JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 72, NO. 12, 2018
ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
THE PRESENT AND FUTURE JACC SCIENTIFIC EXPERT PANEL
Rheumatic Heart Disease Worldwide JACC Scientific Expert Panel David A. Watkins, MD, MPH,a,b,c Andrea Z. Beaton, MD,d Jonathan R. Carapetis, MBBS, PHD,e,f Ganesan Karthikeyan, MD, DM,g Bongani M. Mayosi, MBCHB, DPHIL,b,h Rosemary Wyber, MBCHB, MPH,e,i Magdi H. Yacoub, MD,j Liesl J. Zühlke, MBCHB, MPH, PHDb,c
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Successful completion of this CME activity, which includes participation in
rheumatic heart disease; 2) summarize areas of consensus and the major
the evaluation component, enables the participant to earn up to 1 Medical
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Knowledge MOC point in the American Board of Internal Medicine’s (ABIM)
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Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel will be accredited by the European Board for Accreditation in Cardiology (EBAC)
Author Disclosures: Dr. Watkins has received support from the RHD Action
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Dr. Carapetis has received funding from Novartis Institutes for Biomedical
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Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
From the aDivision of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington; b
Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa; cDepartment of Pae-
diatrics, University of Cape Town and Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; dChildren’s National Health System, Washington, DC; eTelethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia; f
Princess Margaret Hospital for Children, Perth, Western Australia, Australia; gDepartment of Cardiology, All India Institute of
Medical Sciences, New Delhi, India; hThe Deans Suite, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; iOffice of the Chief Scientist, The George Institute for Global Health, UNSW Sydney, Camperdown, New South Wales, Australia; and the jAswan Heart Centre, Aswan, Egypt. Dr. Watkins has received support from the RHD Action grant from Medtronic
ISSN 0735-1097/$36.00
https://doi.org/10.1016/j.jacc.2018.06.063
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JACC VOL. 72, NO. 12, 2018 SEPTEMBER 18, 2018:1397–416
Present Status of Rheumatic Heart Disease
Rheumatic Heart Disease Worldwide JACC Scientific Expert Panel David A. Watkins, MD, MPH,a,b,c Andrea Z. Beaton, MD,d Jonathan R. Carapetis, MBBS, PHD,e,f Ganesan Karthikeyan, MD, DM,g Bongani M. Mayosi, MBCHB, DPHIL,b,h Rosemary Wyber, MBCHB, MPH,e,i Magdi H. Yacoub, MD,j Liesl J. Zühlke, MBCHB, MPH, PHDb,c
ABSTRACT 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. (J Am Coll Cardiol 2018;72:1397–416) © 2018 by the American College of Cardiology Foundation.
O
ver the past decades, rheumatic heart dis-
Because of this renewed interest, the science of
ease (RHD) and its antecedent rheumatic
RHD has evolved rapidly. A number of new or
fever (RF) have largely disappeared from
ongoing studies aim to provide answers to key ques-
wealthy countries, and the clinical caseload of RHD
tions. This Scientific Expert Panel seeks to summarize
has shifted to older age groups. RHD has also been
recent research on RHD—from molecular mechanisms
dwarfed by ischemic heart disease. Additionally, RF/
to health systems—in one coherent, scientifically-
RHD control programs were successfully implemented
grounded vision for the future of science, clinical
in some low- and middle-income countries during the
medicine, and public health practice relating to RHD
latter part of the 20th century, prompting the World
(Central Illustration).
Health Organization (WHO) and others to downscale their RF/RHD activities by the early 2000s (1). Yet, RHD continues unabated in poor countries and
WHAT IS RHEUMATIC HEART DISEASE, AND HOW BIG IS THE PROBLEM?
among vulnerable groups in wealthy ones (2). A 2007 report on RHD among schoolchildren in Cambodia and
PATHOGENESIS. The major driver of acute RF is
Mozambique spawned a whole literature on echocar-
frequent group A beta-hemolytic streptococcal (GAS)
diography and RHD (3). The recent REMEDY study
infection.
(Global Rheumatic Heart Disease Registry) docu-
increased GAS exposure include household crowd-
mented high rates of disability and premature death
ing, poor hygiene, and low access to medical ser-
across African and Asian countries (4). In 2015, a civil
vices (7). Why only a minority of persons (<6%)
society movement, RHD Action, was launched to raise
living in GAS-endemic areas develop RF is less
awareness and support countries looking to address
understood.
RHD (5). In May 2018, the World Health Assembly
H o s t f a c t o r s . There are 2 theories of how GAS
adopted a resolution to reinvigorate global and na-
infection damages host tissues. The basis of the mo-
tional RF/RHD prevention and control efforts (6).
lecular mimicry theory is that molecules on the
Socioeconomic
conditions
Foundation outside of the submitted work. Dr. Carapetis has received funding from Novartis Institutes for Biomedical Research. Dr. Wyber has received funding from the Postgraduate Scholarship from the National Health and Medical Research Council (NHMRC), Australia, and from the Telethon Kids Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received March 22, 2018; revised manuscript received June 13, 2018, accepted June 15, 2018.
leading
to
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Present Status of Rheumatic Heart Disease
infecting organism are antigenically similar to mole-
recognize and activate valve endothelium to
ABBREVIATIONS
cules on host tissues. When the host immune
express adhesion molecules like vascular cell
AND ACRONYMS
response targets these molecules, both are damaged.
adhesion molecule 1, allowing CD4 T cells
In the case of acute RF, 2 main streptococcal antigens
(and others) activated by GAS to invade the
have been implicated: the surface M protein, and
heart valve, encounter antigens, and become
GlcNAc, the immunodominant epitope of the group A
further activated. Over time, tissue break-
carbohydrate (8). The “neo-antigen” theory, a more
down, partly involving autoantibodies and
recent development, suggests that the GAS organism
complement activation, releases additional
gains access to the subendothelial collagen matrix,
endogenous antigens such as collagen, lami-
where M proteins binds to the CB3 region of type IV
nin, myosin, and tropomyosin that may also
collagen, creating a neo-antigen that induces an
serve as autoantigens, stimulating more CD4 T cells,
autoimmune response against collagen (9).
which then produce Th1 and potentially Th17 cyto-
GAS = group A beta-hemolytic streptococcus
RF = rheumatic fever RHD = rheumatic heart disease WHF = World Heart Federation WHO = World Health Organization
In both theories, it is thought that the initial
kines, leading to further inflammation in the heart
damage to cardiac tissues is due mainly to antibodies,
valve. Over time, successive episodes coupled to
with cellular responses subsequently implicated as
resolution leads to neovascularization and fibrosis
the immunological cascade evolves. These antibodies
(Figure 1) (10).
C ENTR AL I LL U STRA T I O N Framework for Rheumatic Heart Disease Control and Eventual Elimination
Prevention
Research
• Innovations in rheumatic fever/rheumatic heart disease diagnosis and risk prediction • Improved delivery of benzathine penicillin G • Raising public and health worker awareness • Comprehensive, community-based programs
Advanced care
Advocacy
Health policy
• Early echocardiographic diagnosis • Reproductive and antenatal services • Medical management of complications • Access to timely, high-quality surgical care
• “Diagonal” health system investments • Integration and cross-sector collaboration • Product development and research priorities (e.g., vaccines)
Implementation Watkins, D.A. et al. J Am Coll Cardiol. 2018;72(12):1397–416.
Global progress on rheumatic heart disease (RHD) will require a combination of advocacy efforts, implementation of existing evidence, and research in key areas. Priority areas for advocacy, implementation, and research are: 1) the prevention of rheumatic fever and RHD, typically through primary healthcare services in community settings; 2) advanced care, which includes tertiary cardiology and, critically, cardiac surgery services; and 3) health policy, including measures that should be taken by national health systems (mostly to deliver health care) and international collective action (mostly to support research, product development, and global stewardship and leadership).
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F I G U R E 1 Possible Pathogenic Mechanisms in Rheumatic Heart Disease
Fibrosis Inflammatory lesions Functional Antibodies
Complement
Neovasularization
Recruitment of cells activated by GAS infection
Anti-endothelial cell antibodies (AECA) generated by GAS infection
Pro-inflammatory cytokine production
AECA-induced adhesion molecule expression
Aschoff Nodule
Autoantibodies
VCAM-1
CD4+Tcell
B cell
Complement
Endogenous peptide loaded on MHCII
CD8+Tcell
Monocyte
Valvular dendritic cell Monocyte-derived dendritic cell
Myofibroblast Antigen Presentation
The schematic shows a cross-section of a heart valve leaflet. Autoreactive antibodies, including antiendothelial cell antibodies (AECA) and autoreactive T cells, are generated by infection with group A beta-hemolytic streptococcus (GAS) in the throat (pharyngitis) or possibly the skin (pyoderma, impetigo) through molecular mimicry and/or anticollagen responses. AECA have multiple effects, including the activation of endothelial cells leading to vascular cell adhesion molecule (VCAM) 1 expression, complement activation leading to cell death, and activation of neuronal cells leading to CaM kinase III signaling. Deposition of complement and immunoglobulin occurs. The presence of M protein in the subendothelial collagen matrix by GAS invasion of endothelial surfaces may lead to the generation of anticollagen type IV responses. Liberation of structural alpha helical coiled coil peptides, including collagen, laminin, keratin, and tropomyosin, occurs in areas of tissue damage such as valvular lesions. Liberated proteins are presented by antigen presenting cells (APC) either in situ or in the draining lymph node to induce autoreactive CD4þT cells. These APC are resident dendritic cells, recruited inflammatory monocytes that have differentiated into APC in the valve interstices or within ectopic Aschoff nodules, or valvular fibroblasts and cardiac endothelial cells that aberrantly express MHC II. The range of reactive T-cell and antibody specificities increases over time with epitope spreading. Th1 cytokines, such as IFNg, and chemokines including CXCL9 are generated in ARF and RHD. Prolonged and repeated cycles of inflammation facilitate ongoing tissue damage. In RHD, TGFb from interstitial cells may contribute not only to Th17 generation but also to new blood vessel growth, allowing greater access to the valve in successive episodes, as well as stimulating collagen deposition from myofibroblasts, leading to fibrosis. Reprinted with permission from Martin et al. (10).
The infrequency of RF/RHD relative to the frequency of childhood GAS infection raises the possi-
and B-cell alloantigens have been implicated (14), but most have not been replicated (15,16).
bility of genetic predisposition (11). Among children
Among genome-wide association studies, 2 had no
raised apart from their parents, those whose parents
significant findings, whereas another found that var-
had RHD had a 2.9-fold higher risk of RF compared
iants at the immunoglobulin heavy chain locus were
with peers whose parents did not have RHD (12). Twin
associated with RHD in 2 populations (17), but this
studies have estimated the heritability of RF at 60%
result was not replicated elsewhere (18). The latter
(13). Small candidate gene case-control studies have
study identified evidence for risk and protective
identified genetic variants associated with RF/RHD.
haplotypes across HLA-DQA/DQB Class II molecules,
Genes controlling the adaptive immune response
supporting molecular mimicry as the key pathogenic
(e.g., human leukocyte antigen [HLA] class II alleles),
mechanism. Although these studies differ in diag-
the innate immune response (e.g., toll-like receptor
nostic method, design, and population studied, they
2), cytokine genes (e.g., tumor necrosis factor alpha),
support the notion of autoimmune pathogenesis.
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T A B L E 1 Clinical Features Among 3,343 African, Yemeni, and
T A B L E 2 World Heart Federation Criteria for the Diagnosis of RHD
Indian Individuals With Symptomatic Rheumatic Heart Disease Median Age, yrs
New York Heart Association functional class III and IV
809 (24.6)
26
Medical history Acute rheumatic fever
1,340 (40.7)
Congestive heart failure
1,110 (33.4)
Pulmonary hypertension
25
957 (28.8)
26
Stroke
235 (7.1)
40
Infective endocarditis
133 (4.0)
25
Major bleeding
89 (2.7)
31
Peripheral embolism
25 (0.8)
43
Atrial fibrillation
586 (21.8)
Echocardiography Decreased LVEF in adults Decreased LVEF in children
661 (26.5) 168 (5.3)
Dilated LVEDD in adults
742 (23.0)
Dilated LVEDD in children
454 (14.1)
Left atrial thrombus
44 (1.4)
Previous percutaneous valvuloplasty
Definite RHD (A, B, C, D) Age >20 yrs
A. Pathological MR and at least 2 morphological features of RHD of the MV
A. Pathological MR and at least 2 morphological features of RHD of the MV
B. MS mean gradient $4 mm Hg*
B. MS with mean gradient $4 mm Hg*
C. Pathological AR and at least 2 morphological features of RHD of the AV
C. Pathological AR and at least 2 morphological features of RHD of the AV in those age <35 yrs
D. Borderline disease of both the AV and MV
D. Pathological AR and at least 2 morphological features of RHD of the MV Borderline Not Applicable to Those Age >20 yrs
Borderline RHD (A, B, C) A. At least 2 morphological features of RHD of the MV without pathological MR or MS B. Pathological MR C. Pathological AR Pathological Mitral Regurgitation
Pathological Aortic Regurgitation
Seen in 2 views
Seen in 2 views
715 (21.4)
In at least 1 view, jet length $2 cm†
In at least 1 view, jet length $1 cm†
135 (4.1)
Velocity $3 m/s for 1 complete envelope
Velocity $3 m/s in early diastole
Pan-systolic jet in at least 1 envelope
Pan-diastolic jet in at least 1 envelope
Surgical history Valve replacement or repair
Definite RHD (A, B, C, D) Age #20 yrs
Values are n (%) or n. Table presents authors’ own re-analysis of data from Zühlke et al. (4). LVEDD ¼ left ventricular end-diastolic diameter; LVEF ¼ left ventricular ejection fraction.
Meta-analyses of thousands of well-characterized cases and controls will be required to identify reliable and reproducible genetic susceptibility and protective factors. Ultimately, genomic analyses could identify high-risk individuals to target for penicillin
Mitral Valve
Aortic Valve
AMVL thickening $3 mm (age #20 yrs), $4 mm (age 21 to 40 yrs), $5 mm (age >40 yrs)
Irregular or focal thickening
Chordal thickening
Coaptation defect
Restricted leaflet motion
Restricted leaflet motion
Excessive leaflet tip motion during systole
Prolapse
*Must rule out congenital anomalies of the mitral and aortic valve. †Jet to be measured from vena contracta to last pixel of color. Modified with permission from Remenyi et al. (24). AMVL ¼ anterior mitral valve leaflet; AR ¼ aortic regurgitation; AV ¼ aortic valve; MR ¼ mitral regurgitation; MS ¼ mitral stenosis; MV ¼ mitral valve; RHD ¼ rheumatic heart disease.
prophylaxis and vaccination against GAS. P a t h o g e n f a c t o r s . Outbreaks of rheumatic fever in North America in the mid-20th century were limited
regions of the M protein and include sequences
to GAS strains belonging to a subset of M types (based
homologous with human actin and cardiac myosin,
on the classical typing system; this has since been
although there are other cross-reactive antigens in
replaced by emm typing based on the genetic
GAS including the group A carbohydrate (10).
sequence of the M protein). Over the past 2 decades, it
While the recent growth in research on RHD path-
has become apparent that GAS strains from regions
ogenesis is promising and has challenged a variety of
where RHD is endemic are much more diverse than
historical paradigms, a number of key scientific
those in nonendemic areas, and that there is no as-
questions remain. Online Appendix Panel 1 suggests
sociation of particular emm types with RF/RHD (19).
priorities for future research.
This work has also suggested that RF-inducing strains
CLINICAL
may be associated with skin infection, supporting the
C l i n i c a l f e a t u r e s . Aside from a subset of children in
hypothesis that RF is not solely a consequence of GAS
whom RF leads to severe carditis and early RHD, RHD
pharyngitis (20–22).
is usually clinically silent (“latent”) until it manifests
AND
ECHOCARDIOGRAPHIC
ASPECTS.
Focus has shifted in recent years to better under-
during adulthood. Many individuals in RHD-endemic
standing the features of RF-associated GAS strains
countries present late in their disease process with 1
rather than emm types. Most attention has been paid
or more sequelae. The REMEDY study followed 3,343
to identifying surface or excreted antigens that have
individuals with symptomatic RHD presenting for
antigenic homology to human tissues and could
care at academic centers in 14 countries (Table 1) (4).
stimulate cross-reactivity. Most of the identified
Most individuals were 15 to 49 years of age, and
cross-reactive regions are in the A- and B-repeat
fewer than one-half recalled a history of RF. Heart
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F I G U R E 2 Parasternal Long-Axis Echocardiography Images of a Child With Borderline RHD
This echocardiogram demonstrates functional but not morphological changes of the mitral valve, including an anterior mitral valve (single arrow) thickness of 2.7 mm (criterion for definite rheumatic heart disease [RHD] is thickness $3 mm, or $4 mm if age >20 years) and jet length (double arrow) of 2.3 cm (criterion for definite RHD is >2 cm in at least 1 view). In addition, there is complete leaflet excursion without restriction. See Table 2 for full details of the WHF criteria for borderline and definite RHD. AAo ¼ aortic arch; LA ¼ left atrium; LV ¼ left ventricle.
failure, pulmonary hypertension, and atrial fibrillation
“Subclinical RHD” refers to RHD seen on echocardi-
were the most frequent medical complications. About
ography in a patient with a normal clinical cardiac
20% demonstrated decreased left ventricular ejection
examination. “Latent” RHD includes a broader spec-
fraction, and about one-third had increased left
trum of disease, including any RHD found on echo-
ventricular end-diastolic diameter—underscoring the
cardiographic screening in the absence of prior RF or
consequences of late presentation.
known RHD. Although latent RHD includes subclini-
Challenges in diagnosing acute RF are a major
cal RHD, one-third (Uganda) (25) to two-thirds (Fiji)
barrier to preventing RHD. Strong evidence of milder
(26) of children with latent definite RHD already have
presentation and the importance of subclinical car-
moderate-to-severe disease. Outcomes for these
ditis prompted revision of the Jones Criteria (the gold
children are poor (26). In Uganda, almost one-half of
standard for RF diagnosis) in 2015 to better account
children with moderate-to-severe RHD progressed (to
for differences in population risk (23). While these
worsening regurgitation, stenosis, or death) over a
criteria will likely increase case detection, barriers
median of 2.3 years, and only 9.5% showed any dis-
such as poor health seeking behavior, lack of pathol-
ease improvement (25).
ogy services, and clinical overlap with other endemic
By contrast, the clinical course of children with
diseases (such as malaria in sub-Saharan Africa) limit
borderline and mild definite RHD is enigmatic. Com-
the efficacy of a simple diagnostic shift within a
parison
clinical decision rule. Better RF diagnosis will require
cautiously: studies have used inconsistent definitions
the development of new (laboratory) technology tests
of progression, have used different outcomes, and in
that could augment or replace clinical decision rules.
some cases, have included children with advanced
R H D . The World Heart
RHD (25,27). Standardization is needed in reporting
Federation (WHF) published the first evidence-based,
outcomes (27). Although most children with border-
Echocardiography
and
across
cohorts
must
be
undertaken
standardized criteria for the echocardiographic diag-
line or mild definite RHD remain stable or show
nosis of RHD in 2012 (Table 2, Figure 2) (24). Since
improvement, 10% to 24% experience disease pro-
then, >2 dozen additional studies covering >100,000
gression (Figure 3). Outcomes are best for children
participants have been conducted. In parallel, studies
with borderline RHD and worst for those with
have investigated the practicalities of echocardio-
advanced RHD (25).
graphic screening in RHD-endemic countries, high-
There is no doubt that some overlap exists be-
lighting many challenges and exploring solutions
tween echocardiographic findings of borderline RHD
(Table 3).
and normal anatomic variation. Early RHD appears to
The vocabulary describing echocardiographically-
be a dynamic, heterogeneous entity with varied
detected RHD lacks precision in the published data.
outcomes (Figure 4). If subclinical RHD detected
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T A B L E 3 Research Progress and Remaining Questions Around Echocardiographic Screening for RHD
Rationale and Challenges
Progress
Next Step(s)
Simplified protocols
Category
2012 WHF criteria were intended for RHD diagnosis by experts In a screening environment, with its rapid pace, providers with varying experience, and suboptimal conditions, these criteria have proved less practical Some portable devices lack spectral Doppler, which is required for the diagnosis of RHD according to the WHF criteria
Simplified acquisition protocols, even a single view has reasonable sensitivity and specificity Abbreviated screening criteria (vs. diagnosis) have good performance Most focus exclusively on valve function; length of mitral regurgitation and presence of aortic insufficiency Practical, but misses isolated morphological abnormalities that can occur in the absence of pathological regurgitation early in RHD
Re-evaluate components of WHF criteria toward simplification of diagnosis Standardize simplified protocols for screening
Handheld equipment
Increased portability Largely reliant on battery vs. need for reliable electricity Less expensive Lacks functionality (spectral Doppler, needed for WHF criteria) Most research on a single system (GE VScan)/other systems increasingly available
Experts show 79% sensitivity and 87% specificity for all latent RHD, improving to 98% sensitivity for definite RHD May miss up to one-third of borderline RHD (even by experts) Need for fully functional machine to meet 2012 WHF criteria increases overall costs
Task sharing
Severe shortage of persons in LMICs trained in echocardiography Severe shortage of physicians in LMICs outside of major metropolitan areas
Nonexpert diagnostic performance following brief training has been promising Performance, even within individual studies, has varied substantially between learners
Standardized training
WHO guidelines recommend continuous monitoring and evaluation during implementation of task sharing Standardized training is central to this endeavor
Freely available online modules in 3 languages developed (WiRED International) Modules show good performance and acceptability among nurses and other health providers Telemedicine shows promise as an adjunct to training and mentorship
Determine best strategies for scaling up training (such as trainthe-trainer, and so on) Development of standardized competency assessments/ accreditation processes
Effect on children and communities
Need to understand the effect of a screening test on a community, on those who test positive, and on those who test negative
Strong support for screening from parents of screened children in New Zealand and screened children and teachers in Uganda Negative screening has no effect on quality of life, but positive result can cause anxiety and decreased physical activity, and can decrease parental and child quality of life Peer support groups may be able to normalize QOL in children with positive screen and to improve social connectedness
Community-engaged research to minimize negative effects of RHD screening on children and communities
Outcomes
It remains unclear at what rate latent RHD progresses and if early detection leads to improved outcomes
Ten longitudinal cohorts, 2 to 7 yrs of follow-up Heterogeneous diagnosis with varied outcomes Outcomes best for borderline RHD, followed by mild definite RHD, and worst for those with moderate/severe RHD at screening Progression rates are challenging to compare— inconsistent definitions of progression, use of different binomial outcomes (stable þ progression), and inclusion of children with advanced RHD
Standardization of reporting outcomes for children with latent RHD is of high priority Randomized controlled trial of secondary prophylaxis in children diagnosed with latent RHD (GOAL trial, planned to start June 2018)
Cost effectiveness
It is not yet known if screening for RHD is cost-effective It is likely that the downstream costs of screening (additional health system burden, impact on patient and family quality of life, and so on) will be significant
3 studies assessing the cost effectiveness of screening Broad assumptions leading to hypothetical conclusions—the impact of secondary prophylaxis on latent RHD (see above) is not fully understood
Reassessment as more data is gathered around outcomes for latent RHD and the impact of secondary prophylaxis, which can more precisely inform the investment case for RHD screening
LMICs ¼ low- and middle-income countries; QOL ¼ quality of life; RHD ¼ rheumatic heart disease; WHF ¼ World Heart Federation.
through echocardiographic screening is indeed part
secondary prevention for early-stage disease (see
of same disease process as RF-associated carditis—as
Part 2 of this review).
suggest
The published echocardiography data has taught
(28,29)—then a high rate of resolution does not
us that latent RHD is neither homogeneously malig-
necessarily cast doubt on RHD diagnosis. It does,
nant
however, raise questions about the added benefits of
screening has played a pivotal role in reinvigorating
studies
in
low-risk
populations
largely
nor
uniformly
benign.
Echocardiographic
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Present Status of Rheumatic Heart Disease
F I G U R E 3 Progression of Borderline RHD
(Top) A 2-cm mitral regurgitant jet is seen in at least 1 view, mitral regurgitation is seen in 2 or more views, and a pan-systolic jet is seen and measures >3 m/s. (Bottom) Two years later, the same features are noted, but in addition there are new signs of restricted posterior leaflet motion and anterior mitral valve leaflet thickness >3 mm. This echocardiogram meets the criteria for definite rheumatic heart disease (RHD) (pathological mitral regurgitation with 2 morphological criteria).
global research and helping to modernize our
followed by stroke or transient ischemic attack (8.5
understanding
In
per 1,000 patient-years) and infective endocarditis
Online Appendix Panel 2, we provide recommenda-
(3.7 per 1,000 patient-years). The incidence of recur-
tions for echocardiography-based RHD research.
rent RF in this cohort was 3.5 per 1,000 patient-years,
DISEASE EPIDEMIOLOGY. Relatively more is known
and regular use of secondary prevention was not
of
disease
pathogenesis.
about the prevalence of RHD compared with other
associated with better outcomes (32). The median age
epidemiological parameters. A systematic review
at death was 28 years, and case-fatality at 24 months
undertaken for the Global Burden of Disease 2015
was highest in low-income countries (21%) and
study identified prevalence data from 59 countries
significantly lower in middle-income countries (12%
(2). Using epidemiological modeling techniques, this
to 17%).
study estimated about 33 million individuals (0.4% of
Less is known about mortality from RHD in the
the global population) currently live with RHD. The
general population. In many countries, RHD is
disease is most common in sub-Saharan Africa, South
captured in nationally-representative vital or sample
Asia, and Oceania. Most prevalence studies have been
registration systems. Using these datasets, the Global
conducted in children attending school; relatively
Burden of Disease 2015 study estimated about
little
children
320,000 deaths from RHD in 2015, or about 0.6% of all
not attending school and among adults. Emerging
deaths. The highest death rates were in the highest-
data suggest that RHD is more common in adults
prevalence regions, and no significant decline in
and
mortality over 1990 to 2015 was detected in a number
is
known
among
about
children
RHD
in
among
community
settings
(compared with children well enough to attend
of countries, whereas other countries—mostly of
school) (30,31).
middle or high income—demonstrated dramatic re-
Hospital-based studies have provided insights into
ductions in mortality (2). The limitations of these
complications of and case-fatality from RHD. REM-
estimates include incomplete vital registration sys-
EDY estimated the incidence of RHD complications
tems in some (predominately African) countries and
over 24 months of follow-up. The most frequent was
the potential for misclassifying RHD deaths as deaths
new-onset heart failure (38 per 1,000 patient-years),
from other causes, for example, stroke (33).
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Present Status of Rheumatic Heart Disease
Online Appendix Panel 3 summarizes priorities for research on the descriptive epidemiology of RHD.
F I G U R E 4 The Spectrum of RHD
HOW SHOULD RHEUMATIC HEART DISEASE
Death due to RHD
BE MANAGED? PREVENTION. We generally endorse current guide-
lines on primary and secondary prevention of
Symptomatic RHD (active disease)
RHD (34). The following section highlights gaps in
P r i m a r y p r e v e n t i o n . Primary prevention of RHD focuses on the prompt recognition and treatment of
RHD causing sequelae* RHD causing cardiac failure
knowledge and needs for research in RHD-endemic countries.
RHD requiring surgery
Asymptomatic RHD (latent disease)
Clinical definite RHD (i.e., murmur present) Subclinical definite RHD (i.e., no murmur)
GAS pharyngitis to decrease the risk of RF in high-risk populations. Research is needed to clarify whether
Borderline echocardiographic findings suggestive of RHD
other Lancefield groups (35) and skin infections (36) can cause RF. Intramuscular benzathine penicillin G (BPG) remains the most widely-used antibiotic for GAS pharyngitis (37). Trials among American military recruits conducted
This model illustrates the distinctions between symptomatic and asymptomatic (or latent) disease and between definite and borderline rheumatic heart disease (RHD).
in the 1950s demonstrated that treating GAS pharyn-
*Sequelae of RHD include heart failure, atrial fibrillation/stroke, and infective endo-
gitis reduced the risk of acute RF by about 80%. A
carditis, among others. Reprinted with permission from Zühlke L, Steer A. Estimates of
meta-analysis summarized the main limitations of
the global burden of rheumatic heart disease. Glob Heart 2013;8:189–95.
the primary prevention trials (38). Most studies were of low quality compared to current standards, and little comparative evidence exists to quantify effects
of recurrence with repeated GAS infection may be as
among females or diverse populations.
high as 50%. Secondary prevention involves contin-
Accurate diagnosis of GAS pharyngitis remains
uous antibiotic chemoprophylaxis to prevent recur-
challenging in resource-limited countries. While
rent RF and reduce progression to RHD (34). Four-
throat culture is the gold standard for diagnosis,
weekly intramuscular BPG remains the standard of
access
often
care in most settings, and contemporary studies have
cost-prohibitive (39). Rapid diagnostic tests offer high
found low rates of RF recurrence (0.07 per 100
sensitivity and specificity, but their performance may
patient-years) with this regimen (44).
to
microbiology
is
limited
and
vary across settings, requiring validation studies prior
A systematic review summarized the findings and
to local adoption (40). Low-cost, portable systems for
limitations of the existing clinical trials on secondary
rapid GAS diagnosis are urgently needed. In the
prevention (45). Compared with doing nothing,
absence of confirmatory testing, clinical decision
providing penicillin appears to confer a 55% relative
rules may be used and may even be more cost-
reduction in risk of RF. Injectable penicillin is
effective (39). There is no consensus clinical deci-
significantly more effective than oral penicillin;
sion rule; most have been developed and tested in
however, the studied formulations of penicillin are no
single populations, with further testing needed to
longer in widespread use. Although secondary pre-
confirm generalizability. The issue of GAS carriage in
vention clearly reduces recurrent RF, less is known
the pharynx also requires further research.
about its effect on RHD. Newer data suggest
Poor health-seeking behavior and lack of community awareness regarding pharyngitis and RHD are
reductions in valvular pathology (46) and possibly mortality (47).
also barriers to primary prevention (41). Successful
The optimal duration of secondary prevention is
RHD programs in the Caribbean emphasized com-
controversial. Current recommendations are based on
munity education (42), and the WHO recommends, as
expert opinion, and no trial has recruited individuals
a pillar of RHD programs, community-based cam-
aged >25 years. Although the risk of GAS (and thus RF)
paigns that emphasize the link between pharyngitis
generally falls with age, this may not be true in certain
and RHD (43).
life stages (e.g., parenthood), among certain pro-
S e c o n d a r y p r e v e n t i o n . Recurrent RF can be trig-
fessions exposed to GAS (e.g., teachers, nurses, mili-
gered by asymptomatic and even appropriately-
tary), and in highly GAS-endemic areas (34). More
treated GAS infection. After the first attack, the risk
rigorous study of this issue is needed given the
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Present Status of Rheumatic Heart Disease
resource implications and risks of long-term antibiotic
who develop severe tricuspid insufficiency late after
use (34).
surgical correction of other valve disease.
Ensuring adherence to secondary prevention has
There is no RHD-specific evidence on optimal drug
proven challenging in limited-resource settings,
therapy for heart failure. Digoxin is widely used
usually reflecting socioeconomic deprivation and
among those who have atrial fibrillation or heart fail-
health
are
ure (4), although its effect on clinical outcomes is not
considered best practice to improve the delivery of
known. Individuals with mitral stenosis in sinus
secondary prevention (49). Improvements in BPG
rhythm awaiting intervention or surgery may gain
formulation could support adherence (50). Therapy-
some symptom relief with heart rate control using
related adherence barriers include fear of adverse
beta-adrenergic blockers, calcium-channel blockers,
drug reactions to BPG (51). Reported risks of allergy
or ivabradine (58,59). It may be reasonable to recom-
and anaphylaxis are 3.2% and 0.2%, respectively; yet,
mend vasodilator therapy with nondihydropyridine
anecdotal experiences suggest higher rates (52). Cre-
calcium blockers, angiotensin-converting enzyme
ation of a global reporting system for BPG adverse
inhibitors or angiotensin receptor blockers, and beta-
events has been proposed to track these risks (53).
blockers for symptomatic patients with severe aortic
system
weaknesses
(48).
Registries
Longitudinal studies provide little evidence that
regurgitation (57). Although there are fewer data
secondary prevention improves outcomes for chil-
supporting the use of these approaches in severe
dren with echocardiographically-detected early and
mitral regurgitation, it is generally accepted that
borderline RHD. In fact, an Australian cohort found
individuals with congestive symptoms and signs
increased risk of progression with penicillin (54), with
should receive these medications. Diuretics can also
similar findings in Uganda (25). Currently, most chil-
be used as needed for symptom relief.
dren presenting with mild definite RHD receive sec-
A t r i a l fi b r i l l a t i o n a n d s t r o k e . About 1 in 5 persons
ondary prevention, whereas most with borderline
with symptomatic RHD are in atrial fibrillation (4).
RHD do not. We recommend at least yearly clinical
Atrial inflammation and chronically elevated left
follow-up and counseling on the signs and symptoms
atrial pressure leading to atrial remodeling are
of GAS infection and RF. The presence of equipoise
important causal factors. Older age and the presence
has prompted a 2-year randomized controlled trial,
of mitral valve disease (especially stenosis) are
beginning in June 2018, of 4-weekly BPG for latent
strongly associated with incident atrial fibrillation. In
RHD (Determining the Impact of Penicillin in Latent
REMEDY, older persons living in upper-middle-
RHD: The GOAL Trial; NCT03346525).
income countries had a higher prevalence of atrial and
fibrillation than younger persons from low-income
research in the area of primary and secondary pre-
countries (28% vs. 18%) despite having milder dis-
vention are provided in Online Appendix Panel 4.
ease (32). From 40% to 75% of individuals with mitral
Recommendations
for
clinical
practice
f a i l u r e . Onset of
stenosis have atrial fibrillation (60). As with heart
heart failure is often associated with advanced RHD
failure, the development of atrial fibrillation gener-
that may not be amenable to corrective surgery. Heart
ally portends a poor prognosis. Among individuals
failure doubles the risk of death independent of other
with symptomatic disease, atrial fibrillation is asso-
prognostic variables (32), and in patients with aortic
ciated with a 40% higher mortality independent of
stenosis or dominant regurgitant lesions portends a
other prognostic markers, and risk of stroke increases
particularly poor prognosis (55). By contrast, the he-
2-fold (2.4% vs. 1.2% at 24 months) (32).
MEDICAL MANAGEMENT. H e a r t
modynamic consequences of mitral stenosis are
Treatment of atrial fibrillation in RHD is directed at
relieved by percutaneous balloon or surgical mitral
the underlying valve disease. Restoration and main-
valvuloplasty.
tenance of sinus rhythm is preferred for younger
Based on studies of nonrheumatic valve disease
persons (61). Although this may be possible using
(55,56), it is recommended that surgical correction be
balloon valvuloplasty in some cases of mitral stenosis
performed before the onset of symptoms in patients
(62), it may not be possible in cases of long-standing
with severe mitral and aortic regurgitation, guided by
disease and very large left atria. In a small random-
echocardiographic indexes of left ventricular func-
ized study, amiodarone following electrical cardio-
tion (57). Likewise, individuals with severe aortic
version for maintenance of sinus rhythm was shown
stenosis should undergo intervention following the
to be superior to placebo in the short-term (63), but
onset of symptoms (57). Medical therapy is reserved
given its toxicity, the value of long-term amiodarone
for those awaiting surgery or deemed unsuitable for
is debatable. Likewise, radiofrequency ablation was
surgery. One subset of individuals with intractable
successful in restoring sinus rhythm in a small case
heart failure who require aggressive therapy are those
series (64), but cannot be recommended for most
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Present Status of Rheumatic Heart Disease
F I G U R E 5 Effect of Percutaneous Transvenous Mitral Commissurotomy
Simultaneous left atrial and left ventricular tracings in a patient with mitral stenosis undergoing percutaneous transvenous mitral commissurotomy. The left atrial pressure normalizes after successful valve opening, with no residual gradient between the left atrium and the left ventricle in diastole.
patients. Some individuals undergoing mitral valve
disease in endemic countries (67). Pregnancy is a
replacement may be suitable candidates for intra-
high-risk period, often resulting in clinical deterio-
operative catheter ablation, but there are limited data
ration and adverse events (68). Most pregnant women
on long-term efficacy (65). Consequently, rate control
with RHD become symptomatic after 24 weeks when
with beta-blockers and nondihydropyridine calcium-
hemodynamic changes peak. The modified WHO
channel blockers remains the mainstay of pharma-
classification IV identifies those with severe mitral
cotherapy for atrial fibrillation in RHD.
stenosis, severe aortic stenosis, and severe pulmo-
There are limited prospective data to assess the risk
of
stroke
from
RHD.
No
validated
nary hypertension as having the highest possible risk
risk-
(69). In these women, perinatal outcomes (stillbirth,
stratification tools or randomized trials evaluating
prematurity, low birthweight, and neonatal mortal-
the efficacy and safety of oral anticoagulation are
ity) are poor. A total of 34% of pregnant Senegalese
available to guide anticoagulation decisions. Never-
women with RHD died, and rates of stillbirth and
theless, nearly all individuals with atrial fibrillation
pregnancy termination were high (70), prompting
are prescribed oral anticoagulation in clinical prac-
calls to screen pregnant women for RHD (71).
tice. The risk of stroke is highest with atrial fibrilla-
Optimal care for RHD-affected women involves
tion from mitral stenosis (about 4%/year), so these
pre-conception counseling (72), and among those
persons probably derive the greatest benefit from
pregnant, a comprehensive risk assessment and
anticoagulation. Among older individuals with RHD,
management plan that includes replacing contra-
the CHADS2 score may be used (66). However, the
indicated medications, optimizing loading condi-
quality of oral anticoagulation with vitamin K antag-
tions, and monitoring and addressing exacerbating
onists in limited-resource countries is poor due to
factors (e.g., anemia). When needed, surgery or
barriers to regular international normalized ratio
percutaneous transvenous mitral commissurotomy
monitoring (4). Direct anticoagulants may prove to be
(see the following text) is best performed after
more effective than vitamin K antagonists. A ran-
24 weeks to minimize radiation risk and improve fetal
domized trial comparing rivaroxaban with vitamin K
survival if early labor occurs (73). Among individuals
antagonists in patients with RHD is underway to test
with complex pathology (e.g., multivalve disease,
this hypothesis (INVICTUS [INVestIgation of rheu-
calcified valves), conservative management is often
matiC AF Treatment Using Vitamin K Antagonists,
preferable because the risk of fetal loss is high with
Rivaroxaban or Aspirin Studies, Non-Inferiority]
cardiopulmonary bypass.
noninferiority trial; NCT02832544).
For individuals with prosthetic heart valves, anti-
Management of RHD in women of reproductive
coagulation during pregnancy is challenging (74,75).
a g e . RHD accounts for the majority of antenatal heart
Current standard practice is “sequential treatment,”
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Present Status of Rheumatic Heart Disease
highest fetal losses; 2) sequential treatment is asso-
F I G U R E 6 Effect of Rheumatic Heart Disease on the
ciated with higher maternal thrombotic/bleeding
Mitral Valve
events then single therapy with vitamin K antagonists; and 3) low-molecular weight heparin is associated with the lowest rate of fetal or neonatal loss but higher risk of valve thrombosis (76,77). Safe, affordable anticoagulation options during pregnancy are needed. The optimal delivery of antenatal care for women with RHD is through a multidisciplinary specialized management team; these are rarely encountered in RHD-endemic
regions
(78).
Standard
practices
include measures to shorten the second stage of labor. In most cases, Cesarean section is not required. Outcomes beyond 42 days postpartum reveal ongoing risk (79). Although recent reviews have found low maternal mortality rates, these do not capture the Pre-operative photograph of a stenotic, regurgitant mitral
highest-risk regions, and even with ideal care,
valve, showing fused commissures and thickened cusps.
morbidity remains high. The Registry of Pregnancy and Cardiac Disease
which
involves
unfractionated
heparin
before
conception if planned or as soon as pregnancy is detected,
vitamin
K
antagonists
from
second
trimester until delivery, then unfractionated heparin in the peripartum period. Two systematic reviews concluded that: 1) vitamin K antagonists are associated with the better maternal outcomes but the
recently reported on the outcomes of 390 pregnant women with RHD and mitral valve disease. Women with moderate and severe mitral stenosis and mixed moderate to severe regurgitation with stenosis had the highest complication rates (80). Mitral stenosis remains an independent risk factor for adverse neonatal outcomes. Aside from valvular pathology, maternal age, body mass index above 28 kg/m 2, New York Heart Association functional class III to IV symptoms, significant pulmonary
F I G U R E 7 Country Performance on Rheumatic Heart Disease Mortality Targets
Percent Reduction in Mortality by 2030 (SDG3 Target)
hypertension,
reduced
ejection
fraction,
and
development of heart failure during pregnancy are
40
strong Georgia
Guam
20 Meeting WHF but not SDG3 target
Underperforming on both targets
Northern Mariana Islands
0
Guinea
India
South Africa China
of
4%
of
Staphylococci, Streptococci, Enterococci, Brucella
Namibia Rwanda
–80
total
fetal
pregnancy (84). The most common pathogens are
Indonesia
–60
endocarditis. A
and
endocarditis cases overall and 12% of cases during
Fiji
–40
maternal
for 15% (China) (82) to 55% (Pakistan) (83) of infective
Egypt Bolivia
poor
endocarditis at initial presentation (4). RHD accounts
Kiribati Lesotho
–20
of
REMEDY participants had native-valve infective
Federated States of Micronesia Niger
predictors
outcome (81). Native-valve
species, Candida albicans, and Stenotrophomonas Meeting SDG3 but not WHF target
Syria
maltophilia (85). Culture positivity ranges from 30% to 65%. A Chilean study that included 22% of
–100
participants with RHD reported a 10-year survival of –100
–80
–60
–40
–20
0
20
40
Percent Reduction in Mortality by 2025 (WHF Target)
49%; Staphylococcus aureus infection, sepsis, heart or renal failure, and lack of surgical treatment during infection were associated with increased mortality
Projected reduction in age-specific mortality from rheumatic heart disease based on country trends 2000 to 2015. The x-axis shows the total percentage reduction in deaths for those age <25 years (World Heart Federation [WHF] target) between 2013 and 2025 if 2000 to 2015 trends continue. The y-axis shows the total percent reduction in deaths
(86). In limited-resource settings, infective endocarditis is often first diagnosed at autopsy (87). These data reflect the need for laboratory diagnostic
for those age 30 to 69 years (Sustainable Development Goal 3 [SDG3] target) between
services, access to antibiotics for medium-term regi-
2015 and 2030 if 2000 to 2015 trends continue. See Online Appendix for details.
mens, and access to interventions or surgery to ameliorate outcomes.
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Present Status of Rheumatic Heart Disease
T A B L E 4 Proposed Indicators for Countries Tracking Progress on the 2018 Global RHD Resolution
Inputs
Outputs and Outcomes
Indicator
/
Measurement Units
Indicator
Measurement Units
National Assessment A1. National RF/RHD strategy
Presence of strategy* and yr of last update
A4. Mortality from RHD§
Deaths per 100,000 population/yr†
A2. Number of persons living with RHD
Prevalent cases per 100,000 population†
B2. Delivery of specialized cardiac services
Number of percutaneous and surgical procedures performed per yr‡
A3. Local guidelines for pharyngitis, RF, and RHD
Presence of guidelines and yr(s) of last update
B1. Access to specialized cardiology services
Presence of national program; density of interventionalists and surgeons per 100,000 population
B3. Outcomes of specialized cardiac services
Proportion dead and/or reoperated on within 90 days‡
C1. RF/RHD registry
Proportion of districts with functioning registry in place
C5. Incidence of acute RF
Number of new cases per 100,000 population/yrk
C2. Availability of BPG
Proportion of health facilities with BPG currently in stock
D1. Adherence to secondary prevention
Proportion receiving >80% of scheduled injections/yrk
C3. In-service training on RF/RHD (relevant to clinical role/ qualification)
Proportion of workforce (re)trained over the past 24 months
D2. Adverse BPG events
Number of events/yr
D3. Acute RF recurrences§
Number of recurrences per registry patient per yr
C4. Availability of echocardiography services
Proportion of districts with functional ultrasound machine
D4. Priority-based follow-up for individuals with RHD
Proportion of new moderate-to-severe cases referredk
Subnational (District or Province/State) Assessment
Indicators were measured as follows: category A ¼ desk review by ministry of health; category B ¼ audit of tertiary healthcare facilities; category C ¼ facility surveys conducted in a random sample of districts stratified according to known geographical variations in access to care; and category D ¼ audit of RF/RHD registries in districts sampled according to category C. *Strategy can be a stand-alone document or embedded in noncommunicable disease or general health sector strategy; however, it must be specific that RHD is a priority condition that requires specific activities, targets, and budget. †Local data are preferred; however, default estimates can be obtained from the Global Burden of Disease Study. ‡Also disaggregates by approach and by lesion (e.g., mitral valve repair, dual valve replacement, and so on). kQuantitative indicators of the quality of care should ideally be supplemented by semi-structured interviews of samples of registry enrollees to assess user experience and trust in the health care system. §Ideally assessed using population-based rather than hospital-based samples. BPG ¼ benzathine penicillin G; PTMC ¼ percutaneous transvenous mitral commissurotomy; RF ¼ rheumatic fever; RHD ¼ rheumatic heart disease.
Recommendations for medical management of
subvalvular fusion and calcification reduce the
RHD and future research priorities are provided in
chances of a durable outcome. Several echocardio-
Online Appendix Panel 5.
graphic scores (90) and more complex multifactorial
PERCUTANEOUS AND OPEN INTERVENTIONS. We
scores that use a combination of demographic, clin-
generally endorse the current ACC/AHA guidelines
ical, and echocardiographic variables (91) are used to
for the interventional and surgical management of
assess suitability for PTMC. Individuals with mitral
RHD (57). However, it should be stressed that most of
stenosis are younger in countries where RHD is
the evidence informing these guidelines is based on
endemic and may have a lower prevalence of age-
nonrheumatic valve disease. The discussion in the
related morphological changes like calcification,
following text highlights some particular issues
making them somewhat more suitable candidates for
related to RHD and challenges delivering these
PTMC. On the contrary, RHD may follow a more
procedures in limited-resource settings.
aggressive course in endemic countries, resulting in with
severe morphological abnormalities including sub-
severe mitral stenosis and suitable valve morphology
valvular disease. Still, PTMC provides acceptable
Interventional
m a n a g e m e n t . Individuals
benefit most from catheter-based interventions,
immediate and medium-term outcomes (Figure 5) and
especially percutaneous transvenous mitral commis-
remains the initial treatment of choice in most
surotomy (PTMC). Although there have been hard-
individuals without unfavorable demographic or
ware improvements over the past 3 decades, the basic
clinical features (91).
procedure is relatively unchanged. Pivotal studies
The main complications associated with PTMC are
established the percutaneous approach to the treat-
severe mitral regurgitation needing urgent surgery
ment of mitral stenosis using single or double con-
(1% to 3%), cardiac tamponade (1% to 2%), systemic
ventional
the
embolism (<1%), and death (<1%) (92). A meta-
self-centering Inoue balloon (Toray, Tokyo, Japan)
analysis of the small randomized studies comparing
has superseded these in clinical practice. Subsequent
PTMC with surgical commissurotomy suggests that
trials comparing PTMC with surgical approaches used
PTMC produces a slightly smaller valve area, a higher
the Inoue balloon and technique (89).
risk of mitral regurgitation, and a nearly 3-fold risk of
valvuloplasty
balloons
(88),
but
The success of PTMC depends to a great extent on
reintervention compared with surgery (93). Never-
the morphology of the mitral valve. The presence of
theless, because of increasing familiarity, ease of use
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Present Status of Rheumatic Heart Disease
T A B L E 5 Product Development Priorities for RHD Prevention and Control
Product
GAS vaccine Reformulation of BPG
Progress
Comments
Phase 2 clinical trials
Substantial benefit in reduced antibiotic use, reduced invasive GAS disease
Candidate identification
Improved rational use of antibiotics, improved acceptability and adherence likely to lead to better clinical outcomes
Rapid antigen detection tests
On market; need local testing and trials
Assists in rational use of antibiotics; not being used in endemic countries
RF diagnostic
Academic research
Syndromic diagnosis means opportunities to initiate disease altering secondary prophylaxis are missed
Handheld echocardiography devices
On market
Affordability and durability of prolonged use in remote settings are the major barriers to use
Point of care INR testing
On market
Not being used in endemic countries; production of cheaper alternatives would be an important short-term advance
Alternatives to current mechanical and bioprosthetic valves
Academic research
Lower-cost mechanical prosthesis, in themselves, would be a critical shortterm advance; in the longer term, percutaneously-delivered mechanical or tissue-engineered valves would be more likely to meet the total need for surgical care at reasonable cost
BPG ¼ benzathine penicillin G; GAS ¼ group A beta-hemolytic streptococcus; INR ¼ international normalized ratio; RF ¼ rheumatic fever; RHD ¼ rheumatic heart disease.
the presence of valve thickening, variable degrees of commissural fusion, and subvalvular disease. Transcatheter treatment of severe tricuspid regurgitation may be more promising (97). S u r g i c a l m a n a g e m e n t . Severe, chronic structural changes in the valves are the major cause of mortality from RHD. Ensuring timely access to definitive surgical care is a key aspect of addressing the current disease burden. Unfortunately, many individuals present too late to benefit from surgery, so early detection efforts (98), accompanied by priority-based follow-up (99), are required to ensure that
surgical
programs
have
maximal
impact.
Although valve replacement provides good early results, long-term outcomes are poorer as the cumulative risk of valve-related complications increases (100). Hence, valve-conserving restorative operations are now the preferred first-line approach. One unanswered question is the timing of surgery for regurgitant lesions; most recommendations are based on extrapolation from nonrheumatic valve disease (56). RHD usually affects all components of the mitral valve (Figure 6), and these should be systematically
of the procedure, improvement in operator experi-
dealt with during surgery. Commissural fusion is
ence, and perhaps the lower direct and opportunity
dealt with by sharp dissection extending into the
costs compared with surgical treatment, PTMC (using
fused papillary muscles while preserving chordal
an Inoue or Inoue-like balloon) remains the treatment
attachment and, if necessary, creating intercostal
of choice for rheumatic mitral stenosis.
spaces and/or inserting artificial chords. The anterior
Catheter-based treatment of rheumatic aortic ste-
and posterior leaflets are then mobilized using a
nosis has not been well-studied, perhaps because of
process of decalcification and peeling to enhance
the rarity of isolated aortic stenosis in RHD and its
mobility, increasing surface area and extent of cusp
tendency to manifest later in life when valve calcifi-
coaptation (101). These techniques are possible
cation is common (4). There is good rationale for
because the disease process spares the elastica and
using balloon dilatation to treat noncalcific rheumatic
part of the fibrosa. Changes in mitral annular shape,
aortic stenosis. In vitro studies have shown that
size, and dynamism can be characterized by modern
balloon dilatation reliably splits the fused commis-
imaging techniques and need to be addressed during
sures in a rheumatic aortic valve (94). Balloon
operative
dilatation has an 86% immediate success rate, with
evolving, and the efficacy of current practices needs
only 14% of patients needing valve replacement at
to be validated in studies involving larger numbers of
repair.
Surgical
techniques
are
still
5-year follow-up (95). Moderate or severe aortic
participants followed for sufficiently long periods,
regurgitation occurs in about 14% of patients as an
specifically focusing on ventricular function and
immediate complication. Transcatheter aortic valve
quality of life, the latter of which is often significantly
replacement is unlikely to be useful in RHD due to the
impaired (102).
rarity of isolated aortic stenosis and the relatively young age of patients with RHD. Rheumatic tricuspid stenosis is rare and almost
Dysfunction of the tricuspid valve can be secondary to mitral valve disease or be affected by the rheumatogenic
process
itself.
Most
changes,
always occurs in association with mitral valve disease,
including annular dilation and cusp fusion, can be
particularly stenosis. A small case series suggested
addressed through repair techniques. Failing to repair
that tricuspid valvuloplasty may be as successful and
the tricuspid valve when affected can result in
durable as PTMC (96). A large-sized Inoue balloon (28
chronic disability and possibly death (103). Aortic
to 30 mm) is usually used for dilation. Mitral regurgi-
valve disease is less common than mitral valve dis-
tation is unlikely to be amenable to the transcatheter
ease, but has a more serious effect on left ventricular
techniques used for nonrheumatic disease because of
function, quality of life, and overall prognosis (104).
Watkins et al.
JACC VOL. 72, NO. 12, 2018 SEPTEMBER 18, 2018:1397–416
Unlike the mitral and tricuspid valves, aortic pathology is infrequently suitable for valve-conserving operations.
Additionally,
currently
available
F I G U R E 8 Rapid Scale-Up of Specialized Cardiac Surgical Services in a
Middle-Income Country
valve
substitutes—with the exception of the Ross opera-
900
tion—are not suitable for use in the relatively young
800
population with RHD (105). of
patches
or
entire
valves
(106).
Although not currently in use, such technologies will hopefully will be available in the near future and could significantly increase access to surgery and at a lower cost. Tissue-engineered products could also be delivered through percutaneous techniques, making them even more attractive in settings where access to open procedures is limited. An important consideration for surgical programs
700 Number of Patients
An emerging area of surgical research is in tissue engineering
600 500 400 300 200 100 0 2009
2010
2011
Increasingly robust standards for post-operative outcome recording have been developed for congenital heart disease surgery for children in these set(107).
Because
patient
demographics
2012
2013
easily be extended to individuals requiring surgery for RHD. More research is needed on ensuring quality
Mitral Valve Repair Mitral Valve Replacement Percutaneous Balloon Mitral Commissurotomy
Between 2010 and 2015, the Aswan Heart Centre in Aswan, Egypt dramatically increased the total number of procedures performed for rheumatic mitral valve disease. Over time, the mix of procedures shifted toward more conservative approaches (i.e., valve repairs and percutaneous interventions). Reprinted with permission from Remenyi et al. (104).
of post-surgical care, including anticoagulation, for those living in remote or deprived areas; some have even argued that younger individuals with RHD should be offered tissue valves (108).
(Online Appendix Panel 7) (6). The resolution man-
A summary of recommendations for practice and
dates Member States to take action on RF/RHD and
research on interventional and surgical care is pro-
resources WHO to provide support to country pro-
vided in Online Appendix Panel 6.
grams. Several tools have recently been published that can assist in technical support of programs
WHAT IS NEEDED TO ERADICATE
(49,111). Drawing on these tools, we propose a set of
RHD WORLDWIDE?
indicators for countries to use in tracking imple-
THE GLOBAL AGENDA. R H D p o l i c y t a r g e t s a n d
mentation of the resolution (Table 4).
s t a t e m e n t s . In 2013, the WHF called for a 25%
I n t e r n a t i o n a l c o l l e c t i v e a c t i o n o n R H D . Ensuring
reduction
individuals
global leadership in RHD has been challenging. RHD
aged <25 years by the year 2025 (109). More recently,
has been neglected by policymakers and civil society
the United Nations Sustainable Development Goal
because it does not sit in a single department (e.g., at
3 (SDG3) proposed a one-third reduction in premature
WHO) nor is it amenable to single-intervention stra-
deaths from noncommunicable diseases by 2030
tegies. Advocacy and engagement are needed to build
RHD
mortality
among
2015
and
providers overlap significantly, these practices could
in
2014
Year
in limited-resource settings is ensuring quality.
tings
1411
Present Status of Rheumatic Heart Disease
(110). Assuming that trends in mortality over the past
relationships with other disciplines—such as maternal
15 years hold, many endemic countries are on track to
and child health—that have larger, more visible con-
achieve either 1 or both of the targets (Figure 7).
stituencies and audiences with decision-makers.
Notable high-performing countries include China,
Additionally, people living with RHD are often
Bangladesh, and Rwanda. A number of Pacific
socially vulnerable and have few opportunities to
Island nations are struggling to meet these targets
share their lived experiences. The Listen to My Heart
(Online Appendix).
program is one promising model of patient engage-
Since the mid-2000s, several policy statements
ment and empowerment (112).
have been issued on RHD. Notable recent statements
This review has provided recommendations for a
include the Addis Ababa communique (2015) and the
number of global public goods, including scientific
WHF roadmap on RHD (2017). A resolution on RHD
research, that warrant investment. Greater public and
was adopted at the 71st World Health Assembly
private funding is needed to support laboratory,
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Present Status of Rheumatic Heart Disease
clinical/translational,
and
policy/implementation
research to address the basic and applied scientific
leveraging the strengths of RHD-specific activities to build overall health system capacity (114).
questions posed throughout this review. In addition,
Workforce challenges in RHD care parallel the
there are a number of urgent RHD product develop-
workforce challenges in other health areas (115). In
ment priorities (Table 5).
the short-term, strengthening primary and secondary
RHD has important links to the global health se-
prevention should be prioritized, for example, using
curity agenda in the area of antimicrobial resistance.
nurse-led primary care (including school-based plat-
Development and enforcement of guidelines on
forms) and community health workers, although
pharyngitis management, including rational use of
further research is needed on these models (44,116). A
antibiotics, are needed in all countries. Better supply
pressing issue for most countries will be to create
and more consistent use of BPG as a first-line anti-
incentives to train and retain cardiovascular special-
biotic for GAS, and eventually the roll-out of a GAS
ists. These providers could care for a wide range of
vaccine, will probably be the most effective long-term
conditions, so while the initial rationale might be to
strategies for curbing antimicrobial resistance risk
address RHD and support the global resolution,
from pharyngitis.
increasing the cardiovascular workforce will have programs.
broader benefits. Cardiac surgery deserves special
The notion that RF can be eliminated is supported by
emphasis given its importance in RHD. The experi-
studies of country control programs conducted dur-
ence of the Aswan Heart Centre has demonstrated
ing the 1970s and 1980s. The largest was a multi-
that, with political and financial commitment, surgi-
country study emphasizing secondary prevention
cal care can be rapidly scaled up and at high quality
(113), and the last study was from Brazil (46). Expe-
(Figure 8) (104).
THE
NATIONAL
AGENDA. Disease
control
rience with primary prevention programs has also
Much has been written on the need for better in-
been favorable, and the WHO recommends combined
formation systems for tracking RHD. Disease registers
primary and secondary prevention efforts delivered
have been recommended since the 1950s, but few
in community settings (43). These programs can
RHD-endemic countries have made significant prog-
achieve the vast majority of their impact within about
ress on expanding registers beyond single centers,
a decade or so (42).
which suggests that novel approaches are needed.
A number of unknowns remain. Most countries
One recent initiative is the smartphone-based Pan
that implemented RF programs were relatively
African Society of Cardiology eRegister (117). How to
economically advanced, limiting their applicability
integrate registers and eRegisters into local health
to current RHD-endemic countries. No program
information systems is less clear and warrants further
used an active case-finding approach, which could
consideration.
in theory lead to a more rapid decline in RF,
Disease notification and surveillance systems pro-
although the appropriateness of screening echocar-
vide opportunities for RHD integration. There is good
diography remains unclear. Finally, the role of sur-
rationale for classifying RF as a notifiable condition
gery
been
because of its outbreak potential, although weak-
established. Cardiac surgery was available in some
nesses in RF notification systems have been described
of
it
(99). Improving RF notification efforts and public
most
health action could have spillover benefits and
in
the
remains
RHD-control
programs
countries
mentioned
largely
unavailable
has
not
previously, today
RHD-endemic countries. Integration of RHD programs
but
in
contribute to global health security. (RF is one of the country
few conditions that involves clinician-based rather
h e a l t h s y s t e m s . There is currently little appetite
than laboratory-based notification. Notification for
among health planners for developing targeted
emerging
programs, especially for chronic noncommunicable
nonlaboratory-based pathway, so strengthening sys-
diseases (114). Yet, historical case studies of RF/RHD
tems for syndromic reporting would have benefits
control frequently used vertical approaches. Conse-
beyond RF/RHD.) Last, improving the quality of death
quently, there is little evidence upon which to make
certification for RHD (33), although important for
technical recommendations for integrating RHD-
obtaining better mortality data, could also be inte-
related
grated into efforts to improve the overall quality of
activities
into
existing
into
health
systems.
Across several health system “building blocks,” discussed in the following text, we find important opportunities overarching
for
integration
approach
of
would
would
need
to
follow
a
vital registration. A final opportunity for RHD integration is health
The
financing. The vast majority of health care in many
“diagonal,”
low- and middle-income countries is financed out-of-
RF/RHD. be
pandemics
Watkins et al.
JACC VOL. 72, NO. 12, 2018 SEPTEMBER 18, 2018:1397–416
Present Status of Rheumatic Heart Disease
“diagonal”
pocket, especially for noncommunicable diseases like
vulnerable.
RHD. Consequently, poor households tend to forgo
lead to rapid progress on RF/RHD and strengthen
health care or borrow money or sell assets to pay for
health systems to address other noncommunicable
care, increasing the so-called “poverty trap” (118).
diseases.
A
approach
could
both
Charitable programs exist for RHD surgery in some
While scientific questions remain, the evidence
countries, but they are neither sufficient to meet the
base is sound for tackling RHD now. Across a wide
populations’ needs nor fiscally sustainable (119).
range of global health interventions, primary and
Increasingly, surgical skills and knowledge will need
secondary prevention of RHD stand out as providing
to be transferred to local health systems to sustain-
excellent value for money (122). Challenges in scale-
ably meet the large unmet need for cardiac surgery,
up of advanced care for RHD are nuanced and
and governments will need to increase budgets for
complex, but it is evident from historical trends that
advanced cardiovascular services.
all countries will eventually require advanced car-
The goal of universal health coverage, which all
diovascular services—not just for RHD—and must
countries have endorsed as part of United Nations
start training the next generation of the cardiovas-
Sustainable Development Goal 3, holds promise for
cular workforce, putting in place incentives to
improving access to and the affordability of RHD-
ensure that these individuals work where needs are
related care. The challenge is mobilizing sufficient
greatest.
domestic resources to finance (relatively inexpensive)
Complementing the national agenda is an agenda
prevention services as well as costly surgical care
for the global community. International agencies,
without displacing other health priorities. Integrated
civil society, and donors will play a critical role in
financing models are needed. Over time, the scale and
the elimination of RHD. Support is needed for
scope of covered services could progressively expand.
research, advocacy, and implementation. Armed
One modeling study suggested that universal coverage
with scientific, economic, and ethical arguments,
of primary prevention would be the first priority
the RHD community can establish links and part-
for most African countries, followed by secondary
nerships across sectors and health areas. The inte-
prevention, then referral and tertiary services (120).
gration of RHD into the broader global health agenda will ensure that the future generations grow
SUMMARY AND CONCLUSIONS
up free from the scourge of this eminently pre-
This Scientific Expert Panel has summarized recent advances in the science and practice of RHD, from laboratory science to population health. We identify a number of pressing issues requiring immediate action and propose a research agenda for the coming years. But, why invest in RHD research and care when there
ventable disease. ACKNOWLEDGMENTS This paper is dedicated to the
memory of Professor Bongani Mayosi, a pre-eminent scientist and visionary who inspired us all to work toward the “eradication of rheumatic fever in our lifetime.”
are many other important health concerns? RHD is a disease of poverty that affects chil-
ADDRESS FOR CORRESPONDENCE: Dr. David A.
dren and working-age adults. The global economic
Watkins, Division of General Internal Medicine,
impact of early death from RHD was about $65
Department of Medicine, University of Washington,
billion in 2015 (121). RHD provides an unparal-
325 9th Avenue, Box 359780, Seattle, Washington 98104.
leled opportunity to advance the global cardio-
E-mail:
[email protected]. Twitter: @davidawatkins,
vascular agenda by giving priority to the most
@UW.
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KEY WORDS cardiac surgery, echocardiography, health services, pathogenesis, prevention, rheumatic heart disease
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