Rheumatic Heart Disease Worldwide · RF = rheumatic fever RHD = rheumatic heart disease WHF = World Heart Federation WHO = World Health Organization JACCVOL.72,NO.12,2018 Watkins

Listen to this manuscript’s

audio summary by

JACC Editor-in-Chief

Dr. Valentin Fuster.

J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 2 , N O . 1 2 , 2 0 1 8

ª 2 0 1 8 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

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

JACC JOURNAL CME/MOC/ECME

This article has been selected as the month’s JACC CME/MOC/ECME

activity, available online at http://www.acc.org/jacc-journals-cme by

selecting the JACC Journals CME/MOC/ECME tab.

Accreditation and Designation Statement

The American College of Cardiology Foundation (ACCF) is accredited by

the Accreditation Council for Continuing Medical Education to provide

continuing medical education for physicians.

The ACCF designates this Journal-based CME activity for a maximum

of 1 AMA PRA Category 1 Credit(s)�. Physicians should claim only the

credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in

the evaluation component, enables the participant to earn up to 1 Medical

KnowledgeMOC point in the American Board of Internal Medicine’s (ABIM)

Maintenance of Certification (MOC) program. Participants will earn MOC

points equivalent to the amount of CME credits claimed for the activity. It is

the CME activity provider’s responsibility to submit participant completion

information to ACCME for the purpose of granting ABIM MOC credit.

Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel will be

accredited by the European Board for Accreditation in Cardiology (EBAC)

for 1 hour of External CME credits. Each participant should claim only

those hours of credit that have actually been spent in the educational

activity. The Accreditation Council for Continuing Medical Education

(ACCME) and the European Board for Accreditation in Cardiology (EBAC)

have recognized each other’s accreditation systems as substantially

equivalent. Apply for credit through the post-course evaluation. While

offering the credits noted above, this program is not intended to provide

extensive training or certification in the field.

Method of Participation and Receipt of CME/MOC/ECME Certificate

To obtain credit for JACC CME/MOC/ECME, you must:

1. Be an ACC member or JACC subscriber.

ISSN 0735-1097/$36.00

From the aDivision of General Internal Medicine, Department of MedicinbDepartment of Medicine, University of Cape Town and Groote Schuur Hosp

diatrics, University of Cape Town and Red Cross War Memorial Children’s Ho

Health System, Washington, DC; eTelethon Kids Institute, University of WesfPrincess Margaret Hospital for Children, Perth, Western Australia, Australi

Medical Sciences, New Delhi, India; hThe Deans Suite, Faculty of Health Sci

Africa; iOffice of the Chief Scientist, The George Institute for Global Health

Australia; and the jAswan Heart Centre, Aswan, Egypt. Dr. Watkins has receive

2. Carefully read the CME/MOC/ECME-designated article available on-

line and in this issue of the Journal.

3. Answer the post-test questions. A passing score of at least 70%must be

achieved to obtain credit.

4. Complete a brief evaluation.

5. Claim your CME/MOC/ECME credit and receive your certificate

electronically by following the instructions given at the conclusion of the

activity.

CME/MOC/ECME Objective for This Article: Upon completion of this

activity, the learner should be able to: 1) identify, within a global context,

populations that remain at elevated risk of acute rheumatic fever and

rheumatic heart disease; 2) summarize areas of consensus and the major

gaps in evidence regarding the prevention and medical management of

rheumatic heart disease; and 3) describe indications for catheter-based or

surgical management of common rheumatic valvular lesions.

CME/MOC/ECME Editor Disclosure: JACC CME/MOC/ECME Editor Raga-

vendra R. Baliga, MD, FACC, has reported that he has no financial re-

lationships or interests to disclose.

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

reported that they have no relationships relevant to the contents of this

paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME/MOC/ECME Term of Approval

Issue Date: September 18, 2018

Expiration Date: September 17, 2019

https://doi.org/10.1016/j.jacc.2018.06.063

e, University of Washington, Seattle, Washington;

ital, Cape Town, South Africa; cDepartment of Pae-

spital, Cape Town, South Africa; dChildren’s National

tern Australia, Subiaco, Western Australia, Australia;

a; gDepartment of Cardiology, All India Institute of

ences, University of Cape Town, Cape Town, South

, UNSW Sydney, Camperdown, New South Wales,

d support from the RHD Action grant fromMedtronic

http://www.acc.org/jacc-journals-cme


https://s3.amazonaws.com/ADFJACC/JACC7212/JACC7212_fustersummary_08




http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2018.06.063&domain=pdf

Watkins et al. J A C C V O L . 7 2 , N O . 1 2 , 2 0 1 8

Present Status of Rheumatic Heart Disease S E P T E M B E R 1 8 , 2 0 1 8 : 1 3 9 7 – 4 1 6

1398

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

Fo

Dr

(N

rel

Ma

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 rheumaticfever (RF) have largely disappeared from

wealthy countries, and the clinical caseload of RHDhas shifted to older age groups. RHD has also beendwarfed by ischemic heart disease. Additionally, RF/RHD control programs were successfully implementedin some low- and middle-income countries during thelatter part of the 20th century, prompting the WorldHealth Organization (WHO) and others to downscaletheir RF/RHD activities by the early 2000s (1).

Yet, RHD continues unabated in poor countries andamong vulnerable groups in wealthy ones (2). A 2007report on RHD among schoolchildren in Cambodia andMozambique 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 deathacross African and Asian countries (4). In 2015, a civilsociety movement, RHD Action, was launched to raiseawareness and support countries looking to addressRHD (5). In May 2018, the World Health Assemblyadopted a resolution to reinvigorate global and na-tional RF/RHD prevention and control efforts (6).

undation outside of the submitted work. Dr. Carapetis has received fundi

. Wyber has received funding from the Postgraduate Scholarship from

HMRC), Australia, and from the Telethon Kids Institute. All other auth

evant to the contents of this paper to disclose.

nuscript received March 22, 2018; revised manuscript received June 13, 2

Because of this renewed interest, the science ofRHD has evolved rapidly. A number of new orongoing studies aim to provide answers to key ques-tions. This Scientific Expert Panel seeks to summarizerecent research on RHD—from molecular mechanismsto health systems—in one coherent, scientifically-grounded vision for the future of science, clinicalmedicine, 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 isfrequent group A beta-hemolytic streptococcal (GAS)infection. Socioeconomic conditions leading toincreased 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 lessunderstood.

Host factors . There are 2 theories of how GASinfection damages host tissues. The basis of the mo-lecular mimicry theory is that molecules on the

ng from Novartis Institutes for Biomedical Research.

the National Health and Medical Research Council

ors have reported that they have no relationships

018, accepted June 15, 2018.

AB BR E V I A T I O N S

AND ACRONYM S

GAS = group A beta-hemolytic

streptococcus

RF = rheumatic fever

RHD = rheumatic heart disease

WHF = World Heart Federation

WHO = World Health

Organization

J A C C V O L . 7 2 , N O . 1 2 , 2 0 1 8 Watkins et al.S E P T E M B E R 1 8 , 2 0 1 8 : 1 3 9 7 – 4 1 6 Present Status of Rheumatic Heart Disease

1399

infecting organism are antigenically similar to mole-cules on host tissues. When the host immuneresponse targets these molecules, both are damaged.In the case of acute RF, 2 main streptococcal antigenshave been implicated: the surface M protein, andGlcNAc, the immunodominant epitope of the group Acarbohydrate (8). The “neo-antigen” theory, a morerecent development, suggests that the GAS organismgains access to the subendothelial collagen matrix,where M proteins binds to the CB3 region of type IVcollagen, creating a neo-antigen that induces anautoimmune response against collagen (9).

In both theories, it is thought that the initialdamage to cardiac tissues is due mainly to antibodies,with cellular responses subsequently implicated asthe immunological cascade evolves. These antibodies

CENTRAL ILLUSTRATION Framework for RheEventual Elimination

Research

Impleme

Prevent

• Innovations in rheumatic disease diagnosis and ris• Improved delivery of ben• Raising public and health• Comprehensive, commun

Advanced care

• Early echocardiographic diagnosis• Reproductive and antenatal services• Medical management of complications• Access to timely, high-quality surgical care

Watkins, D.A. et al. J Am Coll Cardiol. 2018;72(12):1397–416.

Global progress on rheumatic heart disease (RHD) will require a combin

research in key areas. Priority areas for advocacy, implementation, and re

through primary healthcare services in community settings; 2) advanced c

services; and 3) health policy, including measures that should be taken

international collective action (mostly to support research, product dev

recognize and activate valve endothelium toexpress adhesion molecules like vascular celladhesion molecule 1, allowing CD4 T cells(and others) activated by GAS to invade theheart valve, encounter antigens, and becomefurther activated. Over time, tissue break-down, partly involving autoantibodies andcomplement activation, releases additionalendogenous antigens such as collagen, lami-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 heartvalve. Over time, successive episodes coupled toresolution leads to neovascularization and fibrosis(Figure 1) (10).
umatic Heart Disease Control and

ntation

Advocacy

ion

fever/rheumatic heartk predictionzathine penicillin G worker awarenessity-based programs

• “Diagonal” health system investments• Integration and cross-sector collaboration• Product development and research priorities (e.g., vaccines)

Health policy

ation of advocacy efforts, implementation of existing evidence, and

search are: 1) the prevention of rheumatic fever and RHD, typically

are, which includes tertiary cardiology and, critically, cardiac surgery

by national health systems (mostly to deliver health care) and

elopment, and global stewardship and leadership).

FIGURE 1 Possible Pathogenic Mechanisms in Rheumatic Heart Disease

Recruitment of cellsactivated by GAS infection

Anti-endothelial cellantibodies (AECA)

generated by GAS infection

Functional AntibodiesComplement

Inflammatory lesionsFibrosis

Neovasularization

Pro-inflammatorycytokine production

Myofibroblast

AntigenPresentation

Valvular dendritic cellMonocyte-deriveddendritic cell

Monocyte

B cellCD4+TcellVCAM-1

Endogenous peptideloaded on MHCII

Autoantibodies

Complement

Aschoff Nodule

AECA-inducedadhesion molecule expression

CD8+Tcell

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).



1400

The infrequency of RF/RHD relative to the fre-quency of childhood GAS infection raises the possi-bility of genetic predisposition (11). Among childrenraised apart from their parents, those whose parentshad RHD had a 2.9-fold higher risk of RF comparedwith peers whose parents did not have RHD (12). Twinstudies have estimated the heritability of RF at 60%(13). Small candidate gene case-control studies haveidentified 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 receptor2), cytokine genes (e.g., tumor necrosis factor alpha),

and B-cell alloantigens have been implicated (14), butmost have not been replicated (15,16).

Among genome-wide association studies, 2 had nosignificant findings, whereas another found that var-iants at the immunoglobulin heavy chain locus wereassociated with RHD in 2 populations (17), but thisresult was not replicated elsewhere (18). The latterstudy identified evidence for risk and protectivehaplotypes across HLA-DQA/DQB Class II molecules,supporting molecular mimicry as the key pathogenicmechanism. Although these studies differ in diag-nostic method, design, and population studied, theysupport the notion of autoimmune pathogenesis.

TABLE 1 Clinical Features Among 3,343 African, Yemeni, and

Indian Individuals With Symptomatic Rheumatic Heart Disease

MedianAge, yrs

New York Heart Association functionalclass III and IV

809 (24.6) 26

Medical history

Acute rheumatic fever 1,340 (40.7)

Congestive heart failure 1,110 (33.4) 25

Pulmonary hypertension 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 661 (26.5)

Decreased LVEF in children 168 (5.3)

Dilated LVEDD in adults 742 (23.0)

Dilated LVEDD in children 454 (14.1)

Left atrial thrombus 44 (1.4)

Surgical history

Valve replacement or repair 715 (21.4)

Previous percutaneous valvuloplasty 135 (4.1)

Values are n (%) or n. Table presents authors’ own re-analysis of data from Zühlkeet al. (4).

LVEDD¼ left ventricular end-diastolic diameter; LVEF ¼ left ventricular ejectionfraction.

TABLE 2 World Heart Federation Criteria for the Diagnosis of RHD

Definite RHD (A, B, C, D)Age #20 yrs

Definite RHD (A, B, C, D)Age >20 yrs

A. Pathological MR and at least2 morphological features ofRHD of the MV

A. Pathological MR and at least2 morphological featuresof RHD of the MV

B. MS mean gradient $4 mm Hg* B. MS with meangradient $4 mm Hg*

C. Pathological AR and at least2 morphological featuresof RHD of the AV

C. Pathological AR and at least2 morphological features ofRHD of the AV in those age <35 yrs

D. Borderline disease of boththe AV and MV

D. Pathological AR and at least2 morphological features ofRHD of the MV

Borderline RHD (A, B, C)Borderline Not Applicable

to Those Age >20 yrs

A. At least 2 morphologicalfeatures of RHD of the MVwithout pathological MR or MS

B. Pathological MR

C. Pathological AR

Pathological Mitral Regurgitation Pathological Aortic Regurgitation

Seen in 2 views Seen in 2 views

In at least 1 view, jet length $2 cm† In at least 1 view, jet length $1 cm†

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

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 tolast 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.


1401

Meta-analyses of thousands of well-characterizedcases and controls will be required to identify reli-able and reproducible genetic susceptibility and pro-tective factors. Ultimately, genomic analyses couldidentify high-risk individuals to target for penicillinprophylaxis and vaccination against GAS.Pathogen factors . Outbreaks of rheumatic fever inNorth America in the mid-20th century were limitedto GAS strains belonging to a subset of M types (basedon the classical typing system; this has since beenreplaced by emm typing based on the geneticsequence of the M protein). Over the past 2 decades, ithas become apparent that GAS strains from regionswhere RHD is endemic are much more diverse thanthose 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 strainsmay be associated with skin infection, supporting thehypothesis that RF is not solely a consequence of GASpharyngitis (20–22).

Focus has shifted in recent years to better under-standing the features of RF-associated GAS strainsrather than emm types. Most attention has been paidto identifying surface or excreted antigens that haveantigenic homology to human tissues and couldstimulate cross-reactivity. Most of the identifiedcross-reactive regions are in the A- and B-repeat

regions of the M protein and include sequenceshomologous with human actin and cardiac myosin,although there are other cross-reactive antigens inGAS including the group A carbohydrate (10).

While the recent growth in research on RHD path-ogenesis is promising and has challenged a variety ofhistorical paradigms, a number of key scientificquestions remain. Online Appendix Panel 1 suggestspriorities for future research.

CLINICAL AND ECHOCARDIOGRAPHIC ASPECTS.

Cl in ica l features . Aside from a subset of children inwhom RF leads to severe carditis and early RHD, RHDis usually clinically silent (“latent”) until it manifestsduring adulthood. Many individuals in RHD-endemiccountries present late in their disease process with 1or more sequelae. The REMEDY study followed 3,343individuals with symptomatic RHD presenting forcare at academic centers in 14 countries (Table 1) (4).Most individuals were 15 to 49 years of age, andfewer than one-half recalled a history of RF. Heart


FIGURE 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.



1402

failure, pulmonary hypertension, and atrial fibrillationwere the most frequent medical complications. About20% demonstrated decreased left ventricular ejectionfraction, and about one-third had increased leftventricular end-diastolic diameter—underscoring theconsequences of late presentation.

Challenges in diagnosing acute RF are a majorbarrier to preventing RHD. Strong evidence of milderpresentation and the importance of subclinical car-ditis prompted revision of the Jones Criteria (the goldstandard for RF diagnosis) in 2015 to better accountfor differences in population risk (23). While thesecriteria will likely increase case detection, barrierssuch as poor health seeking behavior, lack of pathol-ogy services, and clinical overlap with other endemicdiseases (such as malaria in sub-Saharan Africa) limitthe efficacy of a simple diagnostic shift within aclinical decision rule. Better RF diagnosis will requirethe development of new (laboratory) technology teststhat could augment or replace clinical decision rules.Echocard iography and RHD. The World HeartFederation (WHF) published the first evidence-based,standardized criteria for the echocardiographic diag-nosis of RHD in 2012 (Table 2, Figure 2) (24). Sincethen, >2 dozen additional studies covering >100,000participants have been conducted. In parallel, studieshave 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.

“Subclinical RHD” refers to RHD seen on echocardi-ography in a patient with a normal clinical cardiacexamination. “Latent” RHD includes a broader spec-trum of disease, including any RHD found on echo-cardiographic screening in the absence of prior RF orknown RHD. Although latent RHD includes subclini-cal RHD, one-third (Uganda) (25) to two-thirds (Fiji)(26) of children with latent definite RHD already havemoderate-to-severe disease. Outcomes for thesechildren are poor (26). In Uganda, almost one-half ofchildren with moderate-to-severe RHD progressed (toworsening regurgitation, stenosis, or death) over amedian of 2.3 years, and only 9.5% showed any dis-ease improvement (25).

By contrast, the clinical course of children withborderline and mild definite RHD is enigmatic. Com-parison across cohorts must be undertakencautiously: studies have used inconsistent definitionsof progression, have used different outcomes, and insome cases, have included children with advancedRHD (25,27). Standardization is needed in reportingoutcomes (27). Although most children with border-line or mild definite RHD remain stable or showimprovement, 10% to 24% experience disease pro-gression (Figure 3). Outcomes are best for childrenwith borderline RHD and worst for those withadvanced RHD (25).

There is no doubt that some overlap exists be-tween echocardiographic findings of borderline RHDand normal anatomic variation. Early RHD appears tobe a dynamic, heterogeneous entity with variedoutcomes (Figure 4). If subclinical RHD detected

TABLE 3 Research Progress and Remaining Questions Around Echocardiographic Screening for RHD

Category Rationale and Challenges Progress Next Step(s)

Simplified protocols � 2012 WHF criteria were intendedfor RHD diagnosis by experts

� In a screening environment, with itsrapid pace, providers with varyingexperience, and suboptimal condi-tions, these criteria have provedless practical

� Some portable devices lack spectralDoppler, which is required for thediagnosis of RHD according to theWHF criteria

� Simplified acquisition protocols, even a singleview has reasonable sensitivity and specificity

� Abbreviated screening criteria (vs. diagnosis)have good performance

� Most focus exclusively on valve function; lengthof mitral regurgitation and presence of aorticinsufficiency

� Practical, but misses isolated morphologicalabnormalities that can occur in the absence ofpathological regurgitation early in RHD

� Re-evaluate components of WHFcriteria toward simplification ofdiagnosis

� Standardize simplified protocolsfor 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 increas-ingly available

� 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 2012WHF criteria increases overall costs

Task sharing � Severe shortage of persons in LMICstrained in echocardiography

� Severe shortage of physicians inLMICs outside of major metropol-itan areas

� Nonexpert diagnostic performance followingbrief training has been promising

� Performance, even within individual studies, hasvaried substantially between learners

Standardized training � WHO guidelines recommendcontinuous monitoring and evalua-tion during implementation of tasksharing

� Standardized training is central tothis endeavor

� Freely available online modules in 3 languagesdeveloped (WiRED International)

� Modules show good performance and accept-ability among nurses and other health providers

� Telemedicine shows promise as an adjunct totraining and mentorship

� Determine best strategies forscaling up training (such as train-the-trainer, and so on)

� Development of standardizedcompetency assessments/accreditation processes

Effect on childrenand communities

� Need to understand the effect of ascreening test on a community, onthose who test positive, and onthose who test negative

� Strong support for screening from parents ofscreened children in New Zealand and screenedchildren and teachers in Uganda

� Negative screening has no effect on quality oflife, but positive result can cause anxiety anddecreased physical activity, and can decreaseparental and child quality of life

� Peer support groups may be able to normalizeQOL in children with positive screen and toimprove social connectedness

� Community-engaged research tominimize negative effects of RHDscreening on children andcommunities

Outcomes � It remains unclear at what ratelatent RHD progresses and if earlydetection leads to improvedoutcomes

� 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 withmoderate/severe RHD at screening

� Progression rates are challenging to compare—inconsistent definitions of progression, use ofdifferent binomial outcomes (stable þ progres-sion), and inclusion of children with advancedRHD

� Standardization of reportingoutcomes for children with latentRHD is of high priority

� Randomized controlled trial ofsecondary prophylaxis in childrendiagnosed with latent RHD (GOALtrial, planned to start June 2018)

Cost effectiveness � It is not yet known if screening forRHD is cost-effective

� It is likely that the downstreamcosts of screening (additionalhealth system burden, impact onpatient and family quality of life,and so on) will be significant

� 3 studies assessing the cost effectiveness ofscreening

� Broad assumptions leading to hypotheticalconclusions—the impact of secondary prophy-laxis on latent RHD (see above) is not fullyunderstood

� Reassessment as more data isgathered around outcomes forlatent RHD and the impact ofsecondary prophylaxis, which canmore precisely inform theinvestment case for RHDscreening

LMICs ¼ low- and middle-income countries; QOL ¼ quality of life; RHD ¼ rheumatic heart disease; WHF ¼ World Heart Federation.


1403

through echocardiographic screening is indeed partof same disease process as RF-associated carditis—asstudies in low-risk populations largely suggest(28,29)—then a high rate of resolution does notnecessarily cast doubt on RHD diagnosis. It does,however, raise questions about the added benefits of

secondary prevention for early-stage disease (seePart 2 of this review).

The published echocardiography data has taughtus that latent RHD is neither homogeneously malig-nant nor uniformly benign. Echocardiographicscreening has played a pivotal role in reinvigorating

FIGURE 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).



1404

global research and helping to modernize ourunderstanding of disease pathogenesis. InOnline Appendix Panel 2, we provide recommenda-tions for echocardiography-based RHD research.

DISEASE EPIDEMIOLOGY. Relatively more is knownabout the prevalence of RHD compared with otherepidemiological parameters. A systematic reviewundertaken for the Global Burden of Disease 2015study identified prevalence data from 59 countries(2). Using epidemiological modeling techniques, thisstudy estimated about 33 million individuals (0.4% ofthe global population) currently live with RHD. Thedisease is most common in sub-Saharan Africa, SouthAsia, and Oceania. Most prevalence studies have beenconducted in children attending school; relativelylittle is known about RHD among childrennot attending school and among adults. Emergingdata suggest that RHD is more common in adultsand among children in community settings(compared with children well enough to attendschool) (30,31).

Hospital-based studies have provided insights intocomplications of and case-fatality from RHD. REM-EDY estimated the incidence of RHD complicationsover 24 months of follow-up. The most frequent wasnew-onset heart failure (38 per 1,000 patient-years),

followed by stroke or transient ischemic attack (8.5per 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 notassociated with better outcomes (32). The median ageat death was 28 years, and case-fatality at 24 monthswas highest in low-income countries (21%) andsignificantly lower in middle-income countries (12%to 17%).

Less is known about mortality from RHD in thegeneral population. In many countries, RHD iscaptured in nationally-representative vital or sampleregistration systems. Using these datasets, the GlobalBurden of Disease 2015 study estimated about320,000 deaths from RHD in 2015, or about 0.6% of alldeaths. The highest death rates were in the highest-prevalence regions, and no significant decline inmortality over 1990 to 2015 was detected in a numberof countries, whereas other countries—mostly ofmiddle or high income—demonstrated dramatic re-ductions in mortality (2). The limitations of theseestimates include incomplete vital registration sys-tems in some (predominately African) countries andthe potential for misclassifying RHD deaths as deathsfrom other causes, for example, stroke (33).


FIGURE 4 The Spectrum of RHD

Borderline echocardiographicfindings suggestive of RHD

Subclinical definite RHD (i.e., no murmur)

Clinical definite RHD(i.e., murmur present)

RHD causing cardiacfailure

RHD causingsequelae*

SymptomaticRHD (active

disease)

AsymptomaticRHD (latent

disease)

Death due to RHD

RHD requiring surgery

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.


1405

Online Appendix Panel 3 summarizes priorities forresearch 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 ofRHD (34). The following section highlights gaps inknowledge and needs for research in RHD-endemiccountries.

Pr imary prevent ion . Primary prevention of RHDfocuses on the prompt recognition and treatment ofGAS pharyngitis to decrease the risk of RF in high-riskpopulations. Research is needed to clarify whetherother Lancefield groups (35) and skin infections (36)can cause RF. Intramuscular benzathine penicillin G(BPG) remains the most widely-used antibiotic forGAS pharyngitis (37).

Trials among American military recruits conductedin the 1950s demonstrated that treating GAS pharyn-gitis reduced the risk of acute RF by about 80%. Ameta-analysis summarized the main limitations ofthe primary prevention trials (38). Most studies wereof low quality compared to current standards, andlittle comparative evidence exists to quantify effectsamong females or diverse populations.

Accurate diagnosis of GAS pharyngitis remainschallenging in resource-limited countries. Whilethroat culture is the gold standard for diagnosis,access to microbiology is limited and oftencost-prohibitive (39). Rapid diagnostic tests offer highsensitivity and specificity, but their performance mayvary across settings, requiring validation studies priorto local adoption (40). Low-cost, portable systems forrapid GAS diagnosis are urgently needed. In theabsence of confirmatory testing, clinical decisionrules 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 insingle populations, with further testing needed toconfirm generalizability. The issue of GAS carriage inthe pharynx also requires further research.

Poor health-seeking behavior and lack of commu-nity awareness regarding pharyngitis and RHD arealso barriers to primary prevention (41). SuccessfulRHD programs in the Caribbean emphasized com-munity education (42), and the WHO recommends, asa pillar of RHD programs, community-based cam-paigns that emphasize the link between pharyngitisand RHD (43).

Secondary prevent ion . Recurrent RF can be trig-gered by asymptomatic and even appropriately-treated GAS infection. After the first attack, the risk

of recurrence with repeated GAS infection may be ashigh 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 ofcare in most settings, and contemporary studies havefound low rates of RF recurrence (0.07 per 100patient-years) with this regimen (44).

A systematic review summarized the findings andlimitations of the existing clinical trials on secondaryprevention (45). Compared with doing nothing,providing penicillin appears to confer a 55% relativereduction in risk of RF. Injectable penicillin issignificantly more effective than oral penicillin;however, the studied formulations of penicillin are nolonger in widespread use. Although secondary pre-vention clearly reduces recurrent RF, less is knownabout its effect on RHD. Newer data suggestreductions in valvular pathology (46) and possiblymortality (47).

The optimal duration of secondary prevention iscontroversial. Current recommendations are based onexpert opinion, and no trial has recruited individualsaged >25 years. Although the risk of GAS (and thus RF)generally falls with age, this may not be true in certainlife stages (e.g., parenthood), among certain pro-fessions exposed to GAS (e.g., teachers, nurses, mili-tary), and in highly GAS-endemic areas (34). Morerigorous study of this issue is needed given the




1406

resource implications and risks of long-term antibioticuse (34).

Ensuring adherence to secondary prevention hasproven challenging in limited-resource settings,usually reflecting socioeconomic deprivation andhealth system weaknesses (48). Registries areconsidered best practice to improve the delivery ofsecondary prevention (49). Improvements in BPGformulation could support adherence (50). Therapy-related adherence barriers include fear of adversedrug reactions to BPG (51). Reported risks of allergyand anaphylaxis are 3.2% and 0.2%, respectively; yet,anecdotal experiences suggest higher rates (52). Cre-ation of a global reporting system for BPG adverseevents has been proposed to track these risks (53).

Longitudinal studies provide little evidence thatsecondary prevention improves outcomes for chil-dren with echocardiographically-detected early andborderline RHD. In fact, an Australian cohort foundincreased risk of progression with penicillin (54), withsimilar findings in Uganda (25). Currently, most chil-dren presenting with mild definite RHD receive sec-ondary prevention, whereas most with borderlineRHD do not. We recommend at least yearly clinicalfollow-up and counseling on the signs and symptomsof GAS infection and RF. The presence of equipoisehas prompted a 2-year randomized controlled trial,beginning in June 2018, of 4-weekly BPG for latentRHD (Determining the Impact of Penicillin in LatentRHD: The GOAL Trial; NCT03346525).

Recommendations for clinical practice andresearch in the area of primary and secondary pre-vention are provided in Online Appendix Panel 4.MEDICAL MANAGEMENT. Heart fa i lure . Onset ofheart failure is often associated with advanced RHDthat may not be amenable to corrective surgery. Heartfailure doubles the risk of death independent of otherprognostic variables (32), and in patients with aorticstenosis or dominant regurgitant lesions portends aparticularly poor prognosis (55). By contrast, the he-modynamic consequences of mitral stenosis arerelieved by percutaneous balloon or surgical mitralvalvuloplasty.

Based on studies of nonrheumatic valve disease(55,56), it is recommended that surgical correction beperformed before the onset of symptoms in patientswith severe mitral and aortic regurgitation, guided byechocardiographic indexes of left ventricular func-tion (57). Likewise, individuals with severe aorticstenosis should undergo intervention following theonset of symptoms (57). Medical therapy is reservedfor those awaiting surgery or deemed unsuitable forsurgery. One subset of individuals with intractableheart failure who require aggressive therapy are those

who develop severe tricuspid insufficiency late aftersurgical correction of other valve disease.

There is no RHD-specific evidence on optimal drugtherapy for heart failure. Digoxin is widely usedamong those who have atrial fibrillation or heart fail-ure (4), although its effect on clinical outcomes is notknown. Individuals with mitral stenosis in sinusrhythm awaiting intervention or surgery may gainsome symptom relief with heart rate control usingbeta-adrenergic blockers, calcium-channel blockers,or ivabradine (58,59). It may be reasonable to recom-mend vasodilator therapy with nondihydropyridinecalcium blockers, angiotensin-converting enzymeinhibitors or angiotensin receptor blockers, and beta-blockers for symptomatic patients with severe aorticregurgitation (57). Although there are fewer datasupporting the use of these approaches in severemitral regurgitation, it is generally accepted thatindividuals with congestive symptoms and signsshould receive these medications. Diuretics can alsobe used as needed for symptom relief.Atr ia l fibr i l l a t ion and stroke . About 1 in 5 personswith symptomatic RHD are in atrial fibrillation (4).Atrial inflammation and chronically elevated leftatrial pressure leading to atrial remodeling areimportant causal factors. Older age and the presenceof mitral valve disease (especially stenosis) arestrongly associated with incident atrial fibrillation. InREMEDY, older persons living in upper-middle-income countries had a higher prevalence of atrialfibrillation than younger persons from low-incomecountries (28% vs. 18%) despite having milder dis-ease (32). From 40% to 75% of individuals with mitralstenosis have atrial fibrillation (60). As with heartfailure, the development of atrial fibrillation gener-ally portends a poor prognosis. Among individualswith symptomatic disease, atrial fibrillation is asso-ciated with a 40% higher mortality independent ofother prognostic markers, and risk of stroke increases2-fold (2.4% vs. 1.2% at 24 months) (32).

Treatment of atrial fibrillation in RHD is directed atthe underlying valve disease. Restoration and main-tenance of sinus rhythm is preferred for youngerpersons (61). Although this may be possible usingballoon valvuloplasty in some cases of mitral stenosis(62), it may not be possible in cases of long-standingdisease and very large left atria. In a small random-ized study, amiodarone following electrical cardio-version for maintenance of sinus rhythm was shownto be superior to placebo in the short-term (63), butgiven its toxicity, the value of long-term amiodaroneis debatable. Likewise, radiofrequency ablation wassuccessful in restoring sinus rhythm in a small caseseries (64), but cannot be recommended for most

https://clinicaltrials.gov/ct2/show/NCT03346525?term=NCT03346525&rank=1


FIGURE 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.


1407

patients. Some individuals undergoing mitral valvereplacement may be suitable candidates for intra-operative catheter ablation, but there are limited dataon long-term efficacy (65). Consequently, rate controlwith 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 therisk of stroke from RHD. No validated risk-stratification tools or randomized trials evaluatingthe efficacy and safety of oral anticoagulation areavailable to guide anticoagulation decisions. Never-theless, nearly all individuals with atrial fibrillationare prescribed oral anticoagulation in clinical prac-tice. The risk of stroke is highest with atrial fibrilla-tion from mitral stenosis (about 4%/year), so thesepersons probably derive the greatest benefit fromanticoagulation. Among older individuals with RHD,the CHADS2 score may be used (66). However, thequality of oral anticoagulation with vitamin K antag-onists in limited-resource countries is poor due tobarriers to regular international normalized ratiomonitoring (4). Direct anticoagulants may prove to bemore effective than vitamin K antagonists. A ran-domized trial comparing rivaroxaban with vitamin Kantagonists in patients with RHD is underway to testthis 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 reproduct iveage. RHD accounts for the majority of antenatal heart

disease in endemic countries (67). Pregnancy is ahigh-risk period, often resulting in clinical deterio-ration and adverse events (68). Most pregnant womenwith RHD become symptomatic after 24 weeks whenhemodynamic changes peak. The modified WHOclassification IV identifies those with severe mitralstenosis, severe aortic stenosis, and severe pulmo-nary hypertension as having the highest possible risk(69). In these women, perinatal outcomes (stillbirth,prematurity, low birthweight, and neonatal mortal-ity) are poor. A total of 34% of pregnant Senegalesewomen with RHD died, and rates of stillbirth andpregnancy termination were high (70), promptingcalls to screen pregnant women for RHD (71).

Optimal care for RHD-affected women involvespre-conception counseling (72), and among thosepregnant, a comprehensive risk assessment andmanagement plan that includes replacing contra-indicated medications, optimizing loading condi-tions, and monitoring and addressing exacerbatingfactors (e.g., anemia). When needed, surgery orpercutaneous transvenous mitral commissurotomy(see the following text) is best performed after24 weeks to minimize radiation risk and improve fetalsurvival if early labor occurs (73). Among individualswith complex pathology (e.g., multivalve disease,calcified valves), conservative management is oftenpreferable because the risk of fetal loss is high withcardiopulmonary bypass.

For individuals with prosthetic heart valves, anti-coagulation during pregnancy is challenging (74,75).Current standard practice is “sequential treatment,”

https://clinicaltrials.gov/ct2/show/NCT02832544?term=NCT02832544&rank=1

FIGURE 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.

FIGURE 7 Country

–100

–100

–80

–60

–40

–20

0

20

40

Perc

ent R

educ

tion

in M

orta

lity

by 2

030

(SDG

3 Ta

rget

)

Meebut not

Projected reduction

country trends 2000

for those age <25 ye

2000 to 2015 trend

for those age 30 to 6

2015 and 2030 if 20



1408

which involves unfractionated heparin beforeconception if planned or as soon as pregnancy isdetected, vitamin K antagonists from secondtrimester until delivery, then unfractionated heparinin the peripartum period. Two systematic reviewsconcluded that: 1) vitamin K antagonists are associ-ated with the better maternal outcomes but the

Performance on Rheumatic Heart Disease Mortality Targets

–80 –60 –40 –20 0 20 40Percent Reduction in Mortality by 2025 (WHF Target)

ting WHF SDG3 target

Meeting SDG3but not WHF target

Underperformingon both targets

Bolivia

China

Egypt

Federated States of Micronesia

Fiji

Georgia Guam

Guinea

India

Indonesia

Kiribati

Lesotho

Namibia

Niger

Northern Mariana Islands

Rwanda

South Africa

Syria

in age-specific mortality from rheumatic heart disease based on

to 2015. The x-axis shows the total percentage reduction in deaths

ars (World Heart Federation [WHF] target) between 2013 and 2025 if

s continue. The y-axis shows the total percent reduction in deaths

9 years (Sustainable Development Goal 3 [SDG3] target) between

00 to 2015 trends continue. See Online Appendix for details.

highest fetal losses; 2) sequential treatment is asso-ciated with higher maternal thrombotic/bleedingevents 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 buthigher risk of valve thrombosis (76,77). Safe, afford-able anticoagulation options during pregnancy areneeded.

The optimal delivery of antenatal care for womenwith RHD is through a multidisciplinary specializedmanagement team; these are rarely encountered inRHD-endemic regions (78). Standard practicesinclude measures to shorten the second stage oflabor. In most cases, Cesarean section is not required.Outcomes beyond 42 days postpartum reveal ongoingrisk (79). Although recent reviews have found lowmaternal mortality rates, these do not capture thehighest-risk regions, and even with ideal care,morbidity remains high.

The Registry of Pregnancy and Cardiac Diseaserecently reported on the outcomes of 390 pregnantwomen with RHD and mitral valve disease. Womenwith moderate and severe mitral stenosis andmixed moderate to severe regurgitation with ste-nosis had the highest complication rates (80).Mitral stenosis remains an independent risk factorfor adverse neonatal outcomes. Aside from valvularpathology, maternal age, body mass index above28 kg/m2, New York Heart Association functionalclass III to IV symptoms, significant pulmonaryhypertension, reduced ejection fraction, anddevelopment of heart failure during pregnancy arestrong predictors of poor maternal and fetaloutcome (81).Nat ive-va lve endocard i t i s . A total of 4% ofREMEDY participants had native-valve infectiveendocarditis at initial presentation (4). RHD accountsfor 15% (China) (82) to 55% (Pakistan) (83) of infectiveendocarditis cases overall and 12% of cases duringpregnancy (84). The most common pathogens areStaphylococci, Streptococci, Enterococci, Brucellaspecies, Candida albicans, and Stenotrophomonasmaltophilia (85). Culture positivity ranges from30% to 65%. A Chilean study that included 22% ofparticipants with RHD reported a 10-year survival of49%; Staphylococcus aureus infection, sepsis, heart orrenal failure, and lack of surgical treatment duringinfection were associated with increased mortality(86). In limited-resource settings, infective endo-carditis is often first diagnosed at autopsy (87). Thesedata reflect the need for laboratory diagnosticservices, access to antibiotics for medium-term regi-mens, and access to interventions or surgery toameliorate outcomes.


TABLE 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 withRHD

Prevalent cases per 100,000 population† B2. Delivery of specialized cardiacservices

Number of percutaneous and surgicalprocedures performed per yr‡

A3. Local guidelines for pharyngitis,RF, and RHD

Presence of guidelines and yr(s) of last update

B1. Access to specialized cardiologyservices

Presence of national program; density ofinterventionalists and surgeons per100,000 population

B3. Outcomes of specialized cardiacservices

Proportion dead and/or reoperated onwithin 90 days‡

Subnational (District or Province/State) Assessment

C1. RF/RHD registry Proportion of districts with functioning registryin place

C5. Incidence of acute RF Number of new cases per 100,000population/yrk

C2. Availability of BPG Proportion of health facilities with BPGcurrently in stock

D1. Adherence to secondaryprevention

Proportion receiving >80% ofscheduled injections/yrk

C3. In-service training on RF/RHD(relevant to clinical role/qualification)

Proportion of workforce (re)trained over thepast 24 months

D2. Adverse BPG events Number of events/yr

D3. Acute RF recurrences§ Number of recurrences per registrypatient per yr

C4. Availability of echocardiographyservices

Proportion of districts with functionalultrasound machine

D4. Priority-based follow-up forindividuals with RHD

Proportion of new moderate-to-severecases referredk

Indicators were measured as follows: category A ¼ desk review by ministry of health; category B¼ audit of tertiary healthcare facilities; category C¼ facility surveys conducted in a random sample of districtsstratified 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 orembedded 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 arepreferred; 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.


1409

Recommendations for medical management ofRHD and future research priorities are provided inOnline Appendix Panel 5.PERCUTANEOUS AND OPEN INTERVENTIONS. Wegenerally endorse the current ACC/AHA guidelinesfor the interventional and surgical management ofRHD (57). However, it should be stressed that most ofthe evidence informing these guidelines is based onnonrheumatic valve disease. The discussion in thefollowing text highlights some particular issuesrelated to RHD and challenges delivering theseprocedures in limited-resource settings.Intervent iona l management . Individuals withsevere mitral stenosis and suitable valve morphologybenefit 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 basicprocedure is relatively unchanged. Pivotal studiesestablished the percutaneous approach to the treat-ment of mitral stenosis using single or double con-ventional valvuloplasty balloons (88), but theself-centering Inoue balloon (Toray, Tokyo, Japan)has superseded these in clinical practice. Subsequenttrials comparing PTMC with surgical approaches usedthe Inoue balloon and technique (89).

The success of PTMC depends to a great extent onthe morphology of the mitral valve. The presence of

subvalvular fusion and calcification reduce thechances of a durable outcome. Several echocardio-graphic scores (90) and more complex multifactorialscores that use a combination of demographic, clin-ical, and echocardiographic variables (91) are used toassess suitability for PTMC. Individuals with mitralstenosis are younger in countries where RHD isendemic and may have a lower prevalence of age-related morphological changes like calcification,making them somewhat more suitable candidates forPTMC. On the contrary, RHD may follow a moreaggressive course in endemic countries, resulting insevere morphological abnormalities including sub-valvular disease. Still, PTMC provides acceptableimmediate and medium-term outcomes (Figure 5) andremains the initial treatment of choice in mostindividuals without unfavorable demographic orclinical features (91).

The main complications associated with PTMC aresevere mitral regurgitation needing urgent surgery(1% to 3%), cardiac tamponade (1% to 2%), systemicembolism (<1%), and death (<1%) (92). A meta-analysis of the small randomized studies comparingPTMC with surgical commissurotomy suggests thatPTMC produces a slightly smaller valve area, a higherrisk of mitral regurgitation, and a nearly 3-fold risk ofreintervention compared with surgery (93). Never-theless, because of increasing familiarity, ease of use


TABLE 5 Product Development Priorities for RHD Prevention and Control

Product Progress Comments

GAS vaccine Phase 2 clinical trials Substantial benefit in reduced antibiotic use,reduced invasive GAS disease

Reformulation of BPG Candidateidentification

Improved rational use of antibiotics,improved acceptability and adherencelikely to lead to better clinical outcomes

Rapid antigendetection tests

On market; need localtesting and trials

Assists in rational use of antibiotics; not beingused in endemic countries

RF diagnostic Academicresearch

Syndromic diagnosis means opportunities toinitiate disease altering secondaryprophylaxis are missed

Handheldechocardiographydevices

On market Affordability and durability of prolonged usein remote settings are the major barriersto use

Point of careINR testing

On market Not being used in endemic countries;production of cheaper alternatives wouldbe an important short-term advance

Alternatives to currentmechanical andbioprosthetic valves

Academicresearch

Lower-cost mechanical prosthesis, inthemselves, would be a critical short-term advance; in the longer term,percutaneously-delivered mechanical ortissue-engineered valves would be morelikely to meet the total need for surgicalcare at reasonable cost

BPG ¼ benzathine penicillin G; GAS ¼ group A beta-hemolytic streptococcus; INR ¼ international normalizedratio; RF ¼ rheumatic fever; RHD ¼ rheumatic heart disease.



1410

of the procedure, improvement in operator experi-ence, and perhaps the lower direct and opportunitycosts compared with surgical treatment, PTMC (usingan Inoue or Inoue-like balloon) remains the treatmentof choice for rheumatic mitral stenosis.

Catheter-based treatment of rheumatic aortic ste-nosis has not been well-studied, perhaps because ofthe rarity of isolated aortic stenosis in RHD and itstendency to manifest later in life when valve calcifi-cation is common (4). There is good rationale forusing balloon dilatation to treat noncalcific rheumaticaortic stenosis. In vitro studies have shown thatballoon dilatation reliably splits the fused commis-sures in a rheumatic aortic valve (94). Balloondilatation has an 86% immediate success rate, withonly 14% of patients needing valve replacement at5-year follow-up (95). Moderate or severe aorticregurgitation occurs in about 14% of patients as animmediate complication. Transcatheter aortic valvereplacement is unlikely to be useful in RHD due to therarity of isolated aortic stenosis and the relativelyyoung age of patients with RHD.

Rheumatic tricuspid stenosis is rare and almostalways occurs in association with mitral valve disease,particularly stenosis. A small case series suggestedthat tricuspid valvuloplasty may be as successful anddurable as PTMC (96). A large-sized Inoue balloon (28to 30 mm) is usually used for dilation. Mitral regurgi-tation is unlikely to be amenable to the transcathetertechniques used for nonrheumatic disease because of

the presence of valve thickening, variable degrees ofcommissural fusion, and subvalvular disease. Trans-catheter treatment of severe tricuspid regurgitationmay be more promising (97).Surg ica l management . Severe, chronic structuralchanges in the valves are the major cause of mor-tality from RHD. Ensuring timely access to defini-tive surgical care is a key aspect of addressing thecurrent disease burden. Unfortunately, many in-dividuals present too late to benefit from surgery,so early detection efforts (98), accompanied bypriority-based follow-up (99), are required to ensurethat surgical programs have maximal impact.Although valve replacement provides good earlyresults, long-term outcomes are poorer as the cu-mulative risk of valve-related complications in-creases (100). Hence, valve-conserving restorativeoperations are now the preferred first-line approach.One unanswered question is the timing of surgeryfor regurgitant lesions; most recommendations arebased on extrapolation from nonrheumatic valvedisease (56).

RHD usually affects all components of the mitralvalve (Figure 6), and these should be systematicallydealt with during surgery. Commissural fusion isdealt with by sharp dissection extending into thefused papillary muscles while preserving chordalattachment and, if necessary, creating intercostalspaces and/or inserting artificial chords. The anteriorand posterior leaflets are then mobilized using aprocess of decalcification and peeling to enhancemobility, increasing surface area and extent of cuspcoaptation (101). These techniques are possiblebecause the disease process spares the elastica andpart of the fibrosa. Changes in mitral annular shape,size, and dynamism can be characterized by modernimaging techniques and need to be addressed duringoperative repair. Surgical techniques are stillevolving, and the efficacy of current practices needsto be validated in studies involving larger numbers ofparticipants followed for sufficiently long periods,specifically focusing on ventricular function andquality of life, the latter of which is often significantlyimpaired (102).

Dysfunction of the tricuspid valve can be second-ary to mitral valve disease or be affected by therheumatogenic process itself. Most changes,including annular dilation and cusp fusion, can beaddressed through repair techniques. Failing to repairthe tricuspid valve when affected can result inchronic disability and possibly death (103). Aorticvalve disease is less common than mitral valve dis-ease, but has a more serious effect on left ventricularfunction, quality of life, and overall prognosis (104).

FIGURE 8 Rapid Scale-Up of Specialized Cardiac Surgical Services in a

Middle-Income Country

800

700

600

500

400

300

200

100

0201420132012

Year201120102009 2015

900

Num

ber o

f Pat

ient

s

Mitral Valve RepairMitral Valve ReplacementPercutaneous 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).


1411

Unlike the mitral and tricuspid valves, aortic pathol-ogy is infrequently suitable for valve-conserving op-erations. Additionally, currently available valvesubstitutes—with the exception of the Ross opera-tion—are not suitable for use in the relatively youngpopulation with RHD (105).

An emerging area of surgical research is in tissueengineering of patches or entire valves (106).Although not currently in use, such technologies willhopefully will be available in the near future andcould significantly increase access to surgery and at alower cost. Tissue-engineered products could also bedelivered through percutaneous techniques, makingthem even more attractive in settings where access toopen procedures is limited.

An important consideration for surgical programsin limited-resource settings is ensuring quality.Increasingly robust standards for post-operativeoutcome recording have been developed for congen-ital heart disease surgery for children in these set-tings (107). Because patient demographics andproviders overlap significantly, these practices couldeasily be extended to individuals requiring surgeryfor RHD. More research is needed on ensuring qualityof post-surgical care, including anticoagulation, forthose living in remote or deprived areas; some haveeven argued that younger individuals with RHDshould be offered tissue valves (108).

A summary of recommendations for practice andresearch on interventional and surgical care is pro-vided in Online Appendix Panel 6.

WHAT IS NEEDED TO ERADICATE

RHD WORLDWIDE?

THE GLOBAL AGENDA. RHD pol icy targets andstatements . In 2013, the WHF called for a 25%reduction in RHD mortality among individualsaged <25 years by the year 2025 (109). More recently,the United Nations Sustainable Development Goal3 (SDG3) proposed a one-third reduction in prematuredeaths from noncommunicable diseases by 2030(110). Assuming that trends in mortality over the past15 years hold, many endemic countries are on track toachieve either 1 or both of the targets (Figure 7).Notable high-performing countries include China,Bangladesh, and Rwanda. A number of PacificIsland nations are struggling to meet these targets(Online Appendix).

Since the mid-2000s, several policy statementshave been issued on RHD. Notable recent statementsinclude the Addis Ababa communique (2015) and theWHF roadmap on RHD (2017). A resolution on RHDwas adopted at the 71st World Health Assembly

(Online Appendix Panel 7) (6). The resolution man-dates Member States to take action on RF/RHD andresources WHO to provide support to country pro-grams. Several tools have recently been publishedthat can assist in technical support of programs(49,111). Drawing on these tools, we propose a set ofindicators for countries to use in tracking imple-mentation of the resolution (Table 4).

In ternat iona l co l lect ive act ion on RHD. Ensuringglobal leadership in RHD has been challenging. RHDhas been neglected by policymakers and civil societybecause it does not sit in a single department (e.g., atWHO) nor is it amenable to single-intervention stra-tegies. Advocacy and engagement are needed to buildrelationships with other disciplines—such as maternaland child health—that have larger, more visible con-stituencies and audiences with decision-makers.Additionally, people living with RHD are oftensocially vulnerable and have few opportunities toshare their lived experiences. The Listen to My Heartprogram is one promising model of patient engage-ment and empowerment (112).

This review has provided recommendations for anumber of global public goods, including scientificresearch, that warrant investment. Greater public andprivate funding is needed to support laboratory,






1412

clinical/translational, and policy/implementationresearch to address the basic and applied scientificquestions 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 onpharyngitis management, including rational use ofantibiotics, are needed in all countries. Better supplyand more consistent use of BPG as a first-line anti-biotic for GAS, and eventually the roll-out of a GASvaccine, will probably be the most effective long-termstrategies for curbing antimicrobial resistance riskfrom pharyngitis.

THE NATIONAL AGENDA. Disease control programs.The notion that RF can be eliminated is supported bystudies 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 alsobeen favorable, and the WHO recommends combinedprimary and secondary prevention efforts deliveredin community settings (43). These programs canachieve the vast majority of their impact within abouta decade or so (42).

A number of unknowns remain. Most countriesthat implemented RF programs were relativelyeconomically advanced, limiting their applicabilityto current RHD-endemic countries. No programused an active case-finding approach, which couldin 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 not beenestablished. Cardiac surgery was available in someof the countries mentioned previously, but itremains largely unavailable today in mostRHD-endemic countries.Integrat ion of RHD programs into countryhea l th systems . There is currently little appetiteamong health planners for developing targetedprograms, especially for chronic noncommunicablediseases (114). Yet, historical case studies of RF/RHDcontrol frequently used vertical approaches. Conse-quently, there is little evidence upon which to maketechnical recommendations for integrating RHD-related activities into existing health systems.Across several health system “building blocks,” dis-cussed in the following text, we find important op-portunities for integration of RF/RHD. Theoverarching approach would be “diagonal,”

leveraging the strengths of RHD-specific activities tobuild overall health system capacity (114).

Workforce challenges in RHD care parallel theworkforce challenges in other health areas (115). Inthe short-term, strengthening primary and secondaryprevention should be prioritized, for example, usingnurse-led primary care (including school-based plat-forms) and community health workers, althoughfurther research is needed on these models (44,116). Apressing issue for most countries will be to createincentives to train and retain cardiovascular special-ists. These providers could care for a wide range ofconditions, so while the initial rationale might be toaddress RHD and support the global resolution,increasing the cardiovascular workforce will havebroader benefits. Cardiac surgery deserves specialemphasis given its importance in RHD. The experi-ence of the Aswan Heart Centre has demonstratedthat, 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 registershave been recommended since the 1950s, but fewRHD-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 PanAfrican Society of Cardiology eRegister (117). How tointegrate registers and eRegisters into local healthinformation systems is less clear and warrants furtherconsideration.

Disease notification and surveillance systems pro-vide opportunities for RHD integration. There is goodrationale for classifying RF as a notifiable conditionbecause of its outbreak potential, although weak-nesses in RF notification systems have been described(99). Improving RF notification efforts and publichealth action could have spillover benefits andcontribute to global health security. (RF is one of thefew conditions that involves clinician-based ratherthan laboratory-based notification. Notification foremerging pandemics would need to follow anonlaboratory-based pathway, so strengthening sys-tems for syndromic reporting would have benefitsbeyond RF/RHD.) Last, improving the quality of deathcertification for RHD (33), although important forobtaining better mortality data, could also be inte-grated into efforts to improve the overall quality ofvital registration.

A final opportunity for RHD integration is healthfinancing. The vast majority of health care in manylow- and middle-income countries is financed out-of-


1413

pocket, especially for noncommunicable diseases likeRHD. Consequently, poor households tend to forgohealth care or borrow money or sell assets to pay forcare, increasing the so-called “poverty trap” (118).Charitable programs exist for RHD surgery in somecountries, but they are neither sufficient to meet thepopulations’ needs nor fiscally sustainable (119).Increasingly, surgical skills and knowledge will needto be transferred to local health systems to sustain-ably meet the large unmet need for cardiac surgery,and governments will need to increase budgets foradvanced cardiovascular services.

The goal of universal health coverage, which allcountries have endorsed as part of United NationsSustainable Development Goal 3, holds promise forimproving access to and the affordability of RHD-related care. The challenge is mobilizing sufficientdomestic resources to finance (relatively inexpensive)prevention services as well as costly surgical carewithout displacing other health priorities. Integratedfinancing models are needed. Over time, the scale andscope of covered services could progressively expand.Onemodeling study suggested that universal coverageof primary prevention would be the first priorityfor most African countries, followed by secondaryprevention, then referral and tertiary services (120).

SUMMARY AND CONCLUSIONS

This Scientific Expert Panel has summarized recentadvances in the science and practice of RHD, fromlaboratory science to population health. We identify anumber of pressing issues requiring immediate actionand propose a research agenda for the coming years.But, why invest in RHD research and care when thereare many other important health concerns?

RHD is a disease of poverty that affects chil-dren and working-age adults. The global economicimpact of early death from RHD was about $65billion 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 bothlead to rapid progress on RF/RHD and strengthenhealth systems to address other noncommunicablediseases.

While scientific questions remain, the evidencebase is sound for tackling RHD now. Across a widerange of global health interventions, primary andsecondary prevention of RHD stand out as providingexcellent value for money (122). Challenges in scale-up of advanced care for RHD are nuanced andcomplex, but it is evident from historical trends thatall countries will eventually require advanced car-diovascular services—not just for RHD—and muststart training the next generation of the cardiovas-cular workforce, putting in place incentives toensure that these individuals work where needs aregreatest.

Complementing the national agenda is an agendafor the global community. International agencies,civil society, and donors will play a critical role inthe elimination of RHD. Support is needed forresearch, advocacy, and implementation. Armedwith 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 healthagenda will ensure that the future generations growup free from the scourge of this eminently pre-ventable disease.

ACKNOWLEDGMENTS This paper is dedicated to thememory of Professor Bongani Mayosi, a pre-eminentscientist and visionary who inspired us all to worktoward the “eradication of rheumatic fever in ourlifetime.”

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: [email protected]. Twitter: @davidawatkins,@UW.

RE F E RENCE S

1. Carapetis JR, Zuhlke LJ. Global research prior-ities in rheumatic fever and rheumatic heart dis-ease. Ann Pediatr Cardiol 2011;4:4–12.

2. Watkins DA, Johnson CO, Colquhoun SM, et al.Global, regional, and national burden of rheumaticheart disease, 1990–2015. N Engl J Med 2017;377:713–22.

3. Marijon E, Ou P, Celermajer DS, et al. Prevalenceof rheumatic heart disease detected by echocar-diographic screening. N Engl J Med 2007;357:470–6.

4. Zuhlke L, Engel ME, Karthikeyan G, et al. Char-acteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease:the Global Rheumatic Heart Disease Registry (theREMEDY study). Eur Heart J 2015;36:1115–22a.

5. RHD Action Alliance. RHD Action: united to endrheumatic heart disease. Available at: http://rhdaction.org. Accessed July 24, 2018.

6. WHO. Executive Board, 141st Session: Resolu-tions and Decisions, Annexes, Summary Records.Geneva: World Health Organization, 2017.

7. Carapetis JR, Beaton A, Cunningham MW, et al.Acute rheumatic fever and rheumatic heart dis-ease. Nature Reviews Disease Primers 2016;2:15084.

8. Cunningham MW. Post streptococcal autoim-mune sequelae: rheumatic fever and beyond. In:Ferretti JJ, Stevens DL, Fischetti VA, editors.Streptococcus Pyogenes: Basic Biology to ClinicalManifestations. Oklahoma City, OK: University ofOklahoma Health Sciences Center, 2016:893–929.

mailto:[email protected]

https://twitter.com/davidawatkins

https://twitter.com/UW

http://refhub.elsevier.com/S0735-1097(18)35529-3/sref1
















http://rhdaction.org

http://rhdaction.org

















1414

9. Tandon R, Sharma M, Chandrashekhar Y,Kotb M, Yacoub MH, Narula J. Revisiting thepathogenesis of rheumatic fever and carditis. NatRev Cardiol 2013;10:171–7.

10. Martin WJ, Steer AC, Smeesters PR, et al. Post-infectious group A streptococcal autoimmunesyndromes and the heart. Autoimmun Rev 2015;14:710–25.

11. Carapetis JR, Currie BJ, Mathews JD. Cumula-tive incidence of rheumatic fever in an endemicregion: a guide to the susceptibility of the popu-lation? Epidemiol Infect 2000;124:239–44.

12. Bryant PA, Robins-Browne R, Carapetis JR,Curtis N. Some of the people, some of the time:susceptibility to acute rheumatic fever. Circulation2009;119:742–53.

13. Engel ME, Stander R, Vogel J, Adeyemo AA,Mayosi BM. Genetic susceptibility to acute rheu-matic fever: a systematic review and meta-analysisof twin studies. PloS One 2011;6:e25326.

14. Guilherme L, Kohler KF, Postol E, Kalil J.Genes, autoimmunity and pathogenesis of rheu-matic heart disease. Ann Pediatr Cardiol 2011;4:13–21.

15. Erdem G, Seifried SE. No evidence of humanleukocyte antigen gene association with rheumaticfever among children in Samoa. J Pediatric InfectDis Soc 2015;4:71–3.

16. Tian C, Hromatka BS, Kiefer AK, et al. Genome-wide association and HLA region fine-mappingstudies identify susceptibility loci for multiplecommon infections. Nat Commun 2017;8:599.

17. Parks T, Mirabel MM, Kado J, et al. Associationbetween a common immunoglobulin heavy chainallele and rheumatic heart disease risk in Oceania.Nat Commun 2017;8:14946.

18. Gray LA, D’Antoine HA, Tong SYC, et al.Genome-wide analysis of genetic risk factors forrheumatic heart disease in aboriginal Australiansprovides support for pathogenic molecularmimicry. J Infect Dis 2017;216:1460–70.

19. Steer AC, Law I, Matatolu L, Beall BW,Carapetis JR. Global emm type distribution ofgroup A streptococci: systematic review and im-plications for vaccine development. Lancet InfectDis 2009;9:611–6.

20. O’Sullivan L, Moreland NJ, Webb RH, Upton A,Wilson NJ. Acute rheumatic fever after group Astreptococcus pyoderma and group G strepto-coccus pharyngitis. Pediatr Infect Dis J 2017;36:692–4.

21. Parks T, Smeesters PR, Steer AC. Streptococcalskin infection and rheumatic heart disease. CurrOpin Infect Dis 2012;25:145–53.

22. Williamson DA, Smeesters PR, Steer AC, et al.M-protein analysis of streptococcus pyogenesisolates associated with acute rheumatic fever inNew Zealand. J Clin Microbiol 2015;53:3618–20.

23. Gewitz MH, Baltimore RS, Tani LY, et al.Revision of the Jones Criteria for the diagnosis ofacute rheumatic fever in the era of Dopplerechocardiography: a scientific statement from theAmerican Heart Association. Circulation 2015;131:1806–18.

24. Remenyi B, Wilson N, Steer A, et al. WorldHeart Federation criteria for echocardiographic

diagnosis of rheumatic heart disease—an evidence-based guideline. Nature reviews Cardiology 2012;9:297–309.

25. Beaton A, Aliku T, Dewyer A, et al. Latentrheumatic heart disease: identifying the childrenat highest risk of unfavorable outcome. Circulation2017;136:2233–44.

26. Engelman D, Mataika RL, Ah Kee M, et al.Clinical outcomes for young people withscreening-detected and clinically-diagnosedrheumatic heart disease in Fiji. Int J Cardiol 2017;240:422–7.

27. Karthikeyan G. Measuring and reporting dis-ease progression in subclinical rheumatic heartdisease. Heart Asia 2016;8:74–5.

28. Roberts K, Maguire G, Brown A, et al. Echo-cardiographic screening for rheumatic heart dis-ease in high and low risk Australian children.Circulation 2014;129:1953–61.

29. Clark BC, Krishnan A, McCarter R, Scheel J,Sable C, Beaton A. Using a low-risk population toestimate the specificity of the World HeartFederation Criteria for the diagnosis of rheumaticheart disease. J Am Soc Echocardiogr 2016;29:253–8.

30. Gemechu T, Mahmoud H, Parry EH, Phillips DI,Yacoub MH. Community-based prevalence studyof rheumatic heart disease in rural Ethiopia. Eur JPrev Cardiol 2017;24:717–23.

31. Nascimento BR, Sable C, Nunes MCP, et al.Comparison between different strategies of rheu-matic heart disease echocardiographic screening inBrazil: data from the PROVAR (Rheumatic ValveDisease Screening Program) Study. Journal of theAmerican Heart Association 2018;7:e008039.

32. Zuhlke L, Karthikeyan G, Engel ME, et al.Clinical outcomes in 3343 children and adultswith rheumatic heart disease from 14 low- andmiddle-income countries: two-year follow-up ofthe Global Rheumatic Heart Disease Registry(the REMEDY Study). Circulation 2016;134:1456–66.

33. Davies SB, Hofer A, Reeve C. Mortality attrib-utable to rheumatic heart disease in the Kimber-ley: a data linkage approach. Intern Med J 2014;44:1074–80.

34. Gerber MA, Baltimore RS, Eaton CB, et al.Prevention of rheumatic fever and diagnosis andtreatment of acute Streptococcal pharyngitis.Circulation 2009;119:1541–51.

35. Chandnani HK, Jain R, Patamasucon P. Group CStreptococcus causing rheumatic heart disease in achild. J Emerg Med 2015;49:12–4.

36. Whitehall J, Kuzulugil D, Sheldrick K, Wood A.Burden of paediatric pyoderma and scabies inNorth West Queensland. J Paediatr Child Health2013;49:141–3.

37. Zuhlke LJ, Karthikeyan G. Primary preventionfor rheumatic fever: progress, obstacles, andopportunities. Glob Heart 2013;8:221–6.

38. Robertson KA, Volmink JA, Mayosi BM. Anti-biotics for the primary prevention of acute rheu-matic fever: a meta-analysis. BMC CardiovascDisord 2005;5:11.

39. Irlam J, Mayosi BM, Engel M, Gaziano TA.Primary prevention of acute rheumatic fever and

rheumatic heart disease with penicillin in SouthAfrican children with pharyngitis: a cost-effectiveness analysis. Circ Cardiovasc Qual Out-comes 2013;6:343–51.

40. Rimoin AW, Walker CL, Hamza HS, et al. Theutility of rapid antigen detection testing for thediagnosis of streptococcal pharyngitis in low-resource settings. Int J Infect Dis 2010;14:e1048–53.

41. Bergmark R, Bergmark B, Blander J, Fataki M,Janabi M. Burden of disease and barriers to thediagnosis and treatment of group a beta-hemolyticstreptococcal pharyngitis for the prevention ofrheumatic heart disease in Dar Es Salaam, Tanzania.Pediatr Infect Dis J 2010;29:1135–7.

42. Nordet P, Lopez R, Duenas A, Sarmiento L.Prevention and control of rheumatic fever andrheumatic heart disease: the Cuban experience(1986-1996-2002). Cardiovasc J Afr 2008;19:135–40.

43. WHO. Rheumatic Fever and Rheumatic HeartDisease. Technical Report Series No. 923. Geneva:World Health Organization, 2004.

44. Spinetto H, Lennon D, Horsburgh M. Rheu-matic fever recurrence prevention: a nurse-ledprogramme of 28-day penicillin in an area ofhigh endemnicity. J Paediatr Child Health 2011;47:228–34.

45. Manyemba J, Mayosi BM. Penicillin for sec-ondary prevention of rheumatic fever. CochraneDatabase Syst Rev 2002:CD002227. AccessedApril 5, 2010.

46. Mota CC, Meira ZM, Graciano RN, Graciano FF,Araujo FD. Rheumatic fever prevention program:long-term evolution and outcomes. Front Pediatr2014;2:141.

47. Okello E, Longenecker CT, Beaton A,Kamya MR, Lwabi P. Rheumatic heart disease inUganda: predictors of morbidity and mortality oneyear after presentation. BMC Cardiovasc Disord2017;17:20.

48. Kevat PM, Reeves BM, Ruben AR,Gunnarsson R. Adherence to secondary prophy-laxis for acute rheumatic fever and rheumaticheart disease: a systematic review. Curr CardiolRev 2017 Jan 16 [E-pub ahead of print].

49. Wyber R, Johnson T, Perkins S, Watkins D,Mwangi J, La Vincente S. Tools for ImplementingRheumatic Heart Disease Control Progammes(TIPs) Handbook. 2nd edition. Geneva: RHDAction, 2018.

50. RHD Action. Global Status of BPG report.Perth, Australia: RHD Action, 2017.

51. Kaya A, Erkocoglu M, Senkon OG, et al.Confirmed penicillin allergy among patientsreceiving benzathine penicillin prophylaxis foracute rheumatic fever. Allergol Immunopathol(Madr) 2014;42:289–92.

52. Taubert K, Marko S. Access to essential medi-cines: illuminating disparities in the global supplyof benzathine penicillin G in the context of rheu-matic fever/rheumatic heart disease prevention(abstr). J Am Coll Cardiol 2013;61 Suppl 10:E2004.

53. Wyber R, Taubert K, Marko S, Kaplan EL.Benzathine penicillin G for the management of








































































































































































































1415

RHD: concerns about quality and access, and op-portunities for intervention and improvement.Glob Heart 2013;8:227–34.

54. Remond M, Atkinson D, White A, et al. Areminor echocardiographic changes associated withan increased risk of acute rheumatic fever or pro-gression to rheumatic heart disease? Int J Cardiol2015;198:117–22.

55. Gillinov AM, Mihaljevic T, Blackstone EH, et al.Should patients with severe degenerative mitralregurgitation delay surgery until symptomsdevelop? Ann Thorac Surg 2010;90:481–8.

56. Connolly HM, Oh JK, Orszulak TA, et al. Aorticvalve replacement for aortic stenosis with severeleft ventricular dysfunction. Prognostic indicators.Circulation 1997;95:2395–400.

57. Nishimura RA, Otto CM, Bonow RO, et al. 2017AHA/ACC focused update of the 2014 AHA/ACCGuideline for the Management of Patients WithValvular Heart Disease: a report of the AmericanCollege of Cardiology/American Heart AssociationTask Force on Clinical Practice Guidelines. J AmColl Cardiol 2017;70:252–89.

58. Alan S, Ulgen MS, Ozdemir K, Keles T,Toprak N. Reliability and efficacy of metoprololand diltiazem in patients having mild to moderatemitral stenosis with sinus rhythm. Angiology2002;53:575–81.

59. Agrawal V, Kumar N, Lohiya B, et al. Meto-prolol vs ivabradine in patients with mitral ste-nosis in sinus rhythm. Int J Cardiol 2016;221:562–6.

60. Chandrashekhar Y, Westaby S, Narula J. Mitralstenosis. Lancet 2009;374:1271–83.

61. Hu CL, Jiang H, Tang QZ, et al. Comparison ofrate control and rhythm control in patients withatrial fibrillation after percutaneous mitral balloonvalvotomy: a randomised controlled study. Heart2006;92:1096–101.

62. Tamai J, Yoshioka T, Yasuda S, et al. Increasein peak oxygen uptake by restoration of atrialcontraction in patients after percutaneous trans-venous mitral commissurotomy. The J Heart ValveDis 1993;2:623–8.

63. Vora A, Karnad D, Goyal V, et al. Control ofrate versus rhythm in rheumatic atrial fibrillation: arandomized study. Indian Heart J 2004;56:110–6.

64. Nair M, Shah P, Batra R, et al. Chronic atrialfibrillation in patients with rheumatic heart dis-ease: mapping and radiofrequency ablation offlutter circuits seen at initiation after cardiover-sion. Circulation 2001;104:802–9.

65. Liu X, Tan HW, Wang XH, et al. Efficacy ofcatheter ablation and surgical CryoMaze proced-ure in patients with long-lasting persistent atrialfibrillation and rheumatic heart disease: a ran-domized trial. Eur Heart J 2010;31:2633–41.

66. Oldgren J, Healey JS, Ezekowitz M, et al.Variations in cause and management of atrialfibrillation in a prospective registry of 15,400emergency department patients in 46 countries:the RE-LY Atrial Fibrillation Registry. Circulation2014;129:1568–76.

67. Watkins DA, Sebitloane M, Engel ME,Mayosi BM. The burden of antenatal heart disease

in South Africa: a systematic review. BMC Car-diovasc Disord 2012;12:23.

68. Anthony J, Osman A, Sani MU. Valvular heartdisease in pregnancy. Cardiovasc J Afr 2016;27:111–8.

69. Martins LC, Freire CM, Capurucu CA, NunesMdo C, Rezende CA. Risk prediction of cardiovas-cular complications in pregnant women with heartdisease. Arq Bras Cardiol 2016;106:289–96.

70. Diao M, Kane A, Ndiaye MB, et al. Pregnancy inwomen with heart disease in sub-Saharan Africa.Arch Cardiovasc Dis 2011;104:370–4.

71. Otto H, Saether SG, Banteyrga L, Haugen BO,Skjaerpe T. High prevalence of subclinical rheu-matic heart disease in pregnant women in adeveloping country: an echocardiographic study.Echocardiography 2011;28:1049–53.

72. Zuhlke L, Acquah L. Pre-conception counsel-ling for key cardiovascular conditions in Africa:optimising pregnancy outcomes. Cardiovasc J Afr2016;27:79–83.

73. Vinayakumar D, Vinod GV, Madhavan S,Krishnan MN. Maternal and fetal outcomes inpregnant women undergoing balloon mitral val-votomy for rheumatic mitral stenosis. Ind Heart J2016;68:780–2.

74. Arioli F, Ammirati E. Mitral prosthetic valvethrombosis and cardiogenic shock in a limitedresource setting in sub-Saharan Africa: a tailoredtreatment approach. Int J Cardiol 2015;178:65–6.

75. Basu S, Aggarwal P, Kakani N, Kumar A. Low-dose maternal warfarin intake resulting in fetalwarfarin syndrome: in search for a safe anticoag-ulant regimen during pregnancy. Birth Defects ResA Clin Mol Teratol 2016;106:142–7.

76. D’Souza R, Ostro J, Shah PS, et al. Anti-coagulation for pregnant women with mechanicalheart valves: a systematic review and meta-anal-ysis. Eur Heart J 2017;38:1509–16.

77. Xu Z, Fan J, Luo X, et al. Anticoagulationregimens during pregnancy in patients with me-chanical heart valves: a systematic review andmeta-analysis. Can J Cardiol 2016;32:1248.e1–9.

78. Sliwa K, Libhaber E, Elliott C, et al. Spectrumof cardiac disease in maternity in a low-resourcecohort in South Africa. Heart 2014;100:1967–74.

79. French KA, Poppas A. Rheumatic heart diseasein pregnancy: global challenges and clear oppor-tunities. Circulation 2018;137:817–9.

80. van Hagen IM, Thorne SA, Taha N, et al.Pregnancy outcomes in women with rheumaticmitral valve disease: results from the Registry ofPregnancy and Cardiac Disease. Circulation 2018;137:806–16.

81. Rezk M, Elkilani O, Shaheen A, Gamal A,Badr H. Maternal hemodynamic changes and pre-dictors of poor obstetric outcome in women withrheumatic heart disease: a five-year observationalstudy. J Matern Fetal Neonatal Med 2017:1–6.

82. Xu H, Cai S, Dai H. Characteristics of infectiveendocarditis in a tertiary hospital in east China.PloS One 2016;11:e0166764.

83. Kucukates E, Gultekin N, Bagdatli Y. Cases ofactive infective endocarditis in a university

hospital during a 10-year period. J Pak Med Assoc2013;63:1163–7.

84. Kebed KY, Bishu K, Al Adham RI, et al. Preg-nancy and postpartum infective endocarditis: asystematic review. Mayo Clin Proc 2014;89:1143–52.

85. Elbey MA, Akdag S, Kalkan ME, et al.A multicenter study on experience of 13 tertiaryhospitals in Turkey in patients with infectiveendocarditis. Anatol J Cardiol 2013;13:523–7.

86. Oyonarte M, Montagna R, Braun S, et al.[Clinical characteristics, complications and mor-tality in 506 patients with infective endocarditisand determinants of survival rate at 10 years].Revista medica de Chile 2012;140:1517–28.

87. Fernandez Guerrero ML, Alvarez B,Manzarbeitia F, Renedo G. Infective endocarditisat autopsy: a review of pathologic manifesta-tions and clinical correlates. Medicine 2012;91:152–64.

88. Shrivastava S, Mathur A, Dev V, Saxena A,Venugopal P, SampathKumar A. Comparison ofimmediate hemodynamic response to closedmitral commissurotomy, single-balloon, anddouble-balloon mitral valvuloplasty in rheumaticmitral stenosis. J Thorac Cardiovasc Surg 1992;104:1264–7.

89. Reyes VP, Raju BS, Wynne J, et al. Percuta-neous balloon valvuloplasty compared with opensurgical commissurotomy for mitral stenosis.N Engl J Med 1994;331:961–7.

90. Wilkins GT, Weyman AE, Abascal VM,Block PC, Palacios IF. Percutaneous balloon dila-tation of the mitral valve: an analysis of echocar-diographic variables related to outcome and themechanism of dilatation. Br Heart J 1988;60:299–308.

91. Palacios IF, Sanchez PL, Harrell LC,Weyman AE, Block PC. Which patients benefitfrom percutaneous mitral balloon valvuloplasty?Prevalvuloplasty and postvalvuloplasty variablesthat predict long-term outcome. Circulation 2002;105:1465–71.

92. Palacios IF, Arzamendi D. Percutaneous mitralballoon valvuloplasty for patients with rheumaticmitral stenosis. Interv Cardiol Clin 2012;1:45–61.

93. Hu X, Zhao Q. Systematic comparison of theeffectiveness of percutaneous mitral balloon val-votomy with surgical mitral commissurotomy.Swiss Med Wkly 2011;141:w13180.

94. Ribeiro PA, Al Zaibag M, Rajendran V. Doubleballoon aortic valvotomy for rheumatic aorticstenosis; in vivo studies. Eur Heart J 1989;10:417–22.

95. Pillai AA, Ramasamy C, Saktheeshwaran M,Selvaraj R, Satheesh S, Jayaraman B. Balloon val-vuloplasty in rheumatic aortic valve stenosis: im-mediate and long-term results. Cardiovasc IntervTher 2015;30:45–50.

96. Sancaktar O, Kumbasar SD, Semiz E,Yalcinkaya S. Late results of combined percuta-neous balloon valvuloplasty of mitral and tricuspidvalves. Cathet Cardiovasc Diagn 1998;45:246–50.

97. Van Praet KM, Stamm C, Starck CT, et al. Anoverview of surgical treatment modalities andemerging transcatheter interventions in the






































































































































































































1416

management of tricuspid valve regurgitation.Expert Rev Cardiovasc Ther 2018;16:75–89.

98. Watkins D, Zuhlke L, Engel M, et al. Seven keyactions to eradicate rheumatic heart disease inAfrica: the Addis Ababa communique. Cardiovasc JAfr 2016;27:1–5.

99. Wyber R. Rheumatic heart disease: tools forimplementing programmes. Glob Heart 2015;10:79–80.

100. Antunes MJ. Challenges in rheumaticvalvular disease: surgical strategies for mitralvalve preservation. Glob Cardiol Sci Pract 2015;2015:9.

101. Chotivatanapong T, Lerdsomboon P,Sungkahapong V. Complex surgical repair ofrheumatic mitral stenosis. Ann Cardiothorac Surg2015;4:480–2.

102. Thomson Mangnall LJ, Sibbritt DW, Fry M,Windus M, Gallagher RD. Health-related quality oflife of patients after mechanical valve replacementsurgery for rheumatic heart disease in a devel-oping country. Heart Asia 2014;6:172–8.

103. Bernal JM, Ponton A, Diaz B, et al. Surgery forrheumatic tricuspid valve disease: a 30-yearexperience. J Thorac Cardiovasc Surg 2008;136:476–81.

104. RemenyiB, ElGuindyA, SmithSCJr., YacoubM,Holmes DR Jr. Valvular aspects of rheumatic heartdisease. Lancet 2016;387:1335–46.

105. Sampath Kumar A, Talwar S, Saxena A,Singh R. Ross procedure in rheumatic aortic valvedisease. Eur J Cardiothorac Surg 2006;29:156–61.

106. Yacoub MH. In search of living valve sub-stitutes. J Am Coll Cardiol 2015;66:889–91.

107. Hickey PA, Connor JA, Cherian KM, et al. In-ternational quality improvement initiatives. Car-diol Young 2017;27:S61–8.

108. Choudhary SK, Talwar S, Airan B. Choice ofprosthetic heart valve in a developing country.Heart Asia 2016;8:65–72.

109. Remenyi B, Carapetis J, Wyber R, Taubert K,Mayosi BM, for the World Heart Federation. Posi-tion statement of the World Heart Federation onthe prevention and control of rheumatic heartdisease. Nature Rev Cardiol 2013;10:284–92.

110. United Nations. Sustainable DevelopmentGoals: 17 Goals to Transform Our World. Goal 3:Ensure Healthy Lives and Promote Well-Being ForAll at All Ages. New York: United Nations, 2016.

111. Zuhlke LJ, Watkins DA, Perkins S, et al.A comprehensive needs assessment tool forplanning RHD control programs in limited resourcesettings. Glob Heart 2017;12:25–31.

112. Zuhlke L, Perkins S, Cembi S. Rheumatic heartdisease patient event: Cape Town hosts 4thAnnual Listen to My Heart Rheumatic Heart Dis-ease for patients at the South African Heart As-sociation meeting in 2017. Eur Heart J 2018;39:1669–71.

113. Strasser T, Dondog N, Kholy AE, et al. thecommunity control of rheumatic-fever and rheu-matic heart-disease–report of a WHO internationalcooperative project. Bull World Health Org 1981;59:285–94.

114. Knaul FM, Bhadelia A, Atun R, Frenk J.Achieving effective universal health coverage anddiagonal approaches to care for chronic illnesses.Health Aff 2015;34:1514–22.

115. Vedanthan R, Fuster V. Urgent need forhuman resources to promote global cardiovascularhealth. Nature Rev Cardiol 2011;8:114–7.

116. Lennon D, Stewart J, Farrell E, Palmer A,Mason H. School-based prevention of acuterheumatic fever: a group randomized trial in NewZealand. Pediatr Infect Dis J 2009;28:787–94.

117. van Dam J, Musuku J, Zuhlke LJ, et al. Anopen-access, mobile compatible, electronic pa-tient register for rheumatic heart disease(’eRegister’) based on the World Heart Federa-tion’s framework for patient registers. CardiovascJ Afr 2015;26:227–33.

118. McIntyre D, Thiede M, Dahlgren G,Whitehead M. What are the economic conse-quences for households of illness and of paying forhealth care in low- and middle-income countrycontexts? Soc Sci Med 2006;62:858–65.

119. Nguyen N, Jacobs JP, Dearani JA, et al. Sur-vey of nongovernmental organizations providingpediatric cardiovascular care in low- and middle-income countries. World J Pediatr Congenit HeartSurg 2014;5:248–55.

120. Watkins D, Lubinga SJ, Mayosi B,Babigumira JB. A cost-effectiveness tool to guidethe prioritization of interventions for rheumaticfever and rheumatic heart disease control in afri-can nations. PLoS Negl Trop Dis 2016;10:e0004860.

121. Watkins DA, Chang AY. The economic impactof rheumatic heart disease in low- and middle-income countries. DCP3 working paper #19. 2017.Available at: http://dcp-3.org/sites/default/files/resources/19.%20RHD%20Watkins%20%26%20Chang.pdf. Accessed July 24, 2018.

122. Prabhakaran D, Anand S, Watkins D, et al.Cardiovascular, respiratory, and related disorders:key messages from Disease Control Priorities, 3rdedition. Lancet 2018;391:1224–36.

KEY WORDS cardiac surgery,echocardiography, health services,pathogenesis, prevention, rheumatic heartdisease

APPENDIX For supplemental data, pleasesee the online version of this paper.

Go to http://www.acc.org/jacc-journals-cme to takethe CME/MOC/ECME quizfor this article.


































































































http://dcp-3.org/sites/default/files/resources/19.%20RHD%20Watkins%20%26%20Chang.pdf









Documents

Rheumatic Heart Disease Worldwide · RF = rheumatic fever RHD = rheumatic heart disease WHF = World Heart Federation WHO = World Health Organization JACCVOL.72,NO.12,2018 Watkins