Rheumatic heart disease: The role of global cardiac surgery

Rheumatic heart disease (RHD) remains a neglected disease of poverty. While nearly eradicated in high‐income countries due to timely detection and treatment of acute rheumatic fever, RHD remains highly prevalent in low‐ and middle‐income countries (LMICs) and among indigenous and disenfranchised populations in high‐income countries. As a result, over 30 million people in the world have RHD, of which approximately 300,000 die each year despite this being a preventable and treatable disease. In LMICs, such as in Latin America, sub‐Saharan Africa, and Southeast Asia, access to cardiac surgical care for RHD remains limited, impacting countries' population health and resulting economic growth. Humanitarian missions play a role in this context but can only make a difference in the long term if they succeed in training and establishing autonomous local surgical teams. This is particularly difficult because these populations are typically young and largely noncompliant to therapy, especially anticoagulation required by mechanical valve prostheses, while bioprostheses have unacceptably high degeneration rates, and valve repair requires considerable experience. Devoted and sustained leadership and local government and public health cooperation and support with the clinical medical and surgical sectors are absolutely essential. In this review, we describe historical developments in the global response to RHD with a focus on regional, international, and political commitments to address the global burden of RHD. We discuss the surgical and clinical considerations to properly manage surgical RHD patients and describe the logistical needs to strengthen cardiac centers caring for RHD patients worldwide.


| BACKGROUND
The etiology, incidence, and prevalence of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) have been well-researched, along with widespread recognition and support by the World Health Organization (WHO). 1 Yet, there remain global challenges in eliminating both. ARF results from pharyngeal infection secondary to Group A β-hemolytic Streptococcus. The global incidence of RHD in 2015 was >300,000 with a prevalence of >30 million, an annual death rate of >300,000, and 11.5 million disability-adjusted life years. 2 The evolution of ARF and RHD can be divided into three phases.
Phase one is the communicable disease, followed by immunemediated disease, and finally noncommunicable disease, that is, RHD with the resultant inflammatory heart valve changes, as well as possible sequelae that include heart failure, atrial fibrillation, endocarditis, stroke, systemic thromboembolism, and pulmonary hypertension. While RHD is largely eradicated in high-income countries due to timely detection and treatment of ARF, it remains highly prevalent in low-and middle-income countries (LMICs).
The WHO has recognized the neglect of RHD in national health policies and budgets in LMICs, the paucity of available data regarding RHD efforts, poor access to care, and insufficient clinical understanding by primary and community health workers. 1 Following the WHO Resolution on Rheumatic Fever and Rheumatic Heart Disease in May 2018, the World Heart Federation established a Rheumatic Heart Disease Taskforce. The current approaches to ARF and RHD include early identification and treatment of Group A β-hemolytic Streptococcus, screening and surveillance of RHD, and aggressive medical, interventional, and surgical treatment strategies. 3 Here, we discuss the progress made in addressing the global burden of RHD, present clinical considerations, and stress opportunities moving forward.

| Timeline of ARF and RHD developments
In Brazil, almost 40,000 patients develop chronic RHD each year, a burden that is growing each year and considered to be vastly underestimated. 4,5 Similar trends are observed in the Caribbean, where the annual RHD burden grows and affects a young population, yet surgical and interventional care availability cannot meet the needs of local populations. 6 In Pacific Island States, up to eight percent of the adult population is estimated to have RHD. 6 In sub-Saharan Africa, the epidemiology and demographics of ARF and RHD remain major challenges with a prevalence of 5.7 per 1,000 children aged 5-14 years, whereas endemic regions have adolescent rates up to 21.0 per 1000 people at 16 years. [7][8][9] Although ARF and RHD are driven by a combination of immune, environmental, and genetic factors, high heritability has been shown. 7 Moreover, the most virulent and rapidly progressive forms of ARF and RHD have been found in Africa. 7,8 Thus, most high-level RHD initiatives have stemmed from or with respect to sub-Saharan Africa.
In 1981, the Pan-African Society of Cardiology (PASCAR) was initiated, and in 1985, during the 3rd PASCAR congress, the use of echocardiography to diagnose RHD was highlighted. However, nothing further occurred until 2005, when the Drakensberg Declaration, formulated at the PASCAR meeting in South Africa along with the WHF and the WHO Regional Office for Africa (WHO-AFRO), focused on ARF and RHD in Africa. 10,11 This seminal meeting hosted the 1st All-Africa Workshop on Rheumatic Fever and Rheumatic Heart Disease that stressed both ARF and RHD as major public health problems in Africa. The declaration supported four areas of needed activity: (1) raising awareness, (2) increasing RHD information availability, (3) collaborative partnerships to change public policy, and (4) establishing national primary and secondary prevention programs for ARF. In 2014, at the 2nd All-Africa workshop on ARF and RHD in Livingstone, Zambia, the Mosi-o-Tunya Action plan of PASCAR was endorsed by the WHO-AFRO and called for the elimination of ARF and control of RHD in Africa. 10 In 2015 and 2016, experts from across Africa and across the globe met in Addis Ababa, Ethiopia, to develop a roadmap on the eradication of RHD in Africa. 12 The roadmap included the establishment of prospective RHD registries at sentinel sites to reduce RHD mortality by 25% by 2025. In 2017, the Cairo Accord summarized ten key recommendations that expanded on the need for comprehensive data collection, screening programs, preventive measures, and centers of excellence, as well as a specific focus on valve repair and the development of tissue-engineered valve substitutes. 13,14 These developments culminated with the adoption of the WHO Resolution WHA71.14 on ARF and RHD in 2018. 1 19 In 2020, Vervoort et al. 20 further summarized the need for cardiac surgery in LMICs, highlighting the maldistribution of cardiac surgery worldwide and the need for ready access, affordability, increased capacity, quality care, long-term outcomes, and sustainability. 20 Recently, the Latin American Association of Cardiac and Endovascular Surgery was established to foster a stronger regional network of cardiac surgeons in Latin America to share experiences, create capacity-building opportunities, and advance clinical care in the region. Given the high RHD burden that persists in much of Latin America, RHD prevention and treatment will likely make up an important priority. A memorandum of understanding is crucial and necessary, which should focus on those elements that will increase the quality, quantity, transparency, sustainability, and success strategy. Local government and hospital administration support, along with medical staff leadership, and a committed and motivated faculty with requisite skills are required. Specific metrics or elements related to affordability, ready access, awareness, accountability, transparency, and success strategy must be established. In addition, it is essential that the development also address financial support, local laws and regulations, malpractice, trade/customs/ tariffs, passports, visas, and medical license requirements. Regionalization optimizes the scarce workforce and resources and can fast-track the skillsets of trainee surgeons by increasing institutional volume. Some programs in Africa (e.g., South Africa, Kenya, and Ghana) already have active training programs, whereas some African surgeons seek training in programs abroad (e.g., Pakistan, India, and China). In South America, training program availability is highly variable but generally available locally; nevertheless, many programs remain with vacancies providing opportunities to train aspiring cardiac surgeons from other countries. 23 It remains clear, however, that more programs are needed to adequately supply LMICs, especially in sub-Saharan Africa, with the needed number of cardiac surgeons and other healthcare professionals. 21

| Financial needs
Financial support is crucial and must be secured from multiple sources that include public government, private insurance, combined public/private, charity, and self-pay. The Salam Centre for Cardiac Surgery in Khartoum, Sudan is a model of a bilateral partnership that offers free care to needing patients, treating patients from across the African continent, whereas similar models have been observed elsewhere in the world, such as the UNICAR Cardiac Surgery Hospital in Guatemala. 24 Falase et al. 25  LMICs lack such coverage, requiring substantial out-of-pocket payments by patients and their families. 26,27 However, despite such health coverage, RHD remains a common problem in South America, especially in slums and among poorer populations, giving rise to a healthcare paradox. 28 2.4 | Infrastructure, equipment, disposables, devices, drugs, and logistics For newly developing programs, various health system and infrastructure requirements are critical to ensure sustainability and safe and quality care. 29 New centers in LMICs are often financially con-  Moreover, when purchasing equipment and devices, warranty costs should include maintenance and biomedical support; local distributors play a major role in these areas.

| Screening, registries, and databases
Supporting the public health and primary care sectors with the prevention, education, recognition, screening, diagnosis, treatment, and follow-up care is crucial. Widespread screening of children at risk for RHD is warranted using two-dimensional, continuous-wave, and color-Doppler echocardiography. This is necessary to develop a waiting list for those individuals with RHD who are present or future candidates for intervention or surgery. Additionally, creating a database and/or registry is essential to trace and document both outcomes and transparency.

| Operative phase
The local junior cardiac surgeons must have proctor-supervised education and training, as well as the opportunity to perform an increasing number of cases to improve clinical skillsets and gain more confidence, judgment, responsibility, and both operative and intensive care experience. A major advance in surgery, including cardiac surgery, has been the operative headlamp camera. This has made it easier to view the performed operation on sight or from afar for trainees and the rest of the cardiac team.

| Valve surgery
In LMICs, patients requiring surgery for RHD are, on average, 20-25 years old, whereas half require surgery before the age of 20 years. 38 More than 60% of operated RHD cases in Africa currently receive a mechanical prosthetic valve and require long-term anticoagulation management and follow-up. 39 In Latin America, similar trends are observed, although with variable outcomes. 40 Notable local experiences are described as follows: Yangni-Angate et al. 41 reported the cardiac surgery experience in Cote d'Ivoire between 1978 and 2013.
The majority of the cases were CHD and RHD. The RHD average age was 26 years (4-69 years) with 60% having a functional NYHA class III or IV. Mechanical prosthetic valve replacement was the most common operation, and overall late mortality after surgery was 8%.
In their experience, late presentation in the younger patients with advanced RHD precludes valve repair. In addition, bioprosthetic valve replacement developed early deterioration. However, mechanical valve replacement was compromised by anticoagulation management, and especially with the management of young pregnant women. Nwiloh et al. 42 also favored mechanical valves in Nigeria, reporting a 10-year freedom rate from bleeding and thromboembolism of 70%. 42 Child-bearing age women were at higher risk, as were poor patients with anticoagulation noncompliance. Edwin et al. 43 from Ghana advocated mechanical valves for children (6-18 years). Over a 15-year period, there were 114 operations with eight deaths. Anticoagulation was well-tolerated.
The major complications related to the mechanical prosthetic device include valve thrombosis, thromboembolism, and bleeding which are primarily anticoagulation-related problems. In younger patients, prosthesis-patient mismatch may also become an issue. On the other hand, bioprosthetic mitral prosthetic valves undergo early degeneration and may require early reoperation, especially in younger patients and fertile women. 44 They are also more expensive than a mechanical valve. Finally, prosthetic valve endocarditis, be it mechanical or bioprosthetic, occurs in 3-4% within five years after index surgery. 45 For the above reasons, mitral valve repair is desirable. But repair is more complex, as the RHD valves get worse with time, and requires more experience, confidence, and advanced skills to achieve a favorable operative result. 46 For younger patients, there are a number of surgical repair techniques available. 44,47 Antunes et al. 48 , with a long experience in RHD surgery in South Africa, Mozambique, and Portugal, emphasize that rheumatic mitral valve disease remains a challenge with regard to surgical repair versus valve replacement. 48 Part of this is related to younger patients (20-30 years) with a persistent rheumatic inflammatory process that continues beyond surgery, and requires antibiotic prophylaxis following surgery and continued lifelong. Several pathological and clinical RHD areas need to be understood, 48 notably that rheumatic mitral regurgitation is caused by elongated anterior leaflet chordae that causes prolapse of the leaflet, which is usually small and retracted, as is the posterior leaflet, and that the annulus is dilated in most cases, along with commissural fusion.
Yacoub et al. 49 also point out that mechanical and bioprosthetic aortic valves are not ideal for younger RHD patients. Aortic valve repair and the Ross procedure are not readily performed or available in Africa and require increased surgical expertise and experience.
Mocumbi cautions that the operations described are palliative at best. 50 This is especially true for the younger group and fertile females. Finally, Antunes et al. 51 highlight that tricuspid valve regurgitation is frequently found in association with rheumatic mitral valve disease. It is most commonly secondary to pulmonary hypertension and is treated with tricuspid repair. Rheumatic tricuspid stenosis is rare and treated with a bioprosthesis if indicated. 52 It must be noted that prosthetic valve endocarditis, be it mechanical or bioprosthetic, occurs in up to 5% of patients in the first years after surgery. 45 Studies comparing long-term results between mechanical valves, bioprosthetic valves, and valve repair remain limited. 37  where comparable results are occasionally observed, emphasizing the need for further investigation and careful patient selection. 37 Overall, the choice of operative technique and devices must consider age, sex, cost of the device, and postoperative drugs, especially anticoagulants, long-term access to medical follow-up, and cardiac surgeons' confidence and experience.

| Postoperative phase and outcomes
Early and late postoperative complications include death, bleeding, stroke, endocarditis, valve thrombosis, and structural valve deterioration. Long-term outcomes and follow-up require an organized system. The patient and family should have an operative report and discharge summary. However, RHD in younger individuals remains a notable challenge. They will still require lifetime secondary monthly penicillin therapy following surgery and may require future reoperation. In patients with mechanical prostheses, lifelong anticoagulation requires routine and regular monitoring of international normalized ratio (INR) levels. Due to limited long-term durability, valve repairs and bioprosthetic valves require close follow-up and echocardiographic surveillance.

| PREGNANCY AND RHD
Pregnant women in LMICs with RHD, and especially with isolated mitral valve stenosis, are a high-risk group due to the potential for increased maternal and fetal mortality. 39   and mechanical heart valves can be compromised by the risk of valve thrombosis, stroke, and adverse fetal outcomes, whereas bioprosthetic valves do not require the use of anticoagulation, but are compromised by a higher incidence of structural bioprosthetic deterioration and failure rates that occur in 50% of childbearing women at 10 years. 56

| RESEARCH AND RHD
There has been a steady increase in cardiovascular disease research in Africa, of which RHD has been a major focus. 57 The PASCaR and other African institutions have promoted research of cardiovascular epidemiological data, along with establishing a number of RHD registries. 58 These registries were developed to improve clinical care and epidemiological surveillance, as reported by Longenecker et al. 59 in Uganda (Table 1). More broadly, cardiac surgery research and publications in Africa have increased over the past 20 years. 57 Sir Magdi Yacoub has especially been a major supporter of cardiac research in Africa at the "bench, bush, and bedside levels". 60 Nevertheless, compared to when RHD was still prevalent in high-income countries, research interests in RHD have declined across the globe, including in Latin America. 61 For example, while death rates per year due to malaria are only three times greater than in RHD, research funding for malaria is over 500 times as much as for RHD. 62

| CONCLUSION
Moving forward, the focus should be to continue to decrease the incidence, prevalence, backlog, and surgical waiting lists of RHD patients.
This will require local government and public health cooperation and support with the local clinical medical and surgical sectors. Building increasing capacity and quality of cardiac surgery in LMICs requires devoted and sustained leadership, public (government), and private (corporate) participation, and a well-trained and confident experienced cardiac team that is supported and trusted by the patients they serve.