiographic parameters may serve as screening tools for detecting subclinical ATRCD in resource limited settings.

Prevalence of cardiovascular risk factors in active tuberculosis in Africa: a systematic review and meta-analysis.

People with tuberculosis (TB) are at risk of major adverse cardiovascular events. We estimated the prevalence of cardiovascular risk (CVR) factors among people with active TB in Africa. This was a systematic review and meta-analysis of studies from Africa. We searched EMBASE, MEDLINE through PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, mRCTs, Clinical trials.gov, and International Clinical Trials Registry Platform from inception to 31st December 2021. Among 110 eligible studies, 79 (238,316 participants) were included in the meta-analysis for smoking, 67 (52,793 participants) for current alcohol use, 30 (31,450 participants) for hazardous alcohol use, 51 (37,879 participants) for diabetes mellitus (DM), 19 (18,211 participants) for hypertension and 18 (13,910 participants) for obesity. The pooled prevalence was 26.0% (95% confidence interval 22.0-29.0) for smoking, 30.0% (25.0-35.0) for any current alcohol use, 21.0% (17.0-26.0) for hazardous alcohol use, 14.0% (9.0-18.0) for hypertension, 7.0% (6.0-9.0) for DM, and 4.0% (2.0-5.0) for obesity. Cost-effective strategies are needed to screen for CVR factors among people with active TB in Africa.

Detecting subclinical anthracycline therapy-related cardiac dysfunction in patients attending Uganda Cancer Institute.

Aims: To investigate the incidence of anthracycline therapy-related cardiac dysfunction (ATRCD) and its predictors among Ugandan cancer patients. Patients & methods: The study recruited 207 cancer patients who were followed for 6 months after ending anthracycline therapy. Global longitudinal strain and troponin-I were the diagnostic tools. Results & conclusions: The cumulative incidences of subclinical and clinical ATRCD were 35.0 and 8.8% respectively. The predictors of clinical ATRCD were HIV infection (hazard ratio [HR]: 3.04; 95% CI: 1.26-7.32; p = 0.013), lower baseline global longitudinal strain (HR: 0.61; 95% CI: 0.53-0.71; p < 0.001) and development of subclinical ATRCD at the end of anthracycline therapy (HR: 6.61; 95% CI: 2.60-16.82; p < 0.001). Cardiac surveillance at baseline and at ending of anthracycline therapy is essential to identify high-risk patients.

Anthracyclines are drugs for treating many types of cancers. They may however be harmful to the heart. This anthracycline side effect will first cause subtle heart­cell injury that can be detected and treated if it is handled early. Therefore, this study aims to study patients in the Uganda Cancer Institute to find out how many patients can get and who are likely to get this side effect. We found that 35% of the patients had subtle heart­cell injury and 8.8% had a more severe form of heart­cell injury. The patients who lived with HIV, whose heart was weaker and who got subtle heart­cell injury immediately after treatment were more likely to get the severe form of the side effect. Patients who receive anthracycline therapy need to be monitored closely to prevent serious heart injury.

Clinical Outcomes, Echocardiographic Findings, and Care Quality Metrics for People Living With Human Immunodeficiency Virus (HIV) and Rheumatic Heart Disease in Uganda.

BACKGROUND: Rheumatic heart disease (RHD) affects 41 million people worldwide, mostly in low- and middle-income countries, where it is co-endemic with human immunodeficiency virus (HIV). HIV is also a chronic inflammatory disorder associated with cardiovascular complications, yet the epidemiology of patients affected by both diseases is poorly understood. METHODS: Utilizing the Uganda National RHD Registry, we described the echocardiographic findings, clinical characteristics, medication prescription rates, and outcomes of all 73 people carrying concurrent diagnoses of HIV and RHD between 2009 and 2018. These individuals were compared to an age- and sex-matched cohort of 365 subjects with RHD only. RESULTS: The median age of the HIV-RHD group was 36 years (interquartile range [IQR] 15), and 86% were women. The HIV-RHD cohort had higher rates of prior stroke/transient ischemic attack (12% vs 5%, P = .02) than the RHD-only group, with this association persisting following multivariable adjustment (odds ratio [OR] 3.08, P = .03). Prevalence of other comorbidities, echocardiographic findings, prophylactic penicillin prescription rates, retention in clinical care, and mortality were similar between the 2 groups. CONCLUSIONS: Patients living with RHD and HIV in Uganda are a relatively young, predominantly female group. Although RHD-HIV comorbid individuals have higher rates of stroke, their similar all-cause mortality and RHD care quality metrics (such as retention in care) compared to those with RHD alone suggest rheumatic heart disease defines their clinical outcome more than HIV does. We believe this study to be one of the first reports of the epidemiologic profile and longitudinal outcomes of patients who carry diagnoses of both conditions.

Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

BACKGROUND: Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown. METHODS: We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years. RESULTS: Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis). CONCLUSIONS: Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.).

Rational and design of SATRACD study: detecting subclinical anthracycline therapy related cardiac dysfunction in low income country.

BACKGROUND: Anthracycline therapy-related cardiac dysfunction (ATRCD) is the most notorious adverse side-effect of chemotherapy. It has become a significant cardiovascular health concern for long-term cancer survivors. With the emerging concept of subclinical ATRCD and newer diagnostictools (Speckle Tracking Echocardiography (STE) and biomarkers), detecting anthracycline cardiac toxicity at an early stage has become an important step to prevent severe cardiac dysfunction and improve the cardiovascular outcome in cancer survivors. Despite the increasing population at risk in sub-Saharan Africa (SSA), there is no contemporary data in Uganda to address the burden, pathogenesis and risk factors of subclinical ATRCD. This big gap in knowledge has led to a lack of local guidelines for monitoring and management of ATRCD. METHODS: SATRACD (Detecting Subclinical Anthracycline Therapy Related Cardiac Dysfunction In Low Income Country) study is an observational prospective cohort study. Three hundred and fifty-three anthracycline naïve cancer patients will be recruited at baseline. Patients are followed up on completion of anthracycline-based chemotherapy and at 6 months after completion of anthracycline therapy. Data on demographics, cancer profile and clinical presentation will be collected at baseline. Comprehensive cardiac assessment will be performed at each visit, including electrocardiogram, conventional echocardiography, STE, cardiac and oxidative stress markers. We will be able to determine the incidence of subclinical and clinical ATRCD at 6 months after completion of anthracycline therapy, determine whether hypertension is a major risk factor for ATRCD, evaluate the role of conventional echocardiography parameters, and biomarkers for detecting subclinical ATRCD. CONCLUSION: This SATRACD study will provide contemporary data on Ugandan cancer patients who have subclinical and clinical ATRCD, help in the development of local strategies to prevent and manage ATRCD, and improve cardiovascular outcome for Ugandan cancer survivors.

Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study.

Importance: Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD. Objective: To identify common genetic loci associated with RHD susceptibility in Black African individuals. Design, Setting, and Participants: This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021. Main Outcomes and Measures: Genetic associations with RHD. Results: This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10-8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10-3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10-5) in Black African individuals. Conclusions and Relevance: This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.

Clinical characterization, cardiovascular risk factor profile and cardiac strain analysis in a Uganda cancer population: The SATRACD study.

BACKGROUND: The link between cancer and cardiovascular disease is firmly established. We sought to investigate the prevalence of cardiovascular disease (CVD) risk factors in Uganda cancer patients, their pre-chemotherapy left ventricular strain echocardiographic pattern and its associations with the CVD risk factors. METHODS AND RESULTS: Baseline pre-chemotherapy data of patients who were enrolled in the SATRACD study (a cancer cohort, who were planned for anthracycline therapy), were analyzed. The prevalence of cardiovascular risk factors and baseline strain echocardiographic images were assessed. Among the 355 patients who were recruited over a period of 15 months, 283 (79.7%) were female, with a mean age of 43 years. The types of cancer of the study patients included breast cancer (70.6%), lymphomas, sarcomas, leukemias and hepatocellular carcinoma. Hypertension was the most common comorbidity (27.0%). The prevalence of obesity was 12.1% and that of HIV was 18.3%. All patients had a normal left ventricular ejection fraction (LVEF). The mean global longitudinal strain (GLS) was -20.92 ±2.43%, with females having a significantly higher GLS than males (-21.09±2.42 vs -20.25±2.39, p = 0.008). Fifty-three patients (14.9%) had suboptimal GLS (absolute GLS≤18.00%), which was associated with obesity (POR = 3.07; 95% CI, 1.31-6.98; p = 0.003), alcohol use (POR = 1.94; 95% CI, 1.01-3.74; p = 0.044), long QTc interval in electrocardiogram (POR = 2.54; 95% CI, 1.06-5.74; p = 0.015,) and impaired left ventricular relaxation (POR = 2.24; 95% CI, 1.17-4.25; p = 0.007). On multivariable logistic regression analysis, obesity (POR = 2.95; 95% CI, 1.24-7.03; p = 0.014) was the only independent factor associated with suboptimal GLS. CONCLUSION: There is high prevalence and a unique pattern of cardiovascular risk factors in Uganda cancer patients. In cancer patients with cardiovascular risk conditions, there is reduction in GLS despite preserved LVEF. Longitudinal research is needed to study the predictive value of cardiovascular risk factors and baseline GLS for post chemotherapy cardiac dysfunction.

The inter-rater reliability and individual reviewer performance of the 2012 world heart federation guidelines for the echocardiographic diagnosis of latent rheumatic heart disease.

BACKGROUND: In 2012, the World Heart Federation (WHF) published guidelines for the echocardiographic diagnosis of rheumatic heart disease (RHD). This study assesses individual reviewer performance and inter-rater agreement and reliability on the presence of any RHD, as well classification of RHD based on the 2012 WHF criteria. METHODS: Four cardiologists individually reviewed echocardiograms in the context of a randomized clinical trial (ClinicalTrials.gov:NCT03346525) and participated in a blinded adjudication panel. Panel decision was the reference standard for diagnosis. Performance of individual reviewers to panel adjudication was compared through sensitivity and specificity analyses and inter-rater reliability was assessed between individual panelists using Fleiss free marginal multirater kappa. RESULTS: Echocardiograms from 784 children had two independent reports and panel adjudication. The accuracy of independent reviewers for any RHD had high sensitivity (94%, 95% CI 93-95%) and moderate specificity (62%, 95% CI 53-70%). Sensitivity and specificity for definite RHD was 61.3 (95% CI, 55.3-67.1) and 93.1 (95% CI, 91.6-94.4), with 86.8 (84.7-88.7) and 65.8 (61.0-70.4) for borderline RHD. There was moderate inter-rater agreement (κ = 0.66) on the presence of any RHD while agreement for specific 2012 WHF classification was only fair (κ = 0.51). CONCLUSIONS: The 2012 WHF guidelines are moderately reproducible when used by expert cardiologists. More cases of RHD were diagnosed by an consensus panel than by individual reviewers. A revision to the criteria is now warranted to further increase the reliability of the WHF criteria.

Contemporary Diagnosis and Management of Rheumatic Heart Disease: Implications for Closing the Gap: A Scientific Statement From the American Heart Association.

The global burden of rheumatic heart disease continues to be significant although it is largely limited to poor and marginalized populations. In most endemic regions, affected patients present with heart failure. This statement will seek to examine the current state-of-the-art recommendations and to identify gaps in diagnosis and treatment globally that can inform strategies for reducing disease burden. Echocardiography screening based on World Heart Federation echocardiographic criteria holds promise to identify patients earlier, when prophylaxis is more likely to be effective; however, several important questions need to be answered before this can translate into public policy. Population-based registries effectively enable optimal care and secondary penicillin prophylaxis within available resources. Benzathine penicillin injections remain the cornerstone of secondary prevention. Challenges with penicillin procurement and concern with adverse reactions in patients with advanced disease remain important issues. Heart failure management, prevention, early diagnosis and treatment of endocarditis, oral anticoagulation for atrial fibrillation, and prosthetic valves are vital therapeutic adjuncts. Management of health of women with unoperated and operated rheumatic heart disease before, during, and after pregnancy is a significant challenge that requires a multidisciplinary team effort. Patients with isolated mitral stenosis often benefit from percutaneous balloon mitral valvuloplasty. Timely heart valve surgery can mitigate the progression to heart failure, disability, and death. Valve repair is preferable over replacement for rheumatic mitral regurgitation but is not available to the vast majority of patients in endemic regions. This body of work forms a foundation on which a companion document on advocacy for rheumatic heart disease has been developed. Ultimately, the combination of expanded treatment options, research, and advocacy built on existing knowledge and science provides the best opportunity to address the burden of rheumatic heart disease.

The personal and clinical impact of screen-detected maternal rheumatic heart disease in Uganda: a prospective follow up study.

BACKGROUND: Pre-existing maternal cardiac disease is a significant contributor to adverse maternal, fetal, and neonatal outcomes. In 2015-2017, our team conducted the first community-based study of maternal rheumatic heart disease (RHD) in sub-Saharan Africa and identified RHD in 88% of those with pre-existing heart disease. Here we conducted a follow up investigation of women previously identified with RHD, describing clinical and echocardiographic outcomes, identifying barriers to medical adherence and evaluating the personal impact of RHD. METHODS: A 2 week prospective follow up was completed at sites in Central and Eastern Uganda. Participants underwent a three-step mixed methods study comprising of 1) direct structured interview targeting clinical history and medication adherence, 2) echocardiogram to evaluate left-sided heart valves, and 3) semi-structured guideline interview to elicit personal impacts of RHD. RESULTS: The team evaluated 40 (80%) of the original 51 mothers with RHD at a median post-partum time of 2.5 years after delivery (IQR 0.5). Echocardiographic data showed improvement in nine women with the remaining 31 women showing stable echocardiographic findings. Adherence to Benzathine penicillin G (BPG) prophylaxis was poor, with 70% of patients either poorly adherent or non-adherent. Three major themes emerged from interviews: 1) social determinants of health (World Health Organization, Social determinants of health, 2019) negatively affecting healthcare, 2) RHD diagnosis negatively affecting female societal wellbeing, 3) central role of spouse in medical decision making. CONCLUSIONS: Screening echocardiography can identify women with pre-existing rheumatic heart disease during pregnancy, but long-term follow-up in Uganda reveals adherence to medical care following diagnosis, including BPG, is poor. Additionally, mothers diagnosed with RHD may experience unintended consequences such as social stigmatization. As identification of occult RHD is critical to prevent adverse pregnancy outcomes, further research is needed to determine how to best support women who face a new diagnosis of RHD, and to determine the role of screening echocardiography in high-risk settings.

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.