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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Author Disclosures: Dr. Watkins has received support from the RHD Action
grant from Medtronic 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 Scholar-
ship from the National Health and Medical Research Council (NHMRC),
Australia, and from the Telethon Kids Institute. All other authors have
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From the aDivision of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington;
JACC Editor-in-Chief
b
Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa; cDepartment of Pae-
Dr. Valentin Fuster.
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

1398 Watkins et al. JACC VOL. 72, NO. 12, 2018

Present Status of Rheumatic Heart Disease SEPTEMBER 18, 2018:1397–416

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-

ease (RHD) and its antecedent rheumatic
fever (RF) have largely disappeared from
wealthy countries, and the clinical caseload of RHD
has shifted to older age groups. RHD has also been
dwarfed by ischemic heart disease. Additionally, RF/
RHD control programs were successfully implemented
in some low- and middle-income countries during the
latter part of the 20th century, prompting the World
Health Organization (WHO) and others to downscale
their RF/RHD activities by the early 2000s (1).
Yet, RHD continues unabated in poor countries and
among vulnerable groups in wealthy ones (2). A 2007
report on RHD among schoolchildren in Cambodia and
Because of this renewed interest, the science of
RHD has evolved rapidly. A number of new or
ongoing studies aim to provide answers to key ques-
tions. This Scientific Expert Panel seeks to summarize
recent research on RHD—from molecular mechanisms
to health systems—in one coherent, scientifically-
grounded vision for the future of science, clinical
medicine, and public health practice relating to RHD
(Central Illustration).
WHAT IS RHEUMATIC HEART DISEASE,
AND HOW BIG IS THE PROBLEM?
PATHOGENESIS. The major driver of acute RF is

Mozambique spawned a whole literature on echocar-
diography and RHD (3). The recent REMEDY study
(Global Rheumatic Heart Disease Registry) docu-
mented high rates of disability and premature death
across African and Asian countries (4). In 2015, a civil
society movement, RHD Action, was launched to raise
awareness and support countries looking to address
RHD (5). In May 2018, the World Health Assembly
adopted a resolution to reinvigorate global and na-
tional RF/RHD prevention and control efforts (6).
frequent group A beta-hemolytic streptococcal (GAS)
infection. Socioeconomic conditions leading to
increased GAS exposure include household crowd-
ing, poor hygiene, and low access to medical ser-
vices (7). Why only a minority of persons (<6%)
living in GAS-endemic areas develop RF is less
understood.
H o s t f a c t o r s . There are 2 theories of how GAS
infection damages host tissues. The basis of the mo-
lecular mimicry theory is that molecules on the

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.
JACC VOL. 72, NO. 12, 2018 Watkins et al. 1399
SEPTEMBER 18, 2018:1397–416 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.
In the case of acute RF, 2 main streptococcal antigens
have been implicated: the surface M protein, and
GlcNAc, the immunodominant epitope of the group A
carbohydrate (8). The “neo-antigen” theory, a more
recent development, suggests that the GAS organism
gains access to the subendothelial collagen matrix,
where M proteins binds to the CB3 region of type IV
collagen, creating a neo-antigen that induces an
autoimmune response against collagen (9).
In both theories, it is thought that the initial
damage to cardiac tissues is due mainly to antibodies,
with cellular responses subsequently implicated as
the immunological cascade evolves. These antibodies
adhesion molecule 1, allowing CD4 T cells
GAS = group A beta-hemolytic
(and others) activated by GAS to invade the streptococcus
heart valve, encounter antigens, and become
RF = rheumatic fever
further activated. Over time, tissue break-
RHD = rheumatic heart disease
down, partly involving autoantibodies and
WHF = World Heart Federation
complement activation, releases additional
WHO = World Health
endogenous antigens such as collagen, lami-
Organization
nin, myosin, and tropomyosin that may also
serve as autoantigens, stimulating more CD4 T cells,
which then produce Th1 and potentially Th17 cyto-
kines, leading to further inflammation in the heart
valve. Over time, successive episodes coupled to
resolution leads to neovascularization and fibrosis
(Figure 1) (10).

C ENTR AL I LL U STRA T I O N Framework for Rheumatic Heart Disease Control and

Eventual Elimination

Prevention

• Innovations in rheumatic fever/rheumatic heart

disease diagnosis and risk prediction
• Improved delivery of benzathine penicillin G
Research • Raising public and health worker awareness Advocacy
• Comprehensive, community-based programs

Advanced care Health policy

• Early echocardiographic diagnosis • “Diagonal” health system investments

• Reproductive and antenatal services • Integration and cross-sector collaboration
• Medical management of complications • Product development and research
• Access to timely, high-quality surgical care 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).
1400 Watkins et al. JACC VOL. 72, NO. 12, 2018

Present Status of Rheumatic Heart Disease SEPTEMBER 18, 2018:1397–416

F I G U R E 1 Possible Pathogenic Mechanisms in Rheumatic Heart Disease

Fibrosis
Inflammatory lesions

Complement
Functional Antibodies

Recruitment of cells Neovasularization

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 Valvular dendritic Myofibroblast

cell
Complement Endogenous peptide CD8+Tcell Monocyte Monocyte-derived Antigen
loaded on MHCII dendritic cell 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 immu-
noglobulin 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 fre-
quency of childhood GAS infection raises the possi-
bility of genetic predisposition (11). Among children
raised apart from their parents, those whose parents
had RHD had a 2.9-fold higher risk of RF compared
with peers whose parents did not have RHD (12). Twin
studies have estimated the heritability of RF at 60%
(13). Small candidate gene case-control studies have
identified genetic variants associated with RF/RHD.
Genes controlling the adaptive immune response
(e.g., human leukocyte antigen [HLA] class II alleles),
the innate immune response (e.g., toll-like receptor
2), cytokine genes (e.g., tumor necrosis factor alpha),
and B-cell alloantigens have been implicated (14), but
most have not been replicated (15,16).
Among genome-wide association studies, 2 had no
significant findings, whereas another found that var-
iants at the immunoglobulin heavy chain locus were
associated with RHD in 2 populations (17), but this
result was not replicated elsewhere (18). The latter
study identified evidence for risk and protective
haplotypes across HLA-DQA/DQB Class II molecules,
supporting molecular mimicry as the key pathogenic
mechanism. Although these studies differ in diag-
nostic method, design, and population studied, they
support the notion of autoimmune pathogenesis.
JACC VOL. 72, NO. 12, 2018 Watkins et al. 1401
SEPTEMBER 18, 2018:1397–416 Present Status of Rheumatic Heart Disease

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
Definite RHD (A, B, C, D) Definite RHD (A, B, C, D)
Median Age #20 yrs Age >20 yrs
Age, yrs
A. Pathological MR and at least A. Pathological MR and at least
New York Heart Association functional 809 (24.6) 26 2 morphological features of 2 morphological features
class III and IV RHD of the MV of RHD of the MV
Medical history B. MS mean gradient $4 mm Hg* B. MS with mean
Acute rheumatic fever 1,340 (40.7) gradient $4 mm Hg*

Congestive heart failure 1,110 (33.4) 25 C. Pathological AR and at least C. Pathological AR and at least
2 morphological features 2 morphological features of
Pulmonary hypertension 957 (28.8) 26 of RHD of the AV RHD of the AV in those age <35 yrs
Stroke 235 (7.1) 40 D. Borderline disease of both D. Pathological AR and at least
Infective endocarditis 133 (4.0) 25 the AV and MV 2 morphological features of
Major bleeding 89 (2.7) 31 RHD of the MV

Peripheral embolism 25 (0.8) 43 Borderline Not Applicable

Borderline RHD (A, B, C)
Atrial fibrillation 586 (21.8) to Those Age >20 yrs

Echocardiography A. At least 2 morphological

features of RHD of the MV
Decreased LVEF in adults 661 (26.5)
without pathological MR or MS
Decreased LVEF in children 168 (5.3)
B. Pathological MR
Dilated LVEDD in adults 742 (23.0)
C. Pathological AR
Dilated LVEDD in children 454 (14.1)
Pathological Mitral Regurgitation Pathological Aortic Regurgitation
Left atrial thrombus 44 (1.4)
Surgical history Seen in 2 views Seen in 2 views

Valve replacement or repair 715 (21.4) In at least 1 view, jet length $2 cm† In at least 1 view, jet length $1 cm†

Previous percutaneous valvuloplasty 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
Values are n (%) or n. Table presents authors’ own re-analysis of data from Zühlke Mitral Valve Aortic Valve
et al. (4).
LVEDD ¼ left ventricular end-diastolic diameter; LVEF ¼ left ventricular ejection AMVL thickening $3 mm (age #20 yrs), Irregular or focal thickening
fraction. $4 mm (age 21 to 40 yrs),
$5 mm (age >40 yrs)
Chordal thickening Coaptation defect
Restricted leaflet motion Restricted leaflet motion
Meta-analyses of thousands of well-characterized
Excessive leaflet tip motion during systole Prolapse
cases and controls will be required to identify reli-
able and reproducible genetic susceptibility and pro- *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).
tective factors. Ultimately, genomic analyses could
AMVL ¼ anterior mitral valve leaflet; AR ¼ aortic regurgitation; AV ¼ aortic valve; MR ¼ mitral regurgitation;
identify high-risk individuals to target for penicillin 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
to GAS strains belonging to a subset of M types (based
on the classical typing system; this has since been
replaced by emm typing based on the genetic
sequence of the M protein). Over the past 2 decades, it
has become apparent that GAS strains from regions
where RHD is endemic are much more diverse than
those in nonendemic areas, and that there is no as-
sociation of particular emm types with RF/RHD (19).
This work has also suggested that RF-inducing strains
may be associated with skin infection, supporting the
hypothesis that RF is not solely a consequence of GAS
pharyngitis (20–22).
Focus has shifted in recent years to better under-
standing the features of RF-associated GAS strains
rather than emm types. Most attention has been paid
to identifying surface or excreted antigens that have
antigenic homology to human tissues and could
stimulate cross-reactivity. Most of the identified
cross-reactive regions are in the A- and B-repeat
regions of the M protein and include sequences
homologous with human actin and cardiac myosin,
although there are other cross-reactive antigens in
GAS including the group A carbohydrate (10).
While the recent growth in research on RHD path-
ogenesis is promising and has challenged a variety of
historical paradigms, a number of key scientific
questions remain. Online Appendix Panel 1 suggests
priorities for future research.
CLINICAL AND ECHOCARDIOGRAPHIC ASPECTS.
C l i n i c a l f e a t u r e s . Aside from a subset of children in
whom RF leads to severe carditis and early RHD, RHD
is usually clinically silent (“latent”) until it manifests
during adulthood. Many individuals in RHD-endemic
countries present late in their disease process with 1
or more sequelae. The REMEDY study followed 3,343
individuals with symptomatic RHD presenting for
care at academic centers in 14 countries (Table 1) (4).
Most individuals were 15 to 49 years of age, and
fewer than one-half recalled a history of RF. Heart
1402 Watkins et al.
Present Status of Rheumatic Heart Disease
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
were the most frequent medical complications. About
20% demonstrated decreased left ventricular ejection
fraction, and about one-third had increased left
ventricular end-diastolic diameter—underscoring the
consequences of late presentation.
Challenges in diagnosing acute RF are a major
barrier to preventing RHD. Strong evidence of milder
presentation and the importance of subclinical car-
ditis prompted revision of the Jones Criteria (the gold
standard for RF diagnosis) in 2015 to better account
for differences in population risk (23). While these
criteria will likely increase case detection, barriers
such as poor health seeking behavior, lack of pathol-
ogy services, and clinical overlap with other endemic
diseases (such as malaria in sub-Saharan Africa) limit
the efficacy of a simple diagnostic shift within a
clinical decision rule. Better RF diagnosis will require
the development of new (laboratory) technology tests
that could augment or replace clinical decision rules.
Echocardiography and R H D . The World Heart
Federation (WHF) published the first evidence-based,
standardized criteria for the echocardiographic diag-
nosis of RHD in 2012 (Table 2, Figure 2) (24). Since
then, >2 dozen additional studies covering >100,000
participants have been conducted. In parallel, studies
have investigated the practicalities of echocardio-
graphic screening in RHD-endemic countries, high-
lighting many challenges and exploring solutions
(Table 3).
The vocabulary describing echocardiographically-
detected RHD lacks precision in the published data.
JACC VOL. 72, NO. 12, 2018
SEPTEMBER 18, 2018:1397–416
“Subclinical RHD” refers to RHD seen on echocardi-
ography in a patient with a normal clinical cardiac
examination. “Latent” RHD includes a broader spec-
trum of disease, including any RHD found on echo-
cardiographic screening in the absence of prior RF or
known RHD. Although latent RHD includes subclini-
cal RHD, one-third (Uganda) (25) to two-thirds (Fiji)
(26) of children with latent definite RHD already have
moderate-to-severe disease. Outcomes for these
children are poor (26). In Uganda, almost one-half of
children with moderate-to-severe RHD progressed (to
worsening regurgitation, stenosis, or death) over a
median of 2.3 years, and only 9.5% showed any dis-
ease improvement (25).
By contrast, the clinical course of children with
borderline and mild definite RHD is enigmatic. Com-
parison across cohorts must be undertaken
cautiously: studies have used inconsistent definitions
of progression, have used different outcomes, and in
some cases, have included children with advanced
RHD (25,27). Standardization is needed in reporting
outcomes (27). Although most children with border-
line or mild definite RHD remain stable or show
improvement, 10% to 24% experience disease pro-
gression (Figure 3). Outcomes are best for children
with borderline RHD and worst for those with
advanced RHD (25).
There is no doubt that some overlap exists be-
tween echocardiographic findings of borderline RHD
and normal anatomic variation. Early RHD appears to
be a dynamic, heterogeneous entity with varied
outcomes (Figure 4). If subclinical RHD detected
JACC VOL. 72, NO. 12, 2018
SEPTEMBER 18, 2018:1397–416
T A B L E 3 Research Progress and Remaining Questions Around Echocardiographic Screening for RHD
Category Rationale and Challenges
Simplified protocols  2012 WHF criteria were intended
for RHD diagnosis by experts
 In a screening environment, with its
rapid pace, providers with varying
experience, and suboptimal condi-
tions, 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
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 increas-
ingly available
Task sharing  Severe shortage of persons in LMICs
trained in echocardiography
 Severe shortage of physicians in
LMICs outside of major metropol-
itan areas
Standardized training  WHO guidelines recommend
continuous monitoring and evalua-
tion during implementation of task
sharing
 Standardized training is central to
this endeavor
Effect on children  Need to understand the effect of a
and communities screening test on a community, on
those who test positive, and on
those who test negative
Outcomes  It remains unclear at what rate
latent RHD progresses and if early
detection leads to improved
outcomes
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
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
of same disease process as RF-associated carditis—as
studies in low-risk populations largely suggest
(28,29)—then a high rate of resolution does not
necessarily cast doubt on RHD diagnosis. It does,
however, raise questions about the added benefits of
Watkins et al. 1403
Present Status of Rheumatic Heart Disease
Progress Next Step(s)
 Simplified acquisition protocols, even a single  Re-evaluate components of WHF
view has reasonable sensitivity and specificity criteria toward simplification of
 Abbreviated screening criteria (vs. diagnosis) diagnosis
have good performance  Standardize simplified protocols
 Most focus exclusively on valve function; length for screening
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
 Experts show 79% sensitivity and 87% speci-
ficity 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
 Nonexpert diagnostic performance following
brief training has been promising
 Performance, even within individual studies, has
varied substantially between learners
 Freely available online modules in 3 languages  Determine best strategies for
developed (WiRED International) scaling up training (such as train-
 Modules show good performance and accept- the-trainer, and so on)
ability among nurses and other health providers  Development of standardized
 Telemedicine shows promise as an adjunct to competency assessments/
training and mentorship accreditation processes
 Strong support for screening from parents of  Community-engaged research to
screened children in New Zealand and screened minimize negative effects of RHD
children and teachers in Uganda screening on children and
 Negative screening has no effect on quality of communities
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
 Ten longitudinal cohorts, 2 to 7 yrs of follow-up  Standardization of reporting
 Heterogeneous diagnosis with varied outcomes outcomes for children with latent
 Outcomes best for borderline RHD, followed by RHD is of high priority
mild definite RHD, and worst for those with  Randomized controlled trial of
moderate/severe RHD at screening secondary prophylaxis in children
 Progression rates are challenging to compare— diagnosed with latent RHD (GOAL
inconsistent definitions of progression, use of trial, planned to start June 2018)
different binomial outcomes (stable þ progres-
sion), and inclusion of children with advanced
RHD
 3 studies assessing the cost effectiveness of  Reassessment as more data is
screening gathered around outcomes for
 Broad assumptions leading to hypothetical latent RHD and the impact of
conclusions—the impact of secondary prophy- secondary prophylaxis, which can
laxis on latent RHD (see above) is not fully more precisely inform the
understood investment case for RHD
screening
secondary prevention for early-stage disease (see
Part 2 of this review).
The published echocardiography data has taught
us that latent RHD is neither homogeneously malig-
nant nor uniformly benign. Echocardiographic
screening has played a pivotal role in reinvigorating
1404 Watkins et al.
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
understanding of disease pathogenesis.
Online Appendix Panel 2, we provide recommenda-
tions for echocardiography-based RHD research.
DISEASE EPIDEMIOLOGY. Relatively more is known
about the prevalence of RHD compared with other
epidemiological parameters. A systematic review
undertaken for the Global Burden of Disease 2015
study identified prevalence data from 59 countries
(2). Using epidemiological modeling techniques, this
study estimated about 33 million individuals (0.4% of
the global population) currently live with RHD. The
disease is most common in sub-Saharan Africa, South
Asia, and Oceania. Most prevalence studies have been
conducted in children attending school; relatively
little is known about RHD among
not attending school and among adults. Emerging
data suggest that RHD is more common in adults
and among children in community
(compared with children well enough to attend
school) (30,31).
Hospital-based studies have provided insights into
complications of and case-fatality from RHD. REM-
EDY estimated the incidence of RHD complications
over 24 months of follow-up. The most frequent was
new-onset heart failure (38 per 1,000 patient-years),
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followed by stroke or transient ischemic attack (8.5
In per 1,000 patient-years) and infective endocarditis
(3.7 per 1,000 patient-years). The incidence of recur-
rent RF in this cohort was 3.5 per 1,000 patient-years,
and regular use of secondary prevention was not
associated with better outcomes (32). The median age
at death was 28 years, and case-fatality at 24 months
was highest in low-income countries (21%) and
significantly lower in middle-income countries (12%
to 17%).
Less is known about mortality from RHD in the
general population. In many countries, RHD is
captured in nationally-representative vital or sample
registration systems. Using these datasets, the Global
Burden of Disease 2015 study estimated about
children 320,000 deaths from RHD in 2015, or about 0.6% of all
deaths. The highest death rates were in the highest-
prevalence regions, and no significant decline in
settings mortality over 1990 to 2015 was detected in a number
of countries, whereas other countries—mostly of
middle or high income—demonstrated dramatic re-
ductions in mortality (2). The limitations of these
estimates include incomplete vital registration sys-
tems in some (predominately African) countries and
the potential for misclassifying RHD deaths as deaths
from other causes, for example, stroke (33).
JACC VOL. 72, NO. 12, 2018
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Online Appendix Panel 3 summarizes priorities for
research on the descriptive epidemiology of RHD.
HOW SHOULD RHEUMATIC HEART DISEASE
BE MANAGED?
PREVENTION. We generally endorse current guide-
lines on primary and secondary prevention of
RHD (34). The following section highlights gaps in
knowledge and needs for research in RHD-endemic
countries.
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
GAS pharyngitis to decrease the risk of RF in high-risk
populations. Research is needed to clarify whether
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
in the 1950s demonstrated that treating GAS pharyn-
gitis reduced the risk of acute RF by about 80%. A
meta-analysis summarized the main limitations of
the primary prevention trials (38). Most studies were
of low quality compared to current standards, and
little comparative evidence exists to quantify effects
among females or diverse populations.
Accurate diagnosis of GAS pharyngitis remains
challenging in resource-limited countries. While
throat culture is the gold standard for diagnosis,
access to microbiology is limited and often
cost-prohibitive (39). Rapid diagnostic tests offer high
sensitivity and specificity, but their performance may
vary across settings, requiring validation studies prior
to local adoption (40). Low-cost, portable systems for
rapid GAS diagnosis are urgently needed. In the
absence of confirmatory testing, clinical decision
rules may be used and may even be more cost-
effective (39). There is no consensus clinical deci-
sion rule; most have been developed and tested in
single populations, with further testing needed to
confirm generalizability. The issue of GAS carriage in
the pharynx also requires further research.
Poor health-seeking behavior and lack of commu-
nity awareness regarding pharyngitis and RHD are
also barriers to primary prevention (41). Successful
RHD programs in the Caribbean emphasized com-
munity education (42), and the WHO recommends, as
a pillar of RHD programs, community-based cam-
paigns that emphasize the link between pharyngitis
and RHD (43).
S e c o n d a r y p r e v e n t i o n . Recurrent RF can be trig-
gered by asymptomatic and even appropriately-
treated GAS infection. After the first attack, the risk
Watkins et al. 1405
Present Status of Rheumatic Heart Disease
F I G U R E 4 The Spectrum of RHD
Death due to RHD
RHD requiring surgery
Symptomatic
RHD (active
RHD causing
disease)
sequelae*
RHD causing cardiac
failure
Clinical definite RHD
Asymptomatic (i.e., murmur present)
RHD (latent
disease) Subclinical definite RHD (i.e., no murmur)
Borderline echocardiographic
findings suggestive of RHD
This model illustrates the distinctions between symptomatic and asymptomatic (or
latent) disease and between definite and borderline rheumatic heart disease (RHD).
*Sequelae of RHD include heart failure, atrial fibrillation/stroke, and infective endo-
carditis, among others. Reprinted with permission from Zühlke L, Steer A. Estimates of
the global burden of rheumatic heart disease. Glob Heart 2013;8:189–95.
of recurrence with repeated GAS infection may be as
high as 50%. Secondary prevention involves contin-
uous antibiotic chemoprophylaxis to prevent recur-
rent RF and reduce progression to RHD (34). Four-
weekly intramuscular BPG remains the standard of
care in most settings, and contemporary studies have
found low rates of RF recurrence (0.07 per 100
patient-years) with this regimen (44).
A systematic review summarized the findings and
limitations of the existing clinical trials on secondary
prevention (45). Compared with doing nothing,
providing penicillin appears to confer a 55% relative
reduction in risk of RF. Injectable penicillin is
significantly more effective than oral penicillin;
however, the studied formulations of penicillin are no
longer in widespread use. Although secondary pre-
vention clearly reduces recurrent RF, less is known
about its effect on RHD. Newer data suggest
reductions in valvular pathology (46) and possibly
mortality (47).
The optimal duration of secondary prevention is
controversial. Current recommendations are based on
expert opinion, and no trial has recruited individuals
aged >25 years. Although the risk of GAS (and thus RF)
generally falls with age, this may not be true in certain
life stages (e.g., parenthood), among certain pro-
fessions exposed to GAS (e.g., teachers, nurses, mili-
tary), and in highly GAS-endemic areas (34). More
rigorous study of this issue is needed given the
1406 Watkins et al.
Present Status of Rheumatic Heart Disease
resource implications and risks of long-term antibiotic
use (34).
Ensuring adherence to secondary prevention has
proven challenging in limited-resource settings,
usually reflecting socioeconomic deprivation and
health system weaknesses (48). Registries are
considered best practice to improve the delivery of
secondary prevention (49). Improvements in BPG
formulation could support adherence (50). Therapy-
related adherence barriers include fear of adverse
drug reactions to BPG (51). Reported risks of allergy
and anaphylaxis are 3.2% and 0.2%, respectively; yet,
anecdotal experiences suggest higher rates (52). Cre-
ation of a global reporting system for BPG adverse
events has been proposed to track these risks (53).
Longitudinal studies provide little evidence that
secondary prevention improves outcomes for chil-
dren with echocardiographically-detected early and
borderline RHD. In fact, an Australian cohort found
increased risk of progression with penicillin (54), with
similar findings in Uganda (25). Currently, most chil-
dren presenting with mild definite RHD receive sec-
ondary prevention, whereas most with borderline
RHD do not. We recommend at least yearly clinical
follow-up and counseling on the signs and symptoms
of GAS infection and RF. The presence of equipoise
has prompted a 2-year randomized controlled trial,
beginning in June 2018, of 4-weekly BPG for latent
RHD (Determining the Impact of Penicillin in Latent
RHD: The GOAL Trial; NCT03346525).
Recommendations for clinical practice and
research in the area of primary and secondary pre-
vention are provided in Online Appendix Panel 4.
MEDICAL MANAGEMENT. H e a r t f a i l u r e . Onset of
heart failure is often associated with advanced RHD
that may not be amenable to corrective surgery. Heart
failure doubles the risk of death independent of other
prognostic variables (32), and in patients with aortic
stenosis or dominant regurgitant lesions portends a
particularly poor prognosis (55). By contrast, the he-
modynamic consequences of mitral stenosis are
relieved by percutaneous balloon or surgical mitral
valvuloplasty.
Based on studies of nonrheumatic valve disease
(55,56), it is recommended that surgical correction be
performed before the onset of symptoms in patients
with severe mitral and aortic regurgitation, guided by
echocardiographic indexes of left ventricular func-
tion (57). Likewise, individuals with severe aortic
stenosis should undergo intervention following the
onset of symptoms (57). Medical therapy is reserved
for those awaiting surgery or deemed unsuitable for
surgery. One subset of individuals with intractable
heart failure who require aggressive therapy are those
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who develop severe tricuspid insufficiency late after
surgical correction of other valve disease.
There is no RHD-specific evidence on optimal drug
therapy for heart failure. Digoxin is widely used
among those who have atrial fibrillation or heart fail-
ure (4), although its effect on clinical outcomes is not
known. Individuals with mitral stenosis in sinus
rhythm awaiting intervention or surgery may gain
some symptom relief with heart rate control using
beta-adrenergic blockers, calcium-channel blockers,
or ivabradine (58,59). It may be reasonable to recom-
mend vasodilator therapy with nondihydropyridine
calcium blockers, angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers, and beta-
blockers for symptomatic patients with severe aortic
regurgitation (57). Although there are fewer data
supporting the use of these approaches in severe
mitral regurgitation, it is generally accepted that
individuals with congestive symptoms and signs
should receive these medications. Diuretics can also
be used as needed for symptom relief.
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
with symptomatic RHD are in atrial fibrillation (4).
Atrial inflammation and chronically elevated left
atrial pressure leading to atrial remodeling are
important causal factors. Older age and the presence
of mitral valve disease (especially stenosis) are
strongly associated with incident atrial fibrillation. In
REMEDY, older persons living in upper-middle-
income countries had a higher prevalence of atrial
fibrillation than younger persons from low-income
countries (28% vs. 18%) despite having milder dis-
ease (32). From 40% to 75% of individuals with mitral
stenosis have atrial fibrillation (60). As with heart
failure, the development of atrial fibrillation gener-
ally portends a poor prognosis. Among individuals
with symptomatic disease, atrial fibrillation is asso-
ciated with a 40% higher mortality independent of
other prognostic markers, and risk of stroke increases
2-fold (2.4% vs. 1.2% at 24 months) (32).
Treatment of atrial fibrillation in RHD is directed at
the underlying valve disease. Restoration and main-
tenance of sinus rhythm is preferred for younger
persons (61). Although this may be possible using
balloon valvuloplasty in some cases of mitral stenosis
(62), it may not be possible in cases of long-standing
disease and very large left atria. In a small random-
ized study, amiodarone following electrical cardio-
version for maintenance of sinus rhythm was shown
to be superior to placebo in the short-term (63), but
given its toxicity, the value of long-term amiodarone
is debatable. Likewise, radiofrequency ablation was
successful in restoring sinus rhythm in a small case
series (64), but cannot be recommended for most
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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 commis-
surotomy. 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
replacement may be suitable candidates for intra-
operative catheter ablation, but there are limited data
on long-term efficacy (65). Consequently, rate control
with beta-blockers and nondihydropyridine calcium-
channel blockers remains the mainstay of pharma-
cotherapy for atrial fibrillation in RHD.
There are limited prospective data to assess the
risk of stroke from RHD. No validated
stratification tools or randomized trials evaluating
the efficacy and safety of oral anticoagulation are
available to guide anticoagulation decisions. Never-
theless, nearly all individuals with atrial fibrillation
are prescribed oral anticoagulation in clinical prac-
tice. The risk of stroke is highest with atrial fibrilla-
tion from mitral stenosis (about 4%/year), so these
persons probably derive the greatest benefit from
anticoagulation. Among older individuals with RHD,
the CHADS2 score may be used (66). However, the
quality of oral anticoagulation with vitamin K antag-
onists in limited-resource countries is poor due to
barriers to regular international normalized ratio
monitoring (4). Direct anticoagulants may prove to be
more effective than vitamin K antagonists. A ran-
domized trial comparing rivaroxaban with vitamin K
antagonists in patients with RHD is underway to test
this hypothesis (INVICTUS [INVestIgation of rheu-
matiC AF Treatment Using Vitamin K Antagonists,
Rivaroxaban or Aspirin Studies, Non-Inferiority]
noninferiority trial; NCT02832544).
Management of RHD in women of reproductive
a g e . RHD accounts for the majority of antenatal heart
Watkins et al. 1407
Present Status of Rheumatic Heart Disease
disease in endemic countries (67). Pregnancy is a
high-risk period, often resulting in clinical deterio-
ration and adverse events (68). Most pregnant women
with RHD become symptomatic after 24 weeks when
hemodynamic changes peak. The modified WHO
classification IV identifies those with severe mitral
stenosis, severe aortic stenosis, and severe pulmo-
nary hypertension as having the highest possible risk
risk- (69). In these women, perinatal outcomes (stillbirth,
prematurity, low birthweight, and neonatal mortal-
ity) are poor. A total of 34% of pregnant Senegalese
women with RHD died, and rates of stillbirth and
pregnancy termination were high (70), prompting
calls to screen pregnant women for RHD (71).
Optimal care for RHD-affected women involves
pre-conception counseling (72), and among those
pregnant, a comprehensive risk assessment and
management plan that includes replacing contra-
indicated medications, optimizing loading condi-
tions, and monitoring and addressing exacerbating
factors (e.g., anemia). When needed, surgery or
percutaneous transvenous mitral commissurotomy
(see the following text) is best performed after
24 weeks to minimize radiation risk and improve fetal
survival if early labor occurs (73). Among individuals
with complex pathology (e.g., multivalve disease,
calcified valves), conservative management is often
preferable because the risk of fetal loss is high with
cardiopulmonary bypass.
For individuals with prosthetic heart valves, anti-
coagulation during pregnancy is challenging (74,75).
Current standard practice is “sequential treatment,”
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highest fetal losses; 2) sequential treatment is asso-

F I G U R E 6 Effect of Rheumatic Heart Disease on the
Mitral Valve
Pre-operative photograph of a stenotic, regurgitant mitral
valve, showing fused commissures and thickened cusps.
which involves unfractionated
conception if planned or as soon as pregnancy is
detected, vitamin K antagonists
trimester until delivery, then unfractionated heparin
in the peripartum period. Two systematic reviews
concluded that: 1) vitamin K antagonists are associ-
ated with the better maternal outcomes but the
F I G U R E 7 Country Performance on Rheumatic Heart Disease Mortality Targets
Percent Reduction in Mortality by 2030 (SDG3 Target)
ciated with higher maternal thrombotic/bleeding
events then single therapy with vitamin K antago-
nists; and 3) low-molecular weight heparin is associ-
ated with the lowest rate of fetal or neonatal loss but
higher risk of valve thrombosis (76,77). Safe, afford-
able 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
highest-risk regions, and even with ideal care,
morbidity remains high.
The Registry of Pregnancy and Cardiac Disease
recently reported on the outcomes of 390 pregnant
heparin before
women with RHD and mitral valve disease. Women
with moderate and severe mitral stenosis and
from second
mixed moderate to severe regurgitation with ste-
nosis 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
hypertension, reduced ejection fraction, and
development of heart failure during pregnancy are

40
strong predictors of poor maternal and fetal
Georgia Guam

20
outcome (81).
Meeting WHF
Northern Mariana Islands
Underperforming Native-valve endocarditis. A total of 4% of
but not SDG3 target on both targets
0 Federated States of Micronesia REMEDY participants had native-valve infective
Niger Guinea Kiribati
endocarditis at initial presentation (4). RHD accounts
Lesotho
–20 Egypt for 15% (China) (82) to 55% (Pakistan) (83) of infective
India
Bolivia
Fiji endocarditis cases overall and 12% of cases during
–40 South Africa
Indonesia pregnancy (84). The most common pathogens are
China
–60 Namibia Staphylococci, Streptococci, Enterococci, Brucella
Rwanda
species, Candida albicans, and Stenotrophomonas
Meeting SDG3
–80 Syria
but not WHF target 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 49%; Staphylococcus aureus infection, sepsis, heart or
Percent Reduction in Mortality by 2025 (WHF Target) 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 (86). In limited-resource settings, infective endo-
country trends 2000 to 2015. The x-axis shows the total percentage reduction in deaths
carditis is often first diagnosed at autopsy (87). These
for those age <25 years (World Heart Federation [WHF] target) between 2013 and 2025 if
data reflect the need for laboratory diagnostic
2000 to 2015 trends continue. The y-axis shows the total percent reduction in deaths
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.
JACC VOL. 72, NO. 12, 2018 Watkins et al. 1409
SEPTEMBER 18, 2018:1397–416 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

A1. National RF/RHD strategy
A2. Number of persons living with
RHD
A3. Local guidelines for pharyngitis,
RF, and RHD
B1. Access to specialized cardiology
services
C1. RF/RHD registry
C2. Availability of BPG
C3. In-service training on RF/RHD
(relevant to clinical role/
qualification)
C4. Availability of echocardiography
services
National Assessment
Presence of strategy* and yr of last update A4. Mortality from RHD§ Deaths per 100,000 population/yr†
Prevalent cases per 100,000 population† B2. Delivery of specialized cardiac Number of percutaneous and surgical
services procedures performed per yr‡
Presence of guidelines and yr(s) of last update
Presence of national program; density of B3. Outcomes of specialized cardiac Proportion dead and/or reoperated on
interventionalists and surgeons per services within 90 days‡
100,000 population
Subnational (District or Province/State) Assessment
Proportion of districts with functioning registry C5. Incidence of acute RF Number of new cases per 100,000
in place population/yrk
Proportion of health facilities with BPG D1. Adherence to secondary Proportion receiving >80% of
currently in stock prevention scheduled injections/yrk
Proportion of workforce (re)trained over the D2. Adverse BPG events Number of events/yr
past 24 months D3. Acute RF recurrences§ Number of recurrences per registry
patient per yr
Proportion of districts with functional D4. Priority-based follow-up for Proportion of new moderate-to-severe
ultrasound machine individuals with RHD cases referredk

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
RHD and future research priorities are provided in
Online Appendix Panel 5.
PERCUTANEOUS AND OPEN INTERVENTIONS. We
generally endorse the current ACC/AHA guidelines
for the interventional and surgical management of
RHD (57). However, it should be stressed that most of
the evidence informing these guidelines is based on
nonrheumatic valve disease. The discussion in the
following text highlights some particular issues
related to RHD and challenges delivering these
procedures in limited-resource settings.
Interventional m a n a g e m e n t . Individuals
severe mitral stenosis and suitable valve morphology
benefit most from catheter-based interventions,
especially percutaneous transvenous mitral commis-
surotomy (PTMC). Although there have been hard-
ware improvements over the past 3 decades, the basic
procedure is relatively unchanged. Pivotal studies
established the percutaneous approach to the treat-
ment of mitral stenosis using single or double con-
ventional valvuloplasty balloons (88),
self-centering Inoue balloon (Toray, Tokyo, Japan)
has superseded these in clinical practice. Subsequent
trials comparing PTMC with surgical approaches used
the Inoue balloon and technique (89).
The success of PTMC depends to a great extent on
the morphology of the mitral valve. The presence of
subvalvular fusion and calcification reduce the
chances of a durable outcome. Several echocardio-
graphic scores (90) and more complex multifactorial
scores that use a combination of demographic, clin-
ical, and echocardiographic variables (91) are used to
assess suitability for PTMC. Individuals with mitral
stenosis are younger in countries where RHD is
endemic and may have a lower prevalence of age-
related morphological changes like calcification,
making them somewhat more suitable candidates for
PTMC. On the contrary, RHD may follow a more
aggressive course in endemic countries, resulting in
with severe morphological abnormalities including sub-
valvular disease. Still, PTMC provides acceptable
immediate and medium-term outcomes (Figure 5) and
remains the initial treatment of choice in most
individuals without unfavorable demographic or
clinical features (91).
The main complications associated with PTMC are
severe mitral regurgitation needing urgent surgery
(1% to 3%), cardiac tamponade (1% to 2%), systemic
but the embolism (<1%), and death (<1%) (92). A meta-
analysis of the small randomized studies comparing
PTMC with surgical commissurotomy suggests that
PTMC produces a slightly smaller valve area, a higher
risk of mitral regurgitation, and a nearly 3-fold risk of
reintervention compared with surgery (93). Never-
theless, because of increasing familiarity, ease of use
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the presence of valve thickening, variable degrees of

T A B L E 5 Product Development Priorities for RHD Prevention and Control
commissural fusion, and subvalvular disease. Trans-
Product Progress Comments catheter treatment of severe tricuspid regurgitation
GAS vaccine Phase 2 clinical trials Substantial benefit in reduced antibiotic use, may be more promising (97).
reduced invasive GAS disease
S u r g i c a l m a n a g e m e n t . Severe, chronic structural
Reformulation of BPG Candidate Improved rational use of antibiotics,
identification improved acceptability and adherence changes in the valves are the major cause of mor-
likely to lead to better clinical outcomes
tality from RHD. Ensuring timely access to defini-
Rapid antigen On market; need local Assists in rational use of antibiotics; not being
detection tests testing and trials used in endemic countries tive surgical care is a key aspect of addressing the
RF diagnostic Academic Syndromic diagnosis means opportunities to current disease burden. Unfortunately, many in-
research initiate disease altering secondary dividuals present too late to benefit from surgery,
prophylaxis are missed
Handheld On market Affordability and durability of prolonged use
so early detection efforts (98), accompanied by
echocardiography in remote settings are the major barriers priority-based follow-up (99), are required to ensure
devices to use
that surgical programs have maximal impact.
Point of care On market Not being used in endemic countries;
INR testing production of cheaper alternatives would Although valve replacement provides good early
be an important short-term advance results, long-term outcomes are poorer as the cu-
Alternatives to current Academic Lower-cost mechanical prosthesis, in mulative risk of valve-related complications in-
mechanical and research themselves, would be a critical short-
bioprosthetic valves term advance; in the longer term, creases (100). Hence, valve-conserving restorative
percutaneously-delivered mechanical or operations are now the preferred first-line approach.
tissue-engineered valves would be more
likely to meet the total need for surgical One unanswered question is the timing of surgery
care at reasonable cost for regurgitant lesions; most recommendations are
based on extrapolation from nonrheumatic valve
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. 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 repair. Surgical techniques are still
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
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 Dysfunction of the tricuspid valve can be second-
young age of patients with RHD. ary to mitral valve disease or be affected by the
Rheumatic tricuspid stenosis is rare and almost 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).
JACC VOL. 72, NO. 12, 2018
SEPTEMBER 18, 2018:1397–416
Unlike the mitral and tricuspid valves, aortic pathol-
ogy is infrequently suitable for valve-conserving op-
erations. Additionally, currently available
substitutes—with the exception of the Ross opera-
tion—are not suitable for use in the relatively young
population with RHD (105).
An emerging area of surgical research is in tissue
engineering of patches or entire valves
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
in limited-resource settings is ensuring quality.
Increasingly robust standards for post-operative
outcome recording have been developed for congen-
ital heart disease surgery for children in these set-
tings (107). Because patient demographics
providers overlap significantly, these practices could
easily be extended to individuals requiring surgery
for RHD. More research is needed on ensuring quality
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).
A summary of recommendations for practice and
research on interventional and surgical care is pro-
vided in Online Appendix Panel 6.
WHAT IS NEEDED TO ERADICATE
RHD WORLDWIDE?
THE GLOBAL AGENDA. R H D p o l i c y t a r g e t s a n d
s t a t e m e n t s . In 2013, the WHF called for a 25%
reduction in RHD mortality among individuals
aged <25 years by the year 2025 (109). More recently,
the United Nations Sustainable Development Goal
3 (SDG3) proposed a one-third reduction in premature
deaths from noncommunicable diseases by 2030
(110). Assuming that trends in mortality over the past
15 years hold, many endemic countries are on track to
achieve either 1 or both of the targets (Figure 7).
Notable high-performing countries include China,
Bangladesh, and Rwanda. A number of Pacific
Island nations are struggling to meet these targets
(Online Appendix).
Since the mid-2000s, several policy statements
have been issued on RHD. Notable recent statements
include the Addis Ababa communique (2015) and the
WHF roadmap on RHD (2017). A resolution on RHD
was adopted at the 71st World Health Assembly
Watkins et al. 1411
Present Status of Rheumatic Heart Disease
F I G U R E 8 Rapid Scale-Up of Specialized Cardiac Surgical Services in a
Middle-Income Country
valve
900
800
700
Number of Patients
(106). 600
500
400
300
200
100
0
2009 2010 2011 2012 2013 2014 2015
Year
Mitral Valve Repair
Mitral Valve Replacement
Percutaneous Balloon Mitral Commissurotomy
and
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).
(Online Appendix Panel 7) (6). The resolution man-
dates Member States to take action on RF/RHD and
resources WHO to provide support to country pro-
grams. Several tools have recently been published
that can assist in technical support of programs
(49,111). Drawing on these tools, we propose a set of
indicators for countries to use in tracking imple-
mentation of the resolution (Table 4).
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
global leadership in RHD has been challenging. RHD
has been neglected by policymakers and civil society
because it does not sit in a single department (e.g., at
WHO) nor is it amenable to single-intervention stra-
tegies. Advocacy and engagement are needed to build
relationships with other disciplines—such as maternal
and child health—that have larger, more visible con-
stituencies and audiences with decision-makers.
Additionally, people living with RHD are often
socially vulnerable and have few opportunities to
share their lived experiences. The Listen to My Heart
program is one promising model of patient engage-
ment and empowerment (112).
This review has provided recommendations for a
number of global public goods, including scientific
research, that warrant investment. Greater public and
private funding is needed to support laboratory,
1412 Watkins et al. JACC VOL. 72, NO. 12, 2018

Present Status of Rheumatic Heart Disease SEPTEMBER 18, 2018:1397–416

clinical/translational, and policy/implementation leveraging the strengths of RHD-specific activities to

research to address the basic and applied scientific
questions posed throughout this review. In addition,
there are a number of urgent RHD product develop-
ment priorities (Table 5).
RHD has important links to the global health se-
curity agenda in the area of antimicrobial resistance.
Development and enforcement of guidelines on
pharyngitis management, including rational use of
antibiotics, are needed in all countries. Better supply
and more consistent use of BPG as a first-line anti-
biotic for GAS, and eventually the roll-out of a GAS
vaccine, will probably be the most effective long-term
strategies for curbing antimicrobial resistance risk
from pharyngitis.
THE NATIONAL AGENDA. Disease control
The notion that RF can be eliminated is supported by
studies of country control programs conducted dur-
ing the 1970s and 1980s. The largest was a multi-
country study emphasizing secondary prevention
(113), and the last study was from Brazil (46). Expe-
rience with primary prevention programs has also
been favorable, and the WHO recommends combined
primary and secondary prevention efforts delivered
in community settings (43). These programs can
achieve the vast majority of their impact within about
a decade or so (42).
A number of unknowns remain. Most countries
that implemented RF programs were relatively
economically advanced, limiting their applicability
to current RHD-endemic countries. No program
used an active case-finding approach, which could
in theory lead to a more rapid decline in RF,
although the appropriateness of screening echocar-
diography remains unclear. Finally, the role of sur-
gery in RHD-control programs has
established. Cardiac surgery was available in some
of the countries mentioned previously,
remains largely unavailable today
RHD-endemic countries.
Integration of RHD programs into
h e a l t h s y s t e m s . There is currently little appetite
among health planners for developing targeted
programs, especially for chronic noncommunicable
diseases (114). Yet, historical case studies of RF/RHD
control frequently used vertical approaches. Conse-
quently, there is little evidence upon which to make
technical recommendations for integrating RHD-
related activities into existing health
Across several health system “building blocks,” dis-
cussed in the following text, we find important op-
portunities for integration of RF/RHD.
overarching approach would be “diagonal,”
build overall health system capacity (114).
Workforce challenges in RHD care parallel the
workforce challenges in other health areas (115). In
the short-term, strengthening primary and secondary
prevention should be prioritized, for example, using
nurse-led primary care (including school-based plat-
forms) and community health workers, although
further research is needed on these models (44,116). A
pressing issue for most countries will be to create
incentives to train and retain cardiovascular special-
ists. These providers could care for a wide range of
conditions, so while the initial rationale might be to
address RHD and support the global resolution,
increasing the cardiovascular workforce will have
programs. broader benefits. Cardiac surgery deserves special
emphasis given its importance in RHD. The experi-
ence of the Aswan Heart Centre has demonstrated
that, with political and financial commitment, surgi-
cal care can be rapidly scaled up and at high quality
(Figure 8) (104).
Much has been written on the need for better in-
formation systems for tracking RHD. Disease registers
have been recommended since the 1950s, but few
RHD-endemic countries have made significant prog-
ress on expanding registers beyond single centers,
which suggests that novel approaches are needed.
One recent initiative is the smartphone-based Pan
African Society of Cardiology eRegister (117). How to
integrate registers and eRegisters into local health
information systems is less clear and warrants further
consideration.
Disease notification and surveillance systems pro-
vide opportunities for RHD integration. There is good
rationale for classifying RF as a notifiable condition
not been because of its outbreak potential, although weak-
nesses in RF notification systems have been described
but it (99). Improving RF notification efforts and public
in most health action could have spillover benefits and
contribute to global health security. (RF is one of the
country few conditions that involves clinician-based rather
than laboratory-based notification. Notification for
emerging pandemics would need to follow a
nonlaboratory-based pathway, so strengthening sys-
tems for syndromic reporting would have benefits
beyond RF/RHD.) Last, improving the quality of death
certification for RHD (33), although important for
obtaining better mortality data, could also be inte-
systems. grated into efforts to improve the overall quality of
vital registration.
A final opportunity for RHD integration is health
The financing. The vast majority of health care in many
low- and middle-income countries is financed out-of-
JACC VOL. 72, NO. 12, 2018 Watkins et al. 1413
SEPTEMBER 18, 2018:1397–416 Present Status of Rheumatic Heart Disease

pocket, especially for noncommunicable diseases like
RHD. Consequently, poor households tend to forgo
health care or borrow money or sell assets to pay for
care, increasing the so-called “poverty trap” (118).
Charitable programs exist for RHD surgery in some
countries, but they are neither sufficient to meet the
populations’ needs nor fiscally sustainable (119).
Increasingly, surgical skills and knowledge will need
to be transferred to local health systems to sustain-
ably meet the large unmet need for cardiac surgery,
and governments will need to increase budgets for
advanced cardiovascular services.
The goal of universal health coverage, which all
countries have endorsed as part of United Nations
Sustainable Development Goal 3, holds promise for
improving access to and the affordability of RHD-
related care. The challenge is mobilizing sufficient
domestic resources to finance (relatively inexpensive)
prevention services as well as costly surgical care
without displacing other health priorities. Integrated
financing models are needed. Over time, the scale and
scope of covered services could progressively expand.
One modeling study suggested that universal coverage
of primary prevention would be the first priority
for most African countries, followed by secondary
prevention, then referral and tertiary services (120).
SUMMARY AND CONCLUSIONS
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
are many other important health concerns?
RHD is a disease of poverty that affects chil-
dren and working-age adults. The global economic
impact of early death from RHD was about $65
billion in 2015 (121). RHD provides an unparal-
leled opportunity to advance the global cardio-
vascular agenda by giving priority to the most
vulnerable. A “diagonal” approach could both
lead to rapid progress on RF/RHD and strengthen
health systems to address other noncommunicable
diseases.
While scientific questions remain, the evidence
base is sound for tackling RHD now. Across a wide
range of global health interventions, primary and
secondary prevention of RHD stand out as providing
excellent value for money (122). Challenges in scale-
up of advanced care for RHD are nuanced and
complex, but it is evident from historical trends that
all countries will eventually require advanced car-
diovascular services—not just for RHD—and must
start training the next generation of the cardiovas-
cular workforce, putting in place incentives to
ensure that these individuals work where needs are
greatest.
Complementing the national agenda is an agenda
for the global community. International agencies,
civil society, and donors will play a critical role in
the elimination of RHD. Support is needed for
research, advocacy, and implementation. Armed
with scientific, economic, and ethical arguments,
the RHD community can establish links and part-
nerships across sectors and health areas. The inte-
gration of RHD into the broader global health
agenda will ensure that the future generations grow
up free from the scourge of this eminently pre-
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.”
ADDRESS FOR CORRESPONDENCE: Dr. David A.
Watkins, Division of General Internal Medicine,
Department of Medicine, University of Washington,
325 9th Avenue, Box 359780, Seattle, Washington 98104.
E-mail: davidaw@uw.edu. Twitter: @davidawatkins,
@UW.

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KEY WORDS cardiac surgery,
echocardiography, health services,
pathogenesis, prevention, rheumatic heart
disease
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