Rheumatic Heart Disease in the Twenty-First Century

Abstract

Rheumatic heart disease (RHD) is a chronic valvular disease resulting after severe or repetitive episodes of acute rheumatic fever (ARF), an autoimmune response to group A Streptococcus infection. RHD has been almost eliminated with improved social and health infrastructure in affluent countries while it remains a neglected disease with major cause of morbidity and mortality in many low- and middle-income countries, and resource-limited regions of high-income countries. Despite our evolving understanding of the pathogenesis of RHD, there have not been any significant advances to prevent or halt progression of disease in recent history. Long-term penicillin-based treatment and surgery remain the backbone of a RHD control program in the absence of an effective vaccine. The advent of echocardiographic screening algorithms has improved the accuracy of diagnosing RHD and has shed light on the enormous burden of disease. Encouragingly, this has led to a rekindled commitment from researchers in the most affected countries to advocate and take bold actions to end this disease of social inequality.

Introduction

Rheumatic heart disease (RHD) is an autoimmune phenomenon resulting in valvular damage secondary to a non-suppurative complication of Streptococcus pyogenes or group A streptococcal (GAS) infection. RHD, a disease of poverty, is one of the leading causes of morbidity and mortality from acquired cardiac diseases and disproportionately affects people in low- and middle-income countries (LMIC) and vulnerable populations in higher income countries (HIC) [1, 2, 3••].

RHD accounts for 1.4 million premature deaths annually [4, 5]. It has the highest cardiovascular disease-related loss of disability-adjusted-life-years (DALY) in children among 10–14 years worldwide [2, 6]. In a multicenter study of acute heart failure in sub-Saharan Africa, it was the second most common cause of hospitalization in patients with heart failure [7]. The paucity of high quality epidemiological studies prevents a precise assessment of the burden of the disease. Conservatively extrapolated data estimates 15.6 million people affected by RHD worldwide [8]. More recent data, based on echocardiographic screening, suggests that these figures may be 4- to 5-fold higher [9, 10].

There is a wide variation in the clinical manifestation of GAS infection. Pharyngitis (strep throat), mainly affecting children between the ages of 5 and 15 [1], is thought to be the most common clinical presentation linked to acute rheumatic fever (ARF). ARF is an autoimmune inflammatory process in which antibodies formed to target antigenic bacterial epitopes cross-react with proteins found in synovial, cardiac, and neuronal tissues. ARF can manifest with arthritis, carditis, erythema marginatum, and Sydenham chorea [11]. Most of ARF manifestations are self-limited; however, valvular disease resulting from repeated or severe episodes of rheumatic fever leads to irreversible valvular thickening and fibrosis. The long-term sequelae of valvular regurgitation and eventually valvular stenosis are the hallmark of RHD. Subsequently, RHD predisposes to high risk of morbidity and mortality from stroke, infective endocarditis, heart failure, and arrhythmias.

Epidemiology

The decline of ARF and RHD in HIC occurred prior to widespread use of penicillin for treatment of strep pharyngitis. Although the direct mechanisms remain poorly defined, better living conditions, nutrition, and access to care may have been fundamental to the significant disease reduction in industrialized countries [12]. The high incidence and prevalence of the disease in indigenous communities within affluent countries, such as Australia, New Zealand, Canada, and American Samoa, are examples of how individual or community socioeconomic status is a major determinant in the incidence of the disease [13, 14].

RHD is exceedingly rare in the USA (0.04 cases per 1000 children) [14]. In comparison, studies from LMIC have recorded prevalence of RHD ranging from 30.4 cases per 1000 children in Mozambique [15] to 51.0 per 1000 cases in India [16]. The worst affected regions are sub-Saharan Africa, indigenous populations in Australia and New Zealand, southcentral Asia, and the Pacific [17]. A recent meta-analysis of echocardiogram-based studies in RHD endemic countries estimated a combined prevalence of RHD of 12.9 per 1000 people [3••] and higher rates (21.1 per 1000 people) when clinically undetectable valvular disease visualized only on echocardiogram was incorporated into the definition of RHD. However, because rural areas are more likely to be severely affected by the disease than urban areas [9], reported estimates extrapolated mainly from studies of school children in urban communities are likely to be an underestimate. There is also great variation between and within countries limiting generalizability. The prevalence of RHD also increases with age [15, 18] and studies limited only to school children may merely reflect a small segment of a much more prevalent problem.

Pathophysiology

The current model of ARF pathogenesis is based on a complex interaction between rheumatogenic GAS strains, aberrant immune system, and host susceptibility.

ARF and Rheumatogenic Strains

Outbreaks of GAS pharyngitis have been associated with increased incidence of ARF, tying specific GAS strains (rheumatogenic strains) to the onset of the disease [1, 19, 20]. From a molecular basis, the surface M protein on GAS confers the bacteria its ability to attach to pharyngeal epithelial cells. Specific moieties of M protein in turn cause immune activation that target the host tissue. Molecular mimicry in which antibodies directed at bacterial antigens cross-react to similarly composed proteins in valvular tissue has been traditionally the accepted basis of valvular damage and RHD [21]. Antigenic α-helical moieties on the M protein are structurally homologous to cardiac helical proteins such as myosin, tropomyosin, actin, and laminin [22]. Recurrent GAS infection over time leads to reactivation of the primed immune system and a repetitive inflammatory process in which valvular damage ensues.

This widely accepted model of specific GAS rheumatogenic strains causing ARF is an active area of debate. Studies from ARF endemic areas in Australia revealed that typing of GAS did not match the classically recognized rheumatogenic strains of M serotypes, and group C and G Streptococcus were more common than group A Streptococcus [23, 24]. In addition, pharyngitis may be a rarer presentation of GAS infection with skin infection being the most common clinical manifestation [23].

ARF and the Immune System

There is an interval of approximately 2 to 5 weeks from the onset of GAS pharyngitis to the development of ARF. This latency is thought to be related to the period needed to mount immunity which correlates with the rise of antibodies to streptococcal enzymes such as antistreptolysin O (ASO) titers and anti-DNAse B. Eighty percent of patients with ARF have ASO titers elevated, and when additional GAS-specific antibodies, such as anti-DNAse B or anti-group A carbohydrate, are included, 95 % of ARF patients have elevated titers [22].

Current investigations suggest that antibodies produced as a result of GAS infection may not necessarily target the structural M protein but instead a group A carbohydrate, a component of GAS cell wall structure [25, 26]. Historically, levels of anti-group A carbohydrate antibodies have correlated with severity of valvular disease whereby surgical removal of affected valves results in decline of anti-group A carbohydrate antibodies [27]. Anti-group A carbohydrate antibodies also have high affinity for cardiac proteins such as myosin. However, valves are void of myosin, and myocardial damage, as detected by troponin elevation and myocardial dysfunction based on echocardiography finding, is absent during ARF [28]. Current studies hypothesize antibodies (which cross-react with myosin) bind to laminin and other basement membrane proteins found on endothelial surfaces of valves with similar helical structures to myosin [29]. The initial antibody mediated injury subsequently targets valvular endothelium leading to upregulation of in the inflammatory marker vascular cell adhesion protein 1 (VCAM-1) [30]. VCAM-1 causes the valvular endothelial surface to become porous, allowing T cells to infiltrate into the normally immune-privileged valvular tissue. These specific Tcells in turn recognize M protein and myosin as antigens and continue to proliferate leading to a cascade of inflammation and cytokine production causing valvular damage and scarring in RHD [31]. Although humoral response (mainly antibody mediated) is thought to be the inciting factor for endothelial dysfunction, newer studies point at specific CD4+ T cells [32] targeting connective tissue proteins [33]. These proteins, normally hidden from the immune system, become exposed following the endothelial damage that ensues from the initial inflammatory process. Despite decades of investigation, there is no unifying immunological pathway to explain the nuances of the disease.

ARF and Host Susceptibility

An important link between GAS infection and ARF is the regulating genetic factors determining the immune response to the infection. Only 3–6% [34, 35] of those who are infected with GAS develop ARF, implicating host susceptibility in the pathogenesis of ARF. This rate is also similar in communities where ARF is endemic, suggesting that genetic predisposition to ARF progression following a GAS infection is overall uniform in different populations [35].

Familial clustering and twin studies—showing increased concordance among monozygotic twins compared to dizygotic twins—support the role of genetic susceptibility in ARF [34, 36]. The major histocompatibility human leukocyte antigen (HLA) class II molecules, involved in antigen presentation to T cell receptors, have been associated with increased susceptibility to ARF [20]. Further studies are needed to identify the role of specific HLA haplotypes and their correlation to increased immunogenic predisposition to ARF and RHD in different ethnicities. On the whole, the evidence so far points to a complex interaction between humoral and cellular immune response triggered by GAS infection that is intricately connected to the host’s genetic makeup.

Clinical Manifestation of ARF

The peak incidence of ARF follows a similar pattern as GAS pharyngitis and occurs between the ages of 5–14 [13]. There is a female predominance which remains poorly understood. Increased exposure to GAS infection associated with child rearing and/or an underlying immunologic response could potentially be contributing factors [37].

The most common clinical features associated with ARF are arthritis, which occurs in 35–77 % of cases [13, 38], and carditis in 30–70 % [19, 39]. Other clinical manifestations with lower frequency include Syndeham chorea in 10–30 % (with female predominance) [13, 40], erythema nodosum in <6 %, and subcutaneous nodules in 0–10 % [41••]. All the above ARF manifestations compose the major Jones criteria, a guide established in 1944 [42] to aid in the diagnosis of ARF. In addition to these major criteria, other clinical manifestations such as fever, elevated inflammatory markers, and PR interval prolongation on electrocardiogram compose the minor criteria. The Jones criteria were most recently revised by the American Heart Association (AHA) in 2015 [41••]. The current AHA modified Jones criteria, in line with other international guidelines [43], recognize the variation in the clinical manifestation of the disease in endemic areas and takes into account newer studies that include Doppler echocardiography in the assessment of carditis in ARF [41••]. The updated guideline also differentiates ARF clinical manifestation between moderate/high risk population and low risk population. Furthermore, for all patients with evidence of preceding GAS infection, these criteria can be used to diagnose an initial or a recurrent episode of ARF (Table 1). Studies in endemic areas [44, 45] drew attention to the low sensitivity of Jones criteria in which under-diagnosis of ARF would have significant detrimental implications in RHD prevention. In contrast, the AHA guideline favors low sensitivity and high specificity in lower risk populations to minimize over-diagnosis of the disease.

Table 1.

Revised Jones criteria for diagnosis of ARF

For all patients with evidence of preceding GAS infection
1. Diagnosis of initial ARF
2 Major manifestations or 1 major plus 2 minor manifestations
2. Diagnosis of recurrent ARF
2 Major or 1 major and 2 minor or 3 minor criteria
Low risk population: ARF incidenceof ≤2 per 100,000 school-aged children or all-age RHD prevalence of ≤1 per 1000 population per year
Major criteria	Minor criteria
□ Carditis clinical or subclinical (i.e., echocardiographic) □ Polyarthritis □ Chorea □ Erythema marginatum □ Subcutaneous nodules	□ Polyarthralgia □ Fever >38.5 °C □ ESR ≥60 mm/h in the first hour and/or CRP ≥3.0 mg/dl □ Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion)
Moderate/high risk population:
Major criteria	Minor criteria
□ Carditis clinical or subclinical (i.e., echocardiographic) □ Polyarthritis or monoarthritis or polyarthralgia □ Chorea □ Erythema marginatum □ Subcutaneous nodules	□ Monoarthralgia □ Fever >38 °C □ ESR ≥30 mm/h and or CRP ≥3.0 mg/dl □ Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion)

Adapted with permission from Gewitz et al. [41••]

Most ARF manifestations resolve without any further sequelae. Rheumatic valvular disease resulting from severe or repetitive episodes of ARF is the most significant complication. ARF tends to recur the most in the first 4 years after the initial attack [13]. Subsequently, approximately 60 % of ARF cases progress to RHD within 10 years with the incidence of RHD peaking between the age of 25 and 44 [13, 46, 47]. For the rest of this review, we will focus on the cardiac manifestations of ARF and RHD.

Cardiac Manifestation in ARF

In the acute phase of ARF, the inflammatory process typically involves the valves, pericardium, and the myocardium [1, 48]. Patients with acute rheumatic carditis can present with chest pain attributable to pericarditis, heart failure symptoms, and sinus tachycardia that tends to persist at night [38].

Valvulitis

The mitral valve is the most common site of rheumatic valvulitis (in >70–94 % of cases) [39, 49] with involvement of aortic valve in 20–25 % of those cases. Isolated aortic valvulitis is seen in less than 5–8 % of cases [50]. Inflammation of the valves and subsequent new mitral or aortic regurgitation murmur is central to the pathology of rheumatic carditis. In the absence of these signs, rheumatic carditis is unlikely [51]. It is exceedingly rare for rheumatic carditis to present as isolated right-sided valvular disease. Involvement of mainly mitral and aortic valves in rheumatic carditis is possibly related to the expression of specific endothelial surface proteins and the exposure to higher pressures than the right side [28].

In the acute setting, regurgitation is secondary to inflamed valves, mitral annular dilatation, and leaflet prolapse with or without chordal elongation [41••, 49]. Cellular infiltrate of the valves, edema, and neovascularization create a fibrinous vegetation on the valves [28]. As opposed to infectious vegetations, fibrinous vegetations do not embolize. Left untreated, mitral regurgitation leads to regurgitation-induced volume overload and left ventricular and atrial enlargement causing further dilation of the annulus, chordal tethering, and worsening mitral regurgitation; hence, the adage “mitral regurgitation begets mitral regurgitation” [52].

Traditionally, carditis was a clinical diagnosis based on pathological mitral regurgitation and/or aortic regurgitation on auscultation. An apical soft, blowing, pansystolic murmur is characteristic of mitral regurgitation and a basal early diastolic murmur for aortic regurgitation. With the advances in cardiac imaging and widespread use of echocardiography, we can now identify subclinical carditis—pathological valvular regurgitation on echocardiogram [41••, 44, 53] in the absence of clinical carditis. Echocardiography detects RHD up to ten times more frequently than clinical auscultation [15, 18, 54], and echocardiographic findings are now included as major Jones criteria [41••, 53]. The World Heart Federation (WHF) outlined the echocardiographic criteria that constitute RHD [41••, 55••] (Table 2).

Table 2.

WHF echocardiographic criteria for RHD in adults aged >20 years

Definite RHD is met by any of the following criteria (A, B, C, or D)
A. Pathological MR and at least two morphological features of RHD of the MV
B. MS mean gradient ≥4 mmHg
C. Pathological AR and at least two morphological features of RHD of the AV, only in individuals aged <35 years
D. Pathological AR and at least two morphological features of RHD of the MV
Doppler findings
Pathological mitral regurgitation (all 4 criteria must be met)	1. Seen in at least 2 views 2. Jet length ≥2 cm in at least 1 view 3. Peak velocity ≥3 m/s 4. Pansystolic jet in at least 1 envelope
Pathological aortic regurgitation (all 4 criteria met)	1.Seen in at least 2 views 2. Jet length ≥1 cm in at least 1 view 3. Peak velocity ≥3 m/s in early diastole 4. Pan-diastolic jet in at least one envelope
Morphological findings
Mitral valve changes	1. AMVL thickeninga 2. Chordal thickening 3. Restricted leaflet motion 4. Excessive leaflet tip motion during systole (only for individuals aged <35)
Aortic valve changes	1. Irregular or focal leaflet thickening 2. Coaptation defect 3. Restricted leaflet motion 4. Leaflet prolapse

Reprinted by permission from Macmillan Publishers Ltd, from Remenyi et al. [55••]

MR mitral regurgitation, MV mitral valve, MS mitral stenosis, AR aortic regurgitation, AV aortic valve

^aAMVL (anterior mitral valve leaflet) thickness is age-dependent: ≥4 mm for ages 21–40 years and ≥5 mm for individuals aged >40 years

Pericarditis

Pericarditis in ARF is unlikely to occur in the absence of valvular regurgitation [28] and does not cause constrictive physiology [56]. Pericardial effusion can be present—although rarely large enough to present with tamponade physiology—and should not be attributed to rheumatic carditis in the absence of valvulitis [1]. Clinically, friction rub and electrocardiogram changes consistent with pericarditis can be observed in the acute presentation. Pericarditis due to ARF resolves spontaneously without any sequelae.

Myocarditis

Myocarditis in the setting of ARF loosely describes “unexplained [congestive heart failure] or cardiomegaly” [1]. Myocardial necrosis is not a feature of ARF. Multiple studies have shown that inflammatory changes do not affect the myocytes per se but the perivascular and interstitial areas in the myocardium [25, 48]. Aschoff nodules—granulomatous bodies containing macrophages and T cells—although not a very sensitive finding, are pathognomonic for ARF carditis. These nodules tend to occur near the valves, below the endothelial layer or in the interstitium of the myocardium [57], and are thought to be associated with recurrent ARF. The lack of myocardial damage has been investigated in multiple studies. Troponin-I and creatinine kinase remain normal or minimally elevated [58] in rheumatic carditis and, even in the setting of overt symptoms of congestive heart failure (CHF), ventricular function is not affected [49].

Rheumatic Heart Disease

Following an episode of ARF, 60% of those affected progress to RHD [13]. Once the acute inflammatory course of ARF has subsided, patients should be evaluated for residual valvular damage. Pathological mitral regurgitation on auscultation and/or echocardiographic findings showing mitral regurgitation with thickened valve leaflets (dog leg or elbow deformity) are characteristic of RHD (Fig. 1 and Supplementary online Videos S1 and S2). Specific criteria (Table 2) have to be met to minimize the risk of over-diagnosis by excluding physiological regurgitant murmurs or non-specific valvular findings on echocardiogram [41••, 55••].

Fig. 1.

Rheumatic mitral valve disease on echocardiogram. Still image from an echocardiogram showing rheumatic mitral valve disease from the parasternal long-axis window in mid-diastole. Valve commissural thickening, dilated left atrium, and characteristic “hockey stick” deformity of the anterior mitral valve leaflet are shown

The rate of progression to stenotic valvular disease varies across geographical areas. In North America, there is a longer latency period of 10 to 40 years after initial manifestation of rheumatic carditis, whereas in developing countries patients often present with advanced disease in their late teens and early 20s [1, 59, 60]. The more rapid progression of the disease is presumably associated with recurrences of ARF, severity of carditis, inadequate prophylaxis with penicillin, and socioeconomic status [61, 62].

With echocardiogram-assisted diagnosis of RHD, the concept of latent RHD has been recognized—echocardiographic changes suggesting RHD in asymptomatic individuals without a known history of ARF. A subset of these individuals have subclinical RHD noted by echocardiographic valvular changes without clinically audible cardiac murmur. The natural progression of latent RHD is currently under investigation. A recent study [63] showed that half of patients with latent RHD reverse to normal in a 5-year follow-up with others either remaining stable or progressing. Valvular changes detected on echocardiogram may therefore be dynamic. More research is needed to determine factors associated with progression to definite RHD and the utility of interventions (such as BPG prophylaxis) in halting or reversing progression of disease.

Prevention and Treatment

In most developing countries that lack adequate healthcare infrastructure and preventative services, RHD patients present at an advanced stage with complications such as CHF, thromboembolic events, or infective endocarditis [62]. Even when RHD patients are suitable candidates for life-saving surgical valvular interventions, the services are often inaccessible. Shortage of skilled-personnel and access to those services are cost-prohibitive for the majority of patients affected by RHD. These patients are often identified in the prime wageearning and childbearing ages with attendant serious medical, social, and economical consequences [13, 17].

Prevention of ARF

RHD is a disease of social inequality. Efforts to eradicate poverty, limit overcrowding and implement environmental hygiene, and provide basic needs such as access to clean water, sanitation, and primary health care, would be the center of prevention. However, these interventions are notably transdisciplinary and complex. It should nevertheless raise the awareness of health sectors and disaster response groups to consider ARF, among other infectious diseases, as a potential outbreak threat, as seen in military and civilian communities in the USA in the 1980s and 1990s [11, 19, 64]. Outbreaks have also been seen in the setting of social unrest, urban slums, immigration, and overcrowding of refugee camps [65]. Public education centered at raising awareness of GAS pharyngitis and its many sequelae should be integrated in the preventative public health efforts in ARF/RHD endemic areas.

Primary Prevention

Primary prevention refers to treatment of GAS pharyngitis to prevent an initial episode of ARF. Diagnosis of GAS infection is based on rapid antigen detection or the gold standard of throat culture. Antibiotic therapy aims at eradicating GAS from the upper respiratory track. With its bactericidal activity, penicillin is the treatment of choice for GAS pharyngitis. A single dose of intramuscular injection of benzathine penicillin G (BPG) is effective in eradicating the infection. Alternatively, a 10-day course of oral penicillin can be used but patient compliance should be weighed. However, in countries that lack basic health infrastructure, implementation of sore-throat screening programs may not be a viable alternative. In addition, more than 60 % of ARF cases occur without a prior recollection of symptomatic GAS pharyngitis [11, 66] and may hinder a program focused on surveillance of disease for eradication of GAS pharyngitis. On the other hand, a cost-effective analyses using data from South Africa showed that treating all children presenting with pharyngitis with intramuscular penciling injections without culturing is the least expensive out of seven approaches considered, and that a strategy using a clinical decision rule (which considers the presence of cervical nodes, rhinitis, and rash without culturing) is the overall preferred strategy [67]. The prevalence of mainly skin infection, as opposed to upper respiratory GAS infection, in endemic regions also raises the question of the efficacy of the traditional primary prevention in many resource-poor settings. In a study in Australia, sore-throat screening and treatment programs have not been shown to be cost-effective [43] despite the demonstrated efficacy of penicillin to prevent ARF following GAS pharyngitis [68].

Vaccines

Vaccines for GAS would theoretically be the most cost-effective intervention in countries where ARF/RHD is endemic [66]. Interest and funding for vaccine development however dwindled with dramatic reduction of ARF and RHD in developed countries. There are currently no licensed vaccines. M-protein antigen-based polyvalent vaccines (mainly targeting serotypes in low-risk countries) and others containing conserved GAS antigens are currently being investigated [66, 69, 70•]. In addition to the dearth of funding, incomplete understanding of the pathogenesis of ARF and the lack of epidemiological data from the majority of ARF endemic countries hinders effective and significant advances in the development of a vaccine [37].

Secondary Prevention

Long-term management of rheumatic carditis should include secondary prophylaxis with penicillin to prevent recurrence of GAS infection and repetitive episodes of ARF—which increase the risk of progression to RHD [71]. As opposed to a one-time intramuscular dose of penicillin, secondary prophylaxis requires BPG every 3 to 4 weeks (Table 3). The duration of therapy is dependent on patient’s age, severity of valvular disease, and last recurrence of ARF [1, 72]. Adherence is problematic because of the burden imposed by the long-term need for prophylaxis in patients who often do not have easy access to health care facilities or ability to afford extended treatment. Nonetheless, secondary prophylaxis with BPG has been shown to be cost-effective and is central to preventing rheumatic fever recurrence and strep throat infections [1, 72, 73].

Table 3.

Antibiotic dose for secondary prophylaxis in RHD

Antibiotic	Dose
Benzathine penicillin G	600,000 units intramuscular (≤27 kg) or 1,200,000 units intramuscular (>27 kg) every 3–4 weeks (every 3 weeks in endemic areas)
Penicillin V (phenoxymethyl penicillin)	250 mg oral twice daily
Sulfadiazine	500 mg oral daily (≤27 kg)
(For patients allergic to penicillin)	1000 mg oral daily (>27 kg)
Macrolide	Variable dose
(For patients allergic to penicillin and sulfadiazine)

Although BPG prophylaxis is often the focus of secondary prevention, it heavily relies on RHD case detection. Active surveillance of RHD is fundamental in reaching individuals that would benefit most from BPG prophylaxis by preventing recurrence of GAS infection and potentially limiting progression to chronic RHD. The availability of handheld and portable echocardiography and the updated Jones criteria allow for active screening and identification of undiagnosed and subclinical carditis in ARF/RHD endemic areas. Most attention has been paid to school- or community-based RHD screening [74, 75••]. Handheld echocardiograms have been shown to be equally effective as standard echocardiograms in the diagnosis of definite RHD with comparable sensitivity and specificity [75••]. More recent studies focused on training non-expert healthcare workers (e.g., nurses, clinical officers) [76, 77] in using handheld echocardiograms for RHD detection show promise with this approach as a viable strategy in the implementation of a screening program in areas where there is a dearth of highly trained echocardiogram technicians or cardiologists.

Surgical Management of RHD

Surgical intervention is often needed in chronic RHD. The options for surgical management include mitral commissurotomy, valve repair, and valve replacement with either a mechanical or bioprosthetic valve. The 2014 AHA and American College of Cardiology (ACC) guidelines outline indications for surgical management in valvular disease including RHD-related valvular disease [78••]. Class 1 indications relevant to mitral and aortic RHD are shown in Table 4. Age, childbearing status, symptoms, ventricular function, and feasibility of repair versus valvular replacement also need to be considered in timing and type of surgical intervention. Resource-poor settings with inadequate access to anticoagulation services pose another consideration in choosing bioprosthetic or mechanical valves in patients with RHD who may need long-term anticoagulation.

Table 4.

Class 1 indications for surgical management of RHD-related valvular disease

Lesion	Assessment of severity	Clinical status	Other considerations	Class 1 indication
MS	Severe	Symptomatic	Favorable valve morphology	PMBC
	MVA ≤1.5 cm2		No left atrium clot
	T½ ≥150 ms		No or mild MR
	Very severe		NYHA Class III-IV symptoms	MVR
	MVA ≤1 cm2		Low surgical risk
	T½ ≥220 ms
MR	Severe	Symptomatic	LVEF >30 %	MVRa
		Asymptomatic	LVEF 30–60 % or LVESD ≥40 mm
AR	Severe	Symptomatic		AVR
		Asymptomatic	LVEF <50 %
			Other cardiac surgery

MS mitral stenosis, MVA mitral valve area, T1/2 pressure half-time, PMBC percutaneous mitral balloon commissurotomy, NYHA New York Heart Association, MVR mitral valve surgery (replacement or repair), MR mitral regurgitation, LVEF left ventricular ejection fraction, LVESD left ventricular end-systolic dimension, AVR aortic valve replacement (valve repair may be appropriate in selected patients)

^aMitral valve repair is preferred over mitral valve replacement (MVR) whenever possible

Mitral valve repair has better outcomes than mitral valve replacement in rheumatic mitral regurgitation [79, 80]. Repair is less invasive and avoids the need for long-term anticoagulation, but should be considered in light of the need for early reoperation (10 % need repair within 2 years) [72].

In the case of isolated symptomatic severe mitral stenosis, percutaneous balloon commissurotomy is the procedure of choice [78••, 81]. Younger patients with favorable valve morphology have better outcomes. Valve morphology can be assessed with a mitral valvuloplasty score [82] which considers leaflet mobility, valve thickening, calcification, and subvalvular thickening. However, patients in developing countries often present late with involvement of multiple valves precluding the option of these less invasive procedures. Patients with mitral stenosis are at risk of atrial fibrillation, increasing their risk for thromboembolic disease but also hemodynamic compromise due to abrupt loss of atrial contribution in ventricular filling. Therapy aimed at rate control and anticoagulation is key in mitral stenosis.

Although there have been advances in surgical therapy of valvular disease, it should be noted that the majority of patients living in these poor-resource settings will not be able to access these services. Surgical interventions in these communities are associated with high morbidity [4] and are not by any means a cost-effective solution to the great burden of RHD remaining in LMIC.

Eradication—the Final Frontier in RHD

While there is much work to be done at the bench and at the bedside for patients with and at risk for RHD, the twenty-first century issue with RHD relates to advocacy, awareness, and political will to finally eradicate this disease. The disproportionate burden of RHD in LMIC and impoverished regions of high-income countries is a social injustice. Advances in the social and ecological environments in many nations have virtually eradicated this disease from the practice of physicians in HIC. As the world focuses on sustainable development goals and achieving the World Heart Federation/World Health Organization “25 by 25” goals [83] of reducing premature deaths from cardiovascular diseases by 25 % by 2025, RHD must remain on the agenda.

The last decade has witnessed great attention to RHD in sub-Saharan Africa. There have been four All-Africa Workshops on Rheumatic Fever and RHD since 2005, producing compelling statements such as The Drakensburg Declaration [84] (2005), the Mosi-o-Tunya call to action [85] (2014) and, most recently, the Addis Abbaba communiqué [86] (2016). These workshops were convened with support, in part, by the South African government, the World Heart Federation, and the World Health Organization. Historically, recommended actions to eradicate RHD in Africa have been wide reaching encompassing vaccine development, ending poverty, educating teachers, and a number of other cross-cutting themes.

Although there has been progress on understanding the burden of RHD in at-risk regions of the world, much work remains in terms of establishing national prevention policies and programs. The historical challenges of translating principles and policy into practice notwithstanding, the Addis Ababa communiqué [86] outlines several specific bold recommendations to the African Union and member states. These include the following: (1) establishing prospective RHD registries at sentinel sites; (2) ensuring adequate supply of benzathine penicillin; (3) guaranteeing access to reproductive health services; (4) decentralizing of technical expertise; (5) establishing centers of excellence for cardiac surgery; (6) fostering multi-sectoral national RHD control programs; and (7) cultivating a communication framework and partnership within key stakeholders in the region. National action to combat RHD can be effective as demonstrated by concerted action in other nations [87].

Conclusion

RHD remains a major cause of morbidity and mortality mostly affecting LMIC. Despite advances in understanding the pathology of the disease, efforts at implementation of coordinated national programs to raise awareness, assess disease burden, and offer preventative services remain the major hindrance in eradication of the disease. Advocacy and action plans to address these issues are encouragingly being pursued by advocates from LMIC [86, 88, 89] and roadmaps with the ambitious goal of ending ARF and RHD are underway to being implemented in regions affected the most. For the twenty-first century, the remaining work related to RHD spans many disciplines; however, eradication of this disease remains the penultimate goal.