David A. Watkins

Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015.

BACKGROUND Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low‐income and middle‐income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study. METHODS We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod‐MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty. RESULTS We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age‐standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age‐standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub‐Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability‐adjusted life‐years due to rheumatic heart disease globally. CONCLUSIONS We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25‐year period. The health‐related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.)

Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the Arrhythmogenic Right Ventricular Cardiomyopathy Registry of South Africa

Little is known about arrhythmogenic right ventricular cardiomyopathy (ARVC) in Africa. The objective of this study was to delineate the clinical characteristics, survival, and genetics of ARVC in South Africa. Information on clinical presentation, electrocardiographic and cardiac imaging findings, histology, and outcome of cases with suspected ARVC was collected using the standardised form of the ARVC Registry of South Africa. Genomic DNA was screened for mutations in plakophylin-2 (PKP2) gene. Survival and its predictors were analyzed using the Kaplan-Meier and Cox proportional hazards regression methods, respectively. Fifty unrelated cases who met the diagnostic criteria for ARVC were enrolled between January 2004 and April 2009. Clinical presentation was similar to that reported in other studies. Annual mortality rate was 2.82%, five-year cumulative mortality rate 10%, and mean age at death 36.9 +/- 14.7 years. Overall survival was similar to the general South African population (P = 0.25). Independent risk factors for death were syncope (Hazard Ratio [HR] 10.73, 95% Confidence Interval [CI] 1.88-61.18, P = 0.008) and sustained ventricular tachycardia (HR = 22.97, 95%CI 2.33-226.18, P = 0.007). Seven PKP2 gene mutations were found in 9/36 (25%) unrelated participants, five being novel. The novel C1162T mutation occurred in four white South Africans sharing a common haplotype, suggesting a founder effect. Compound heterozygotes exhibited a severe phenotype signifying an allele dose effect. ARVC is associated with early mortality that is no different to the general South Africa population whose lifespan is shortened by HIV/AIDS. PKP2 gene mutations are common, have an allele dose effect, and a novel founder effect in white South Africans.

Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué.

Abstract Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major causes of heart failure, stroke and death among African women and children, despite being preventable and imminently treatable. From 21 to 22 February 2015, the Social Cluster of the Africa Union Commission (AUC) hosted a consultation with RHD experts convened by the Pan-African Society of Cardiology (PASCAR) in Addis Ababa, Ethiopia, to develop a ‘roadmap’ of key actions that need to be taken by governments to eliminate ARF and eradicate RHD in Africa. Seven priority areas for action were adopted: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards the reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralise technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centres of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectoral RHD programmes within NCD control programmes of affected countries, and (7) foster international partnerships with multinational organsations for resource mobilisation, monitoring and evaluation of the programme to end RHD in Africa. This Addis Ababa communiqué has since been endorsed by African Union heads of state, and plans are underway to implement the roadmap in order to end ARF and RHD in Africa in our lifetime.

Rheumatic Fever: Neglected Again

We appreciate M. Enserinks News of the Week story (“Some neglected diseases are more neglected than others,” 6 February, p. [700][1]) on the Moran et al. study analyzing the current state of research into so-called “neglected diseases” ([1][2]). We would like to highlight one neglected

The burden of antenatal heart disease in South Africa: a systematic review

BackgroundMaternal mortality in South Africa is rising, and heart conditions currently account for 41 per cent of indirect causes of deaths. Little is known about the burden of heart disease in pregnant South Africans.MethodsWe systematically reviewed the contemporary epidemiology and peripartum outcomes of heart disease in South African women attending antenatal care. Searches were performed in PubMed, ISI Web of Science, the EBSCO Africa-Wide database, the South African Union Catalogue, and the Current and Completed Research database (South Africa). References of included articles were also hand-searched. Studies reporting epidemiologic data on antenatal heart disease in South Africa were included. Data on morbidity and mortality were also collected.ResultsSeven studies were included in the systematic review. The prevalence of heart disease ranged from 123 to 943 per 100,000 deliveries, with a median prevalence of 616 per 100,000. Rheumatic valvular lesions were the commonest abnormalities, although cardiomyopathies were disproportionately high in comparison with other developing countries. Peripartum case-fatality rates were as high as 9.5 per cent in areas with limited access to care. The most frequent complications were pulmonary oedema, thromboembolism, and major bleeding with warfarin use. Perinatal mortality ranged from 8.9 to 23.8 per cent, whilst mitral lesions were associated with low birth weight. Meta-analysis could not be performed due to clinical and statistical heterogeneity of the included studies.ConclusionApproximately 0.6 per cent of pregnant South Africans have pre-existing cardiac abnormalities, with rheumatic lesions being the commonest. Maternal and perinatal morbidity and mortality continue to be very high. We conclude this review by summarising limitations of the current literature and recommending standard reporting criteria for future reports.

Lessons from the first report of the Arrhythmogenic Right Ventricular Cardiomyopathy Registry of South Africa.

The Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Registry of South Africa was established in 2004, under the auspices of the Cardiac Arrhythmia Society of Southern Africa (CASSA). In the November 2009 supplement of Heart Rhythm, the Registry investigators published the first large, multicentre series of patients with ARVC in South Africa. The report, which is based on the first 50 participants with a confirmed diagnosis of ARVC, has practical implications for the clinical profile, diagnosis and management of patients with ARVC in South Africa.

Extended Cost-Effectiveness Analyses of Cardiovascular Risk Factor Reduction Policies:

Recent improvements in prevention and treatment have led to marked reductions in age-standardized mortality rates from cardiovascular disease (CVD) in lowand middle-income countries (LMICs). However, because of rapid population growth and aging in these countries, the number of fatal and nonfatal cases of CVD continues to rise (Roth and others 2015). This increase in the absolute burden of CVD is accompanied by an increase in the economic impact of CVD that includes financial risks related to accessing treatment (Bloom and others 2011; Jha and others 2013). The findings from a systematic review indicate incidence of catastrophic health expenditure (CHE) of greater than 70 percent in patients with CVD or stroke in China, India, and Tanzania, and 68 percent in patients with cancer (Huffman and others 2011). CVD and its risk factors are frequently distributed across populations in different ways. A popular notion is that CVD is a condition of older, urban males; however, evidence suggests that younger individuals in poorer and rural areas are often disproportionately affected (Gaziano 2009). Furthermore, recent studies have shown that the poorest countries and world regions have the highest incidence and case-fatality ratios from CVD, compared with the wealthiest areas. This observation could be due in part to disparities in access to health services in general and evidence-based interventions in particular (Yusuf and others 2014). Extended cost-effectiveness analysis (ECEA) is a new economic evaluation method developed as part of the Disease Control Priorities Network grant funded by the Bill & Melinda Gates Foundation and the Disease Control Priorities, 3rd edition (DCP3, http://www.dcp-3.org). The rationale for ECEA is to extend the scope of costeffectiveness analysis (CEA) to assess health policies more adequately. CEA centers on the summary metric of incremental cost-effectiveness—cost per amount of health gained—and is a key part of health technology assessment. ECEA goes beyond simply measuring health outcomes to estimate incremental gains in nonhealth outcomes that are important to health systems, such as financial risk protection (FRP) and distributional consequences like equity and fairness (Verguet, Laxminarayan, and Jamison 2015). ECEA results are usually presented in “dashboard” format, that is, disaggregated into health and nonhealth outcomes per dollar spent on a particular health policy and estimated separately for different socioeconomic groups. ECEA is well designed to respond to the policy questions posed in the World Health Reports of 2010 and 2013, specifically, how to move efficiently to universal health coverage (UHC) (WHO 2010, 2013).

Limb-girdle weakness in a marfanoid man: distinguishing calpainopathy from Becker's muscular dystrophy

A 24-year-old man had experienced hip-girdle weakness since the age of 15u2005years and exercise-induced muscle cramps with ‘toe-walking’ since aged 12u2005years. He was thought to have Marfans syndrome but had no known family history of muscle disease. His marfanoid features prompted a transthoracic echocardiogram at 18u2005years, showing a normal aortic root and cardiac size/function without mitral valve prolapse.nnOn examination at the age of 24, he was tall (6 feet, 7 inches; 201u2005cm) with an asthenic habitus, disproportionate arm length to height (1.06), high-arched palate, arachnodactyly, marked pectus excavatum and pes planus, but no other features of Marfans syndrome. Neuromuscular examination showed hypertrophy of calf muscles and shortening of the Achilles’ tendons as well as selective atrophy of the sternal heads of sternocleidomastoid muscles, proximal arms and quadriceps muscles. There was no scapular winging. The limb-girdle pattern of weakness was of moderate severity (Medical Research Council (MRC) grade 3) in the hip extensors and adductors, and knee flexors and mild weakness (MRC grade 4) in neck flexors, hip flexors and abductors, as well as knee extensors. The strength in other muscle groups and the remaining neurological examination, including tendon reflexes, was normal.nnHe remained fully ambulant and functional at the age of 31u2005years, albeit with a moderately waddling gait.nnHis 12-lead ECG at age 24 was abnormal, with a right-bundle branch pattern and a prominent R wave in chest lead V2. Echocardiography showed borderline dilatation and reduced function of both ventricles. The ECG and echocardiogram were unchanged when re-examined 7u2005years later.nnLaboratory tests showed a serum creatine kinase of 1640u2005IU/L (>10 times the upper limit of normal). Biopsy of the quadriceps femoris showed an increase in endomysial connective tissue, infiltration of adipose tissue and focal necrotic fibres. Immunohistochemistry showed normal spectrin and caveolin staining but decreased intensity (∼50%) in the …

Benzathine penicillin for recurrence of rheumatic fever: the jury is still out.

We appreciate the recent investigation by Seckeler et al. [2] into the impact of secondary prophylaxis on the recurrence of acute rheumatic fever. Regrettably, the title of their study, which claims ‘‘no demonstrable effect of benzathine penicillin on recurrence of rheumatic fever’’ overstates their findings and could be misleading to clinicians and policymakers because two major study limitations were not addressed in their discussion. First, ‘‘compliance’’ was defined as the proportion of benzathine penicillin G (BPG) doses delivered versus the number of doses expected over the duration of the followup period (it is unfortunate that the mean and median duration of the follow-up period is not given in this study). Thus in their study, a patient followed for 4 years could be 100% compliant for 3 years and 0% compliant for 1 year and still be classified as ‘‘compliant’’ while remaining at high risk for recurrence and potentially misclassified. It also is not surprising that their logistic regression did not find compliance to be associated with lower odds of recurrence. ‘‘One-unit’’ increases in compliance thus defined are, in our judgment, not clinically meaningful. Second, as the authors rightly note, there is clinical equipoise as to the optimal dosing regimen for BPG. Although the 4-weekly intramuscular injection is considered to be the historical standard, a recent systematic review presents data that suggest otherwise. Dosing at 2-weekly intervals is shown to be significantly better at preventing recurrences than dosing at 4-weekly intervals, and compliance with more frequent dosing regimens is comparable with compliance with a 4-weekly regimen [1]. However, all the patients in the Seckeler et al. study received 4-weekly BPG, preventing assessment of any differential efficacy, effectiveness, or compliance related to 3or 2-weekly dosing. Thus, in addition to the noncontrolled, retrospective nature of the Seckeler et al. [2] study, we find insufficient evidence to conclude that BPG has no demonstrable effect on recurrence. Future studies should evaluate delivery methods and compliance in a more rigorous fashion.

Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel

Rheumatic heart disease (RHD) is a preventable heart condition that remains endemic among vulnerable groups in many countries. After a period of relative neglect, there has been a resurging interest in RHD worldwide over the past decade. In this Scientific Expert Panel, the authors summarize recent advances in the science of RHD and sketch out priorities for current action and future research. Key questions for laboratory research into disease pathogenesis and epidemiological research on the burden of disease are identified. The authors present a variety of pressing clinical research questions on optimal RHD prevention and advanced care. In addition, they propose a policy and implementation research agenda that can help translate current evidence into tangible action. The authors maintain that, despite knowledge gaps, there is sufficient evidence for national and global action on RHD, and they argue that RHD is a model for strengthening health systems to address other cardiovascular diseases in limited-resource countries.