REVIEW

CURRENT
OPINION Update on rheumatic heart disease
Bobby Yanagawa a, Jagdish Butany b, and Subodh Verma a

Purpose of review
The purpose is to provide a broad overview of the current state of knowledge of pathogenesis, diagnosis,
and management of rheumatic heart disease (RHD).
Recent findings
Studies on pathogenesis of RHD have focused on autoimmunity because of molecular mimicry between the
streptococcal M antigen a-helical coiled-coil structure and sarcomeric proteins such as myosin and
tropomyosin. More recently, nonsarcomeric autoantigens, endothelial injury and the innate immune system
have been proposed to play key roles in the pathogenesis of RHD. In the 2015 revised Jones Criteria, the
importance of echocardiography and subclinical carditis in the diagnosis of acute rheumatic fever is
highlighted. Experimental studies with targeted anti-inflammatory therapeutics have been largely
unsuccessful and the only established treatment is still lifelong antibiotics. Efforts to improve patient selection
and outcomes with percutaneous mitral balloon valvuloplasty are ongoing. With regard to surgical
management, several groups have demonstrated excellent operative and midterm outcomes from valve
repair as opposed to valve replacement.
Summary
There are still many unanswered questions regarding RHD pathogenesis. The only accepted medical
treatment is still long-term antibiotic therapy, whereas advances in mitral repair techniques have led to
successful durable repairs being performed in high-volume, expert centers.
Keywords
autoimmune, mitral stenosis, rheumatic heart disease

INTRODUCTION cardiovascular mortality and morbidity among you-

Acute rheumatic fever (ARF) is the sequela of
untreated oropharyngeal infection by group A
hemolytic Streptococcus. The most common mani-
&
festations are carditis, arthritis and chorea [1 ]. The
extracardiac manifestations are self-limiting and
with no residual injury. In terms of carditis, there
is no lymphocytic myocarditis or significant tropo-
nin release, even in patients with congestive heart
failure, suggesting a lack of fulminant myocardial
injury [2]. Pericarditis occurs infrequently and any
pericardial effusion is self-limiting. On the other
hand, rheumatic heart disease (RHD) is a progressive
valvulopathy that occurs in approximately 60% of
those patients with ARF [3]. In addition, a significant
proportion of patients will also have initial subclin-
ical carditis that may progress to end-stage valvul-
& Ontario, Canada
opathy [1 ]. Clinically apparent RHD affects 15.6
million people worldwide, with 282 000 new cases
added each year [3]. Echocardiographic screening
studies in endemic areas have revealed an approxi-
mately 10 times greater incidence, and as such, we
likely underestimate the true prevalence of this dis-
ease [4,5]. RHD still accounts for a majority of the
ng people in developing countries. If left untreated,
RHD can result in mean age of death less than 25
years in some endemic countries [6]. The dispropor-
tionately high prevalence in developing countries
affecting the most vulnerable communities is
related to overcrowding, inadequate hygiene, poor
access to healthcare, and poor compliance with
medications. Although RHD primarily affects those
in developing countries today, there have been iso-
lated resurgences of ARF in the developed world [7].
In 2015, the American Heart Association revised
the 1992 Jones Criteria for the diagnosis of ARF in the
a
Division of Cardiac Surgery, St Michael’s Hospital and bDivision of
Pathology, Toronto General Hospital, University of Toronto, Toronto,
Correspondence to Bobby Yanagawa, MD, PhD, FRCSC, Department of
Surgery, University of Toronto, Division of Cardiac Surgery, St. Michael’s
Hospital, 30 Bond Street, 8th Floor, Bond Wing, Toronto, ON M5B 1W8,
Canada. Tel: +1 416 864 5706; fax: +1 416 864 5031;
e-mail: yanagawab@smh.ca
Curr Opin Cardiol 2016, 31:162–168
DOI:10.1097/HCO.0000000000000269

www.co-cardiology.com Volume 31  Number 2  March 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Update on rheumatic heart disease Yanagawa et al.

medical management, as well as surgical manage-

KEY POINTS
 RHD is still largely considered an autoimmune disease,
but work to identify novel upstream inflammatory
regulatory events and genetic and genomic
determinants of susceptibility is underway.
 Despite studies to find targeted treatments to slow the
progression of RHD, medical treatment is limited to
lifelong antibiotic therapy.
 PMBV can be an effective intervention for
hemodynamically significant but nonsevere MS. Efforts
are underway to identify the ideal candidate to
optimize outcomes.
 Several experienced surgical groups have published
their experience of valve repair with excellent long-term
survival and freedom from reintervention.
&
era of Doppler echocardiography [1 ] (Table 1). With
regard to RHD, a major advance is the use of echo-
cardiography, as opposed to clinical examination, to
detect mitral or aortic valve regurgitation. In this
regard, subclinical carditis, or valvulopathy revealed
by echocardiography but not by classic auscultation,
is a criterion for ARF and can beget RHD.
In this overview, we will review the current
knowledge of histopathology, pathogenesis, and
ment. For each section, we will highlight the major
unanswered questions.
PATHOLOGY OF RHEUMATIC HEART
DISEASE
RHD is a pancarditis that affects the myocardium
in the form of focal interstitial granulomas or
Aschoff bodies, fibrinous pericarditis, and vege-
tations (verrucous) on the valve leaflets with late-
stage manifestation of stenotic valvulopathy. In
the myocardium, Aschoff bodies are aggregates of
interstitial fibroinflammatory lesions containing
lymphocytes, macrophages, B cells, and giant cells
as well as collagen necrosis, considered pathogno-
monic for RHD. However, there is rarely significant
myocardial injury, including protracted myo-
carditis, dilated cardiomyopathy or constrictive
pericarditis, associated with end-stage rheumatic
valve disease [8].
The primary cardiac phenotype is valvulopathy,
with the mitral valve most often affected and the
aortic valve the next most common [9]. Acute rheu-
matic valvulitis shows gross features of small pink
vegetations (verrucae) on the rough zone of the
valve leaflets. Histologically, active inflammation
and edema can be seen. In the acute phase, the

Table 1. 2015 Revised Jones Criteria. Adapted from Gewitz et al. [1 ] &

A.
Diagnosis Criteria

Initial ARF Evidence of GAS infection and two major or one major and two minor
Recurrent ARF Evidence of GAS infection and two major or one major and two minor or three minor

B.
Major criteria Low-risk patients Moderate and high-risk patients

Carditis (clinical or subclinical) Carditis (clinical or subclinical)

Polyarthritis Monoarthritis or polyarthritis or polyarthralgia
Chorea Chorea
Erythema marginatum Erythema marginatum
Subcutaneous nodules Subcutaneous nodules

Minor criteria Low-risk patients Moderate and high-risk patients

Polyarthralgia
Fever (38.58C)
ESR  60 mm in the first hour and/or CRP 3.0 mg/dl
Prolonged PR interval, after accounting for age variability
(unless carditis is a major criterion)
Monoarthralgia
Fever (388C)
ESR  30 mm/h and/or CRP  3.0 mg/dl
Prolonged PR interval, after accounting for age variability
(unless carditis is a major criterion)

ARF, acute rheumatic fever; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GAS, group A streptococcal infection.
Low-risk patients are those who come from a population in which ARF incidence is 2 per 1 00 000 or less in school-aged children or rheumatic heart disease
prevalence is 1 per 1000 or less per year for all ages.

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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Valvular heart disease
leaflets exhibit focal evidence of immune cell
infiltration, fibrosis, neoangiogenesis, and later
evidence of calcification. Areas of angiogenesis stain
positively for vascular endothelial growth factor
[10]. Regarding cellular infiltration in the mitral
valve, CD4þ and CD8þ T lymphocytes and macro-
phages are expressed in the valvular endothelium
and in perineovascular areas. A vicious cycle of
inflammation, neovascularization, healing, and
further damage results in chronic RHD with prolif-
erative and exudative inflammation involving
primarily collagen or ground substance. Extensive
gross pathological studies of end-stage rheumatic
valves demonstrate a fibrotic and firm leaflet with
postinflammatory leaflet thickening, scarring,
fusion, and shortening of the commissures and
chordae. These patients can develop severe ‘fun-
nel-shaped’ severe mitral valve stenosis, whose ori-
fice resembles a ‘fish mouth,’ its classic descriptor.
PATHOGENESIS: ENDOTHELIAL INJURY
AND INNATE IMMUNE RESPONSE
Rheumatic disorders can be divided into primarily
autoimmune and autoinflammatory, with some
overlap, but each having distinct mechanisms
[11]. Autoinflammatory disorders are primarily of
the innate immune response and driven by inflam-
masome-induced IL(interleukin)-1b and IL-18 [12].
On the other hand, autoimmune diseases are prim-
arily adaptive immune responses, driven by T-and
B-cell activity and interferon type I. RHD has been
understood as an autoimmune disease but also has a
component of active inflammation, as evidenced
by elevated C-reactive protein (CRP) release both
acutely and chronically [13–16]. CRP levels have
been shown to correlate with more rapid pro-
gression of mitral stenosis (MS) [17]. The proinflam-
matory milieu is also associated with higher
expression of plasma fibrinogen, IL-6, IL-8, tumor
necrosis factor (TNF)a, and high-sensitivity CRP
[15]. Furthermore, IL-6 and TNFa levels are strongly
correlated with valve calcification [18]. The vaso-
constrictor endothelin-1 is also upregulated in
patients with RHD [19].
Endothelial injury may be an important primary
event in RHD. Galvin et al. [20] demonstrated that
antistreptococcal antibodies were cytotoxic for cul-
tured human endothelial cells as well as human
valvular endothelium and underlying basement
membrane. Scalzi et al. [21] showed potentially
pathogenic direct antiendothelial cell antibodies
in 40% of RHD patients. Explanted rheumatic valve
tissues at the time of surgery show activation of
surface valvular endothelium with expression of
vascular cell adhesion molecule-1 and extravasation
164 www.co-cardiology.com
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of CD4þ and CD8þ lymphocytes into the subendo-
thelial space [22]. Complement activation may
also be important, as mannose-binding lectin
(MBL) and MBL2-associated genotypes associated
with the high production of the soluble pathogen
recognition receptor MBL were found in patients
with RHD [23].
PATHOGENESIS: AUTOIMMUNITY
The importance of autoimmunity in the pathogen-
esis of rheumatic fever was based on the demon-
stration of focal deposits of bound g globulin in the
myocardium of rheumatic atrial appendages [24]
and valvulitis and focal myocarditis in Lewis rats
immunized with recombinant streptococcal M
protein [25]. Furthermore, human and rat cardiac
myosin induced severe myocarditis in the Lewis rats,
and myosin-sensitized lymphocytes from the hearts
of Lewis rats with peptides of streptococcal M5
protein responded most strongly to peptides within
the B repeat region of streptococcal M protein [24].
Streptococcal antigen presentation by HLA class II
molecules to T-cell receptor with antigenic mimicry
between streptococcal M protein and several cardiac
sarcomeric and structural proteins may lead to infil-
tration and activation of CD4þ/CD8þ T lympho-
cytes and macrophages [18,26,27].
The M protein is the most important antigenic
structure of S. pyogenes. It shares structural
homology with g-helical coiled-coil human proteins
such as cardiac myosin, tropomyosin, keratin,
laminin, and vimentin [26,28–31]. Vimentin, a
major type III intermediate filament protein, is
expressed in endothelial and other mesenchymal
cells that regulate focal adhesions. Antivimentin
antibodies cross-reactive with streptococcal proteins
were present in patients with RHD [30]. Group A
carbohydrates have also been shown to trigger auto-
antibodies [32]. Antigroup A carbohydrate anti-
bodies correlated with need for valve replacement
and decreased following surgical removal of the
diseased valve [33,34].
As explained by Tandon et al. [35], antigenic
mimicry with sarcomeric antigens may not fully
explain RHD pathogenesis, as myocardial sarco-
meric proteins are intracellular and thus relatively
inaccessible as an autoantigen; sacromeric proteins
are absent in heart valves, the primary focus of
immune injury; and where sarcomeric proteins
are abundant in the myocardium, inflammation is
not found clinically. One such novel mechanism for
immune activation is streptococcal M protein bind-
ing to the cyanogen bromide peptide fragment 3
(CB3) region in subendothelial basement mem-
brane collagen type IV, initiating an antibody
Volume 31  Number 2  March 2016

response to the collagen [35–38]. Finally, immuno-
editing is a newly discovered autoimmune mecha-
nism whereby somatic mutations in normally
tolerant self-antigens result in neoantigens,
which may become immunogenic [39]. Whether
immunoediting is involved in RHD is completely
unknown.
GENETICS
The fact that only a small subset of children with
untreated Streptococcal sore throat develop ARF,
and that a subset of those predisposed to protracted
inflammation will go on to develop chronic RHD,
suggests a genetic component for determination of
susceptibility. Furthermore, familial clustering and
high concordance of ARF and RHD among mono-
zygous twins strengthen this argument [40,41]. The
risk of ARF in a monozygotic twin with a positive
history is increased by more than six times com-
pared with that of dizygotic twins. A meta-analysis
of 435 twin pairs with ARF confirmed that the
monozygotic twin concordance substantially
exceeded the dizygotic twin concordance [42].
Several studies have identified candidate genes
and loci in association with RHD susceptibility. The
HLA-DR7 allele is the HLA class II gene most con-
sistently associated with genetic susceptibility to
RHD [43,44]. This enzyme presents antigens to
the T-cell receptor, leading to the recruitment of
CD4þ T cells that recognize antigenic peptides, and
activates the adaptive immune response. Other
potentially important polymorphisms associated
with RHD include signal transducer and activator
of transcription (STAT)3, STAT5b, ficolin-2 (FCN2),
TNFa and its promoter region, toll-like receptor
2 (TLR)2, IL-10, IL-6, IL-1Ra, MBL, and TGFb1
[45–50]. There are several genes that encode pro-
inflammatory cytokines, and the TGFb1 gene
encodes a key regulator of fibrosis and calcification.
The precise roles of these mutations in RHD patho-
genesis remain unclear.
MEDICAL MANAGEMENT OF RHEUMATIC
HEART DISEASE
Regular and possibly lifelong antibiotics are cur-
rently the only established treatment for secondary
prevention of RHD based on the importance of
prevention of recurrent infections with group A
streptococcus (GAS).
There are several lines of investigation into nov-
el medical treatments to delay the progression
of RHD. Hydroxymethylglutaryl coenzyme-A
reductase inhibitors, or statins, are lipid-lowering
medications with pleotropic anti-inflammatory and
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Update on rheumatic heart disease Yanagawa et al.
antithrombotic properties that stabilize endo-
thelium and atherosclerotic plaques and protect
against oxidative stress. Treatment with statins
has been shown to slow the progression of aortic
valve calcification, but the results from prospective
trials have been inconclusive [51–53]. Similarly, a
retrospective study found that statins were associ-
ated with a lower progression of transmitral gradient
and transaortic velocity [54,55]. The mechanism is
thought to be secondary to anti-inflammatory or
endothelial-protective effects of statins [56]. The
potential protective role of statins in RHD needs
confirmation in a prospective study. A prospective
trial of immunoglobulin treatment [intravenous
immunoglobulin (IVIG)] did not show any improve-
ment in erythrocyte sedimentation rate or echo-
cardiographic cardiac involvement in patients
with ARF at 1 year (41 vs. 50%) [57]. A recent
meta-analysis of mostly historical trials demon-
strated no benefit of corticosteroids or IVIG in
reducing the risk of developing carditis in patients
with ARF [58]. A difficulty in treatment of ARF is the
time delay from the start of infection, as patients
often present weeks into the course of their disease.
Finally, despite decades of work, there is currently
no vaccine for primary prevention of suppurative
and nonsuppurative infection with GAS, the causa-
tive agent of ARF and RHD.
INTERVENTIONAL AND SURGICAL
MANAGEMENT OF RHEUMATIC HEART
DISEASE
Percutaneous mitral balloon valvuloplasty (PMBV)
remains an effective intervention for rheumatic MS.
Commissural splitting is the dominant mechanism
for enlargement of the mitral valve area, reduction
of the transmitral gradient, and observed clinical
improvement [59]. For patients with low Wilkins
Score (<8) and not in atrial fibrillation, there was no
difference in event-free survival and clinical events
for PMBV versus surgery [60]. Candidacy for PMBV
includes a comprehensive echocardiographic evalu-
ation of mitral pathology, including Wilkins Score,
degree, and mechanism of mitral regurgitation (MR)
as well as characteristics such as asymmetrical
involvement, severe commissural fibrosis and calci-
fication, and subvalvular involvement that contrib-
utes to decision making for individual patients.
Efforts to better predict the types of valvular
anatomy most amenable to successful PMBV and
thus standardize outcomes are ongoing.
Regarding surgical management, valve replace-
ment is the gold standard. This is increasingly being
performed via a minimally invasive, direct vision, or
robotic small thoracotomy approach [61,62]. Valve
www.co-cardiology.com 165
Valvular heart disease
replacement can be performed with excellent out-
comes, but for young patients who require a mech-
anical prosthesis, there is a burden of lifelong
anticoagulation and associated yearly risk of throm-
boembolism and bleeding [63,64]. In such patients,
valve repair is associated with better preservation of
left ventricular function, improved survival, and
lower long-term morbidity [65–68]. Even in the
developing world, the argument that replacement
is preferred for patients with restricted access to
ongoing care is under question.
In adults, a large retrospective series of patients
undergoing surgery for RHD from the Toronto
General Hospital found that repair was associated
with improved survival and that replacement was
associated with greater freedom from reoperation
but more thromboembolic complications [69].
Dillon et al. [70] reported 83.3  4.3% 10-year
survival and 98.4  0.9% freedom from reoperation.
Waikittipong [71] reports a very high rate of
success for complex valve repair using primarily
leaflet mobilization with chordal cutting, papillary
muscle splitting, and commissurotomy for type
IIIb restricted leaflet motion and neochords, chordal
transfer, or shortening for type II leaflet prolapse.
The author emphasizes three criteria for success-
ful repair: selection of patients who are beyond
the acute inflammatory phase with suitable
morphology for repair; repair based on surgical
principles of leaflet mobilization, correction of pro-
lapse and ring annuloplasty; and secondary prophy-
laxis using penicillin. Bhadwar’s group in Pittsburgh
report their simplified and reproducible three-
part technique of bicommissural release, anterior
leaflet augmentation, and oversized annuloplasty
in 35 patients [72]. Notably, they standardized
Table 2. Stages of mitral stenosis. Adapted from Nishimura et al. [73 ]
Anatomy
Stage A Mild diastolic
doming
Stage B Commissural
fusion
Stage C Fusion/
thickening/
retraction
Stage D
LAE, left atrial enlargement; MVA, mitral valve area; PASP, pulmonary artery systolic pressure; pressure T1/2, pressure half-time.
166 www.co-cardiology.com
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repair without the need for complex subvalvular
procedures, which is appealing to surgeons who
rarely see such pathology.
GUIDELINES
The most recent 2014 AHA/ACC Guidelines for
the Management of Patients with Valvular Heart
Disease includes important changes for patients
&
with rheumatic MS [73 ]. MS is conceptualized
according to the stages of disease based on valve
anatomy, hemodynamics, ventricular effect, and
symptoms (Table 2).
PMBV is recommended for symptomatic
patients with severe MS and favorable valve
morphology in the absence of left atrial thrombus
or moderate-to-severe MR [Class I, level of evidence
(LOE) A] and is reasonable for asymptomatic very
severe MS (mitral valve area 1.0 cm2) (Class IIa,
LOE C). PMBV may be considered for asymptomatic
severe MS with new onset of AF (Class IIb, LOE C)
and for symptomatic patients with mitral valve area
more than 1.5 cm2 and pulmonary artery wedge
pressure greater than 25 mmHg or mean mitral valve
gradient more than 15 mmHg during exercise (Class
IIb, LOE C). Finally, it may be considered for patients
with symptomatic severe MS who are not candidates
or are at high risk for surgery (Class IIB, LOE C).
Mitral valve surgery is indicated for patients
with severe symptomatic MS who are not candidates
for or have failed percutaneous mitral balloon com-
missurotomy (Class I, LOE B). Mitral valve surgery is
reasonable for concomitant severe MS (Class I, LOE
C) and may be considered for concomitant moder-
ate MS (Class IIb, LOE C). Finally, mitral valve
surgery and excision of the left atrial appendage
&
Hemodynamics Hemodynamic Symptoms
consequence
Increased Mild–moderate
transmitral LAE
flow velocities
MVA ≤ 1.5 cm2
Pressure T1/2 Severe LAE
≥150 ms PASP > 30mmHg Decreased exercise
tolerance and
dyspnea
Volume 31  Number 2  March 2016

may be considered for patients with severe MS
and recurrent embolic events on anticoagulation
(Class IIb, LOE C).
CONCLUSION
RHD is considered to be an autoimmune disease
caused by a dysregulated immune system triggered
by molecular mimicry between bacterial epitopes
and cardiac self-antigens. Current work to reveal
novel autoantigens and to elucidate injurious mech-
anisms including inflammation and genetic and
genomic involvement are underway. Medical treat-
ment is limited to lifelong antibiotic therapy. PMBV
remains an important intervention for ‘mild’ rheu-
matic stenosis. Surgery for rheumatic MS has prim-
arily been replacement, leaving young patents with
mechanical prostheses and the burden and compli-
cations of lifelong oral anticoagulation. Several
experienced groups have published their experience
of valve repair with excellent long-term survival and
freedom from reintervention.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 31  Number 2  March 2016