Mortality and Heart Transplantation After Hybrid Palliation of Hypoplastic Left Heart Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Newborns with hypoplastic left heart syndrome (HLHS) who are considered at increased risk for death following Norwood/Sano surgery often undergo hybrid palliation (HP) as initial surgery. We aimed to compile the HP experience in HLHS and its variants and assess the rates of, and risk factors for, death and heart transplantation. METHODS: CINAHL, CINAHL PLUS, PubMed/MEDLINE, and SCOPUS were systematically searched for HP outcome studies of death or heart transplantation in HLHS between 1998 and 2022. Pooled incidence was estimated, and potential risk factors were identified using random-effects meta-analysis and reconstructed time-to-event data from Kaplan-Meier curves. RESULTS: Thirty-three publications were included in our review. Overall, of 1,162 patients 417 died and 57 underwent heart transplantation, resulting in a combined outcome of 40.7%, (474/1,162). There was a trend toward decreasing mortality risk across the stages of palliation. Pooled mortality between HP and comprehensive stage 2 palliation was 25%, after stage 2 up to Fontan palliation was 16%, and 6% post-Fontan. The incidence of death or heart transplantation was higher in high-risk patients-43% died and 10% received heart transplantation. CONCLUSION: Our systematic review and meta-analysis found high rates of death or heart transplantation in HP of HLHS patients between HP and Fontan surgeries. All patients should be closely followed during the initial interstage period, which is associated with the highest hazard. Prospective studies on appropriate patient selection, indications, and / or alternatives, as well as refining HP strategies for managing newborns with HLHS are needed to improve outcomes.

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.

Serum Immune Responses to Group A Streptococcal Antigens following Pharyngeal Acquisitions among Children in Cape Town, South Africa.

There is limited information on the human immune response following infection with group A Streptococcus (Strep A). Animal studies have shown, in addition to the M protein, that shared Strep A antigens elicit protective immunity. This study aimed to investigate the kinetics of antibody responses against a panel of Strep A antigens in a cohort of school-aged children in Cape Town, South Africa. Participants provided serial throat cultures and serum samples at two-monthly follow-up visits. Strep A recovered were emm-typed, and serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) to assess immune responses to thirty-five Strep A antigens (10-shared and 25-M peptides). Serologic evaluations were performed on serial serum samples from 42 selected participants (from 256 enrolled) based on the number of follow-up visits, the frequency of visits, and throat culture results. Among these, there were 44 Strep A acquisitions, 36 of which were successfully emm-typed. Participants were grouped into three clinical event groups based on culture results and immune responses. A preceding infection was most convincingly represented by a Strep A-positive culture with an immune response to at least one shared antigen and M peptide (11 events) or a Strep A-negative culture with antibody responses to shared antigens and M peptides (9 events). More than a third of participants demonstrated no immune response despite a positive culture. This study provided important information regarding the complexity and variability of human immune responses following pharyngeal acquisition of Strep A, as well as demonstrating the immunogenicity of Strep A antigens currently under consideration as potential vaccine candidates. IMPORTANCE There is currently limited information regarding the human immune response to group A streptococcal throat infection. An understanding of the kinetics and specificity of antibody responses against a panel of Group A Streptococcus (GAS) antigens will serve to refine diagnostic approaches and contribute to vaccine efforts, which together will serve to reduce the burden of rheumatic heart disease, a major source of morbidity and mortality especially in the developing world. This study, utilizing an antibody-specific assay, uncovered three patterns of response profiles following GAS infection, among 256 children presenting with sore throat to local clinics. Overall, the response profiles were complex and variable. Of note, a preceding infection was most convincingly represented by a GAS-positive culture with an immune response to at least one shared antigen and M peptide. Also, more than a third of participants demonstrated no immune response despite a positive culture. All antigens tested were immunogenic, providing guidance for future vaccine development.

Recommendations for developing effective and safe paediatric and congenital heart disease services in low-income and middle-income countries: a public health framework.

The global burden of paediatric and congenital heart disease (PCHD) is substantial. We propose a novel public health framework with recommendations for developing effective and safe PCHD services in low-income and middle-income countries (LMICs). This framework was created by the Global Initiative for Children's Surgery Cardiac Surgery working group in collaboration with a group of international rexperts in providing paediatric and congenital cardiac care to patients with CHD and rheumatic heart disease (RHD) in LMICs. Effective and safe PCHD care is inaccessible to many, and there is no consensus on the best approaches to provide meaningful access in resource-limited settings, where it is often needed the most. Considering the high inequity in access to care for CHD and RHD, we aimed to create an actionable framework for health practitioners, policy makers and patients that supports treatment and prevention. It was formulated based on rigorous evaluation of available guidelines and standards of care and builds on a consensus process about the competencies needed at each step of the care continuum. We recommend a tier-based framework for PCHD care integrated within existing health systems. Each level of care is expected to meet minimum benchmarks and ensure high-quality and family centred care. We propose that cardiac surgery capabilities should only be developed at the more advanced levels on hospitals that have an established foundation of cardiology and cardiac surgery services, including screening, diagnostics, inpatient and outpatient care, postoperative care and cardiac catheterisation. This approach requires a quality control system and close collaboration between the different levels of care to facilitate the journey and care of every child with heart disease. This effort was designed to guide readers and leaders in taking action, strengthening capacity, evaluating impact, advancing policy and engaging in partnerships to guide facilities providing PCHD care in LMICs.

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.

Sex differences in the etiology and burden of heart failure across country income level: analysis of 204 countries and territories 1990-2019.

BACKGROUND: Heart failure (HF) is a global epidemic. OBJECTIVE: To assess global sex differences in HF epidemiology across country income levels. METHODS AND RESULTS: Using Global Burden of Disease (GBD) data from 204 countries and territories 1990-2019, we assessed sex differences in HF prevalence, etiology, morbidity, and temporal trends across country sociodemographic index or gross national income. We derived age-standardized rates. Of 56.2 million (95% uncertainty interval [UI] 46.4-67.8 million) people with HF in 2019, 50.3% were females and 69.2% lived in low- and middle-income countries; age-standardized prevalence was greater in males and in high-income countries. Ischaemic and hypertensive heart disease were top causes of HF in males and females, respectively. There were 5.1 million (95% UI 3.3-7.3 million) years lived with disability, distributed equally between sexes. Between 1990 and 2019, there was an increase in HF cases, but a decrease in age-standardized rates per 100 000 in males (9.1%, from 864.2 to 785.7) and females (5.8%, from 686.0 to 646.1). High-income regions experienced a 16.0% decrease in age-standardized rates (from 877.5 to 736.8), while low-income regions experienced a 3.9% increase (from 612.1 to 636.0), largely consistent across sexes. There was a temporal increase in age-standardized HF from hypertensive, rheumatic, and calcific aortic valvular heart disease, and a decrease from ischaemic heart disease, with regional and sex differences. CONCLUSION: Age-standardized HF rates have decreased over time, with larger decreases in males than females; and with large decreases in high-income and small increases in low-income regions. Sex and regional differences offer targets for intervention.

Investigation of Copy Number Variation in South African Patients With Congenital Heart Defects.

BACKGROUND: Congenital heart disease (CHD) is a leading non-infectious cause of pediatric morbidity and mortality worldwide. Although the etiology of CHD is poorly understood, genetic factors including copy number variants (CNVs) contribute to the risk of CHD in individuals of European ancestry. The presence of rare CNVs in African CHD populations is unknown. This study aimed to identify pathogenic and likely pathogenic CNVs in South African patients with CHD. METHODS: Genotyping was performed on 90 patients with nonsyndromic CHD using the Affymetrix CytoScan HD platform. These data were used to identify large, rare CNVs in known CHD-associated genes and candidate genes. RESULTS: We identified eight CNVs overlapping known CHD-associated genes (GATA4, CRKL, TBX1, FLT4, B3GAT3, NSD1) in six patients. The analysis also revealed CNVs encompassing five candidate genes likely to play a role in the development of CHD (DGCR8, KDM2A, JARID2, FSTL1, CYFIP1) in five patients. One patient was found to have 47, XXY karyotype. We report a total discovery yield of 6.7%, with 5.6% of the cohort carrying pathogenic or likely pathogenic CNVs expected to cause the observed phenotypes. CONCLUSIONS: In this study, we show that chromosomal microarray is an effective technique for identifying CNVs in African patients diagnosed with CHD and have demonstrated results similar to previous CHD genetic studies in Europeans. Novel potential CHD genes were also identified, indicating the value of genetic studies of CHD in ancestrally diverse populations.

IL27 gene expression distinguishes multisystem inflammatory syndrome in children from febrile illness in a South African cohort.

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a severe acute inflammatory reaction to SARS-CoV-2 infection in children. There is a lack of data describing differential expression of immune genes in MIS-C compared to healthy children or those with other inflammatory conditions and how expression changes over time. In this study, we investigated expression of immune-related genes in South African MIS-C patients and controls. Methods: The cohort included 30 pre-treatment MIS-C cases and 54 healthy non-inflammatory paediatric controls. Other controls included 34 patients with juvenile systemic lupus erythematosus, Kawasaki disease or other inflammatory conditions. Longitudinal post-treatment MIS-C specimens were available at various timepoints. Expression of 80 immune-related genes was determined by real-time quantitative PCR. Results: A total of 29 differentially expressed genes were identified in pre-treatment MIS-C compared to healthy controls. Up-regulated genes were found to be overrepresented in innate immune pathways including interleukin-1 processing and pyroptosis. Post-treatment follow-up data were available for up to 1,200 hours after first treatment. All down-regulated genes and 17/18 up-regulated genes resolved to normal levels in the timeframe, and all patients clinically recovered. When comparing MIS-C to other febrile conditions, only IL27 expression could differentiate these two groups with high sensitivity and specificity. Conclusions: These data indicate a unique 29-gene signature of MIS-C in South African children. The up-regulation of interleukin-1 and pyroptosis pathway genes highlights the role of the innate immune system in MIS-C. IL-27 is a potent anti-inflammatory and antiviral cytokine that may distinguish MIS-C from other conditions in our setting.

Data-independent acquisition mass spectrometry in severe rheumatic heart disease (RHD) identifies a proteomic signature showing ongoing inflammation and effectively classifying RHD cases.

BACKGROUND: Rheumatic heart disease (RHD) remains a major source of morbidity and mortality in developing countries. A deeper insight into the pathogenetic mechanisms underlying RHD could provide opportunities for drug repurposing, guide recommendations for secondary penicillin prophylaxis, and/or inform development of near-patient diagnostics. METHODS: We performed quantitative proteomics using Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectrometry (SWATH-MS) to screen protein expression in 215 African patients with severe RHD, and 230 controls. We applied a machine learning (ML) approach to feature selection among the 366 proteins quantifiable in at least 40% of samples, using the Boruta wrapper algorithm. The case-control differences and contribution to Area Under the Receiver Operating Curve (AUC) for each of the 56 proteins identified by the Boruta algorithm were calculated by Logistic Regression adjusted for age, sex and BMI. Biological pathways and functions enriched for proteins were identified using ClueGo pathway analyses. RESULTS: Adiponectin, complement component C7 and fibulin-1, a component of heart valve matrix, were significantly higher in cases when compared with controls. Ficolin-3, a protein with calcium-independent lectin activity that activates the complement pathway, was lower in cases than controls. The top six biomarkers from the Boruta analyses conferred an AUC of 0.90 indicating excellent discriminatory capacity between RHD cases and controls. CONCLUSIONS: These results support the presence of an ongoing inflammatory response in RHD, at a time when severe valve disease has developed, and distant from previous episodes of acute rheumatic fever. This biomarker signature could have potential utility in recognizing different degrees of ongoing inflammation in RHD patients, which may, in turn, be related to prognostic severity.

Health trends, inequalities and opportunities in South Africa's provinces, 1990-2019: findings from the Global Burden of Disease 2019 Study.

BACKGROUND: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019. METHODS: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990-2007 and 2007-2019. Additionally, we decomposed changes in life expectancy by cause of death and assessed healthcare system performance. RESULTS: Across the nine provinces, inequalities in mortality and life expectancy increased over 1990-2007, largely due to differences in HIV/AIDS, then decreased over 2007-2019. Demographic change and increases in non-communicable diseases nearly doubled the number of years lived with disability between 1990 and 2019. From 1990 to 2019, risk factor burdens generally shifted from communicable and nutritional disease risks to non-communicable disease and injury risks; unsafe sex remained the top risk factor. Despite widespread improvements in healthcare system performance, the greatest gains were generally in economically advantaged provinces. CONCLUSIONS: Reductions in HIV/AIDS and related conditions have led to improved health since 2007, though most provinces still lag in key areas. To achieve health targets, provincial governments should enhance health investments and exchange of knowledge, resources and best practices alongside populations that have been left behind, especially following the COVID-19 pandemic.

Utility of Human Immune Responses to GAS Antigens as a Diagnostic Indicator for ARF: A Systematic Review.

Background: Previous studies have established that streptococcal antibody titer is correlated with a diagnosis of acute rheumatic fever (ARF). However, results vary in the usefulness of GAS antibodies, particularly anti-streptolysin-O (ASO) and anti-DNase B, in confirming a recent GAS infection. Therefore, we sought to provide, from published studies, an evidence-based synthesis of the correlation of streptococcal serology to establish the usefulness of immunological data in aiding the diagnosis of ARF. These findings are anticipated to have implications where echocardiography is not freely available, especially where ARF is rampant. Methods: We conducted a comprehensive search across a number of databases. Applying a priori criteria, we selected articles reporting on studies, regardless of study design, that evaluate the levels of antibodies against GAS-specific antigens in ARF subjects against control values or a published standard. Data were extracted onto data extraction forms, captured electronically, and analyzed using Stata software. Risk of bias was assessed in included studies using the Newcastle-Ottawa Scale (NOS). Results and Conclusion: The search strategy yielded 534 studies, from which 24 met the inclusion criteria, reporting on evaluation of titers for SLO (n = 10), DNase B (n = 9), anti-streptokinase (ASK) (n = 3) amongst others. Elevation in titers was determined by comparison with controls and upper limit of normal (ULN) antibody values as determined in healthy individuals. Meta-analysis of case-controlled studies revealed moderate odds ratio (OR) correlations between ARF diagnosis and elevated titers for SLO (OR = 10.57; 95% CI, 3.36-33.29; 10 studies) and DNAse B (OR = 6.97; 95% CI, 2.99-16.27; 7 studies). While providing support for incorporating SLO and DNase B in the diagnosis of ARF, we present the following reflections: an elevation in SLO and DNase B levels are not consistently associated with an ARF diagnosis; increasing the number of GAS proteins in the test is warranted to improve sensitivity; paired (acute and convalescent) samples could provide a more accurate indication of a rising titer. Use of community-based controls as a standard is not a reliable marker by which to gauge recent GAS infection.

Health system costs of rheumatic heart disease care in South Africa.

BACKGROUND: Rheumatic Heart Disease (RHD) is a disease of poverty that is neglected in developing countries, including South Africa. Lack of adequate evidence regarding the cost of RHD care has hindered national and international actions to prevent RHD related deaths. The objective of this study was to estimate the cost of RHD-related health services in a tertiary hospital in the Western Cape, South Africa. METHODS: The primary data on service utilisation were collected from a randomly selected sample of 100 patient medical records from the Global Rheumatic Heart Disease Registry (the REMEDY study) - a registry of individuals living with RHD. Patient-level clinical data, including, prices and quantities of medications and laboratory tests, were collected from the main tertiary hospital providing RHD care. All annual costs from a health system perspective were estimated in 2017 (base year) in South African Rand (ZAR) using a combination of ingredients and step-down costing approaches and later converted to United States dollars (USD). Step-down costing was used to estimate provider time costs and all other facility costs such as overheads. A 3% discount rate was also employed in order to allow depreciation and opportunity cost. We aggregated data to estimate the total annual costs and the average annual per-patient cost of RHD and conducted a one-way sensitivity analysis. RESULTS: The estimated total cost of RHD care at the tertiary hospital was USD 2 million (in 2017 USD) for the year 2017, with surgery costs accounting for 65%. Per-patient, average annual costs were USD 3900. For the subset of costs estimated using the ingredients approach, outpatient medications, and consumables related to cardiac catheterisation and heart valve surgery were the main cost drivers. CONCLUSIONS: RHD-related healthcare consumes significant tertiary hospital resources in South Africa, with annual per-patient costs higher than many other non-communicable and infectious diseases. This analysis supports the scaling up of primary and secondary prevention programmes at primary health centers in order to reduce future tertiary care costs. The study could also inform resource allocation efforts and provide cost estimates for future studies of intervention cost-effectiveness.

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.

The RHD Action Small Grants Programme: Small Investment, Big Return!

Rheumatic Heart Disease (RHD) remains endemic in low- and middle-income countries (LMICs) despite its virtual elimination in high-income countries. RHD Action was launched to amplify global efforts to control RHD in 2015 by World Heart Federation and Reach, with demonstration projects in Uganda and Tanzania, and support from Medtronic Foundation. The Small Grants Programme focuses on three domains: People and Communities, Medicines and Technologies, and Systems and Services. It is designed to support patient and community groups in promoting awareness, advocacy, and to build health workers' capacity to prevent and treat RHD in LMICs. Our study evaluates the impact and effectiveness of the RHD Action Small Grants Programme. Methods: We conducted a mixed method study that involved both quantitative and qualitative surveys, through phone interviews and online surveys amongst the grant beneficiaries, to assess the impact and effectiveness of the small grant programme. An invitation to complete an online survey, using a Google Forms format, was issued to Small Grant Project Directors and Co-Directors that received funding for projects between 2017 and 2019. The online survey requested basic project information using tick boxes, Likert scales, and short answer open-ended questions about successes and challenges faced by recipients. The questionnaire also addressed recipients' experience with the RHD Action Small Grants process - applying for the grant, nature and quality of support received to carry out project, the reporting process, and any media coverage provided. For the phone interviews, responses to the short-answer questions were used as the basis for follow up phone interviews. The discussions were recorded, transcribed and thematically analysed for new and recurring themes emerging from the in-depth discussions. Initiated in 2017, RHD Action has funded 21 proposals from a pool of 60 submissions. Recipient countries include Zambia, Uganda (2), Namibia, Kenya, Malawi (2), Egypt, Ethiopia, Nigeria (3), Rwanda (2), Mozambique, and Cameroon (2) as well as Fiji (2), the Philippines and Nepal. Five recipients were funded in 2017, eight in 2018 and eight in 2019. Project directors are primarily junior doctors and project managers supervised by senior mentors. In most cases, this is their first funding award. These projects have demonstrated tangible impact and have provided content for first manuscript and abstract submissions and presentations at professional conferences. Grant reports are presented as website stories showcasing the achievements of small local efforts with meaningful impact. For RHD Action, there is large return on a modest monetary investment resulting in a very visible, viable global RHD networking platform for enthusiastic community and provider activists.

Integrating the Prevention and Control of Rheumatic Heart Disease into Country Health Systems: A Systematic Review and Meta-Analysis.

Background: National and international political commitments have been made recently on rheumatic heart disease (RHD), a preventable heart condition that is endemic in low-resource countries. To inform best practice and identify evidence gaps, we assessed the effectiveness of RHD prevention and control programmes and the extent and nature of their integration into local health systems. Methods: We conducted a systematic review and meta-analysis using a previously published protocol that included electronic and manual searches for studies published between January 1990 and July 2019 reporting on prevention and control programmes for populations at risk for streptococcal pharyngitis, rheumatic fever, and/or RHD. We analysed programme integration according to a previously published framework and programme effectiveness using a results-chain framework. We meta-analysed secondary prophylaxis adherence using random-effects models. Study quality was assessed using peer-reviewed checklists (CASP and PRISM). PROSPERO registration: CRD42017076307. Findings: Five observational studies met with the inclusion criteria. Studies were similar in extent and nature of integration into health systems; no programme was completely integrated or non-integrated. A single study reported on programme impact. Secondary prophylaxis adherence improved among partially integrated RHD programmes (RR, 1.18 [95% CI, 1.03 to 1.36], 3 studies, n = 618). Risk of bias was low in two studies, and indeterminable in the remaining three studies. Interpretation: There is evidence that partially integrated RHD programmes are beneficial for a range of intermediate health outcomes. This review provides a starting point for the design and implementation of future RHD programmes by outlining current best practice for integration and identifying key gaps in knowledge. Funding: National Research Foundation of South Africa.

Echocardiographic Findings in a Cohort of Perinatally HIV-Infected Adolescents Compared with Uninfected Peers from the Cape Town Adolescent Antiretroviral Cohort.

BACKGROUND: Little is known about the cardiac health of perinatally HIV-infected (PHIV+) adolescents on antiretroviral therapy (ART) in sub-Saharan Africa. The authors examined cardiac structure and function in PHIV+ adolescents on ART compared with HIV-uninfected (HIV-) adolescents. METHODS: Echocardiography was performed on PHIV+ and age- and sex-frequency-matched HIV- adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort. Participants were eligible if they were 9 to 14 years of age and had been on ART for ≥6 months. RESULTS: Overall, 474 PHIV+ adolescents (median age, 12 years; 51% boys; mean age at ART initiation, 5 years) and 109 HIV- adolescents (median age, 11.8 years; 45% boys) were included. The mean duration on ART was 7 years, with 37% starting treatment before 2 years of age. Compared with HIV- adolescents, PHIV+ adolescents had higher median Z scores for left ventricular (LV) internal end-diastolic dimension, LV end-systolic posterior wall thickness, and end-systolic interventricular septal thickness. PHIV+ adolescents had a lower median Z score for right ventricular internal end-diastolic dimension as compared with HIV- adolescents. There was no difference in ejection fraction or diastolic function between groups. Later initiation of ART (after 6 years) was associated with increased risk for LV hypertrophy (odds ratio, 2.9; 95% CI, 1.3-6.6; P = .01) compared with those who started ART earlier. PHIV+ adolescents with World Health Organization stage IV HIV infection were at increased risk (odds ratio, 2.2; 95% CI, 1.0-4.6; P = .05) of having LV diastolic dysfunction compared with those with less advanced clinical disease. CONCLUSIONS: This study revealed subtle differences in echocardiographic parameters between PHIV+ and HIV- adolescents. Although these were not clinically significant, starting ART at an older age was a significant risk factor for LV hypertrophy, while more advanced clinical disease was associated with LV diastolic dysfunction.

Pediatric systemic lupus erythematosus patients in South Africa have high prevalence and severity of cardiac and vascular manifestations.

BACKGROUND: Pediatric onset of systemic lupus erythematosus (SLE) is associated with major organ involvement, and African patients tend to develop more aggressive disease than patients of European descent. Although cardiovascular involvement is common in pediatric SLE, there are few published reports on the subject. This study describes the frequency and characteristics of cardiac and vascular manifestations of pediatric SLE in a multi-ethnic South African cohort. METHODS: Demographic, clinical, and echocardiographic data were collected from pediatric SLE patients at two centers in Cape Town, South Africa. At the time of investigation, this cohort consisted of 93 participants diagnosed with SLE according to international classification criteria prior to the age of 19. Individuals with cardiac and/or vascular involvement were identified by retrospective chart review. Cardiac manifestations were defined as presence of pericardial effusion, myocarditis, cardiomyopathy, cardiac failure, Libman-Sacks endocarditis, myocardial infarction, and arrhythmia. Vascular manifestations included deep vein thrombosis, pulmonary embolism, sinus thrombosis, stroke, critical limb ischemia, cerebral vasculitis and systemic vasculitis. Statistical analysis was performed using R (v3.4.1). RESULTS: Cardiac and vascular involvement was present in 47% of the cohort. Previous studies have reported prevalence of 5%-50%. Demographic features of those with cardiac/vascular involvement did not differ from the overall cohort. Echocardiographic data were available for 23 participants. The most common cardiac manifestations were pericardial effusion (n = 24) and cardiac failure (n = 8), while the most common vascular manifestations were cerebral vasculitis (n = 9), stroke (n = 7), and pulmonary embolism (n = 7). Cardiovascular manifestations were frequently severe; one third of pericardial effusion cases required intervention, including three cases of cardiac tamponade. Cardiac and vascular involvement conferred an increased risk of mortality (31.1% versus 10.4%). CONCLUSIONS: Cardiac and vascular involvement were highly prevalent in this South African cohort. The mortality rate was high, and severe manifestations were frequent. Prospective research is needed to improve knowledge of pediatric SLE in Africa and to improve outcomes for this high-risk population.

Integrating the prevention and control of rheumatic heart disease into country health systems: a systematic review protocol.

INTRODUCTION: Rheumatic heart disease (RHD) is a preventable chronic condition affecting the valves of the heart. RHD prevention and care programmes have historically originated in more developed countries, implemented in a targeted (or vertical) manner and evaluated using non-controlled approaches. Taking a broad view of the integration of RHD activities within the whole system is critical for health planning in low-income regions with a high burden of RHD and less robust health systems. Therefore, we propose to conduct a systematic review to assess RHD programme models in order to gain a better understanding of the extent of integration within relevant health systems. METHODS AND ANALYSIS: A predefined search strategy will be used to search for relevant articles published in English from January 1990 to December 2017. Electronic databases PubMed, Scopus, Web of Science, Africa Wide, CINAHL, Cochrane Central Register of Controlled Trials, Google Scholar and Global Index Medicus will be searched, as well as reference lists of relevant articles published. A standardised data extraction form will be used to obtain information for analysis from the included studies. The quality, reliability and risk of bias of included studies will be assessed using design-specific criteria. Programme integration will be analysed according to stewardship and governance, financing, planning, service delivery, monitoring and evaluation, and demand generation. Programme inputs, outputs and impact will also be described. ETHICS AND DISSEMINATION: No ethical approval is required. Findings will be disseminated in a peer-review journal in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. PROSPERO REGISTRATION NUMBER: CRD42017076307.

The Namibian Children's Heart Project: a South-South partnership to provide cardiac care.

IntroductionCongenital and acquired heart diseases are highly prevalent in developing countries despite limited specialised care. Namibia established a paediatric cardiac service in 2009 with significant human resource and infrastructural constraints. Therefore, patients are referred for cardiac interventions to South Africa. OBJECTIVES: To describe the diagnoses, clinical characteristics, interventions, post-operative morbidity and mortality, and follow-up of patients referred for care. METHODS: Demographics, diagnoses, interventions, intra- and post-operative morbidity and mortality, as well as longitudinal follow-up data of all patients referred to South Africa, were recorded and analysed. RESULTS: The total cohort constituted 193 patients of which 179 (93%) had CHD and 7% acquired heart disease. The majority of patients (78.8%) travelled more than 400 km to Windhoek before transfer. There were 28 percutaneous interventions. Palliative and definitive surgery was performed in 27 and 129 patients, respectively. Out of 156 patients, 80 (51.3%) had post-operative complications, of which 15 (9.6%) were a direct complication of surgery. Surgical mortality was 8/156 (5.1%, 95% confidence interval 2.2-9.8), with a 30-day mortality of 3.2%. Prolonged ICU stay was associated with a 5% increased risk of death with hazard ratio 1.05, 95% confidence interval 1.02-1.08, p=0.001. Follow-up was complete in 151 (78%) patients for more than 7 years. CONCLUSIONS: Despite the challenges associated with a cardiac programme for referring patients seeking intervention in a neighbouring country and the adverse characteristics of multiple lesions and complexity associated with late presentation, we report good surgical and interventional outcomes. Our goal remains to develop a comprehensive sustainable cardiac service in Namibia.

Infective endocarditis in infants and children in the Western Cape, South Africa: a retrospective analysis.

Infective endocarditis is a microbial infection of the endothelial surface of the heart, predominantly the heart valves, that is associated with high mortality and morbidity. Few contemporary data exist regarding affected children in our context. AIMS AND OBJECTIVES: We aimed to describe the profile and treatment outcomes of infant and childhood endocarditis at our facilities. METHODS: This is a retrospective analysis of infants and children with endocarditis at two public sector hospitals in the Western Cape Province of South Africa over a 5-year period. Patients with "definite" and "possible" endocarditis according to Modified Duke Criteria were included in the review. RESULTS: Forty-nine patients were identified for inclusion; 29 had congenital heart disease as a predisposing condition; 64% of patients met "definite" and 36% "possible" criteria. The in-hospital mortality rate was 20%; 53% of patients underwent surgery with a post-operative mortality rate of 7.7%. The median interval from diagnosis to surgery was 20 days (interquartile range, 9-47 days). Valve replacement occurred in 28% and valve repair in 58%. There was a significant reduction in valvular dysfunction in patients undergoing surgery and only a marginal improvement in patients treated medically. Overall, 43% of patients had some degree of residual valvular dysfunction. CONCLUSION: Endocarditis is a serious disease with a high in-hospital mortality and presents challenges in making an accurate diagnosis. Despite a significant reduction in valvular dysfunction, a portion of patients had residual valvular dysfunction. Early surgery is associated with a lower mortality rate, but a higher rate of valve replacement compared with delayed surgery.