Advances in Genetics
Genetic Basis of Familial Valvular Heart Disease
Ratnasari Padang, MBBS, FRACP; Richard D. Bagnall, PhD;
Christopher Semsarian, MBBS, FRACP, PhD
V
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alvular heart disease (VHD) is a major cause of morbidity and premature death from cardiovascular diseases,
making it an important clinical entity. Despite a dramatic
decline in the incidence of rheumatic heart disease in industrialized countries, VHD remains highly prevalent. Although
many VHDs are acquired during adult life, familial clustering and heritability have been noted for common heart valve
defects, such as bicuspid aortic valve and myxomatous mitral
valve prolapse, denoting an underlying genetic basis. Over
the past decade, advances in our understanding of the genetic
basis of familial VHD have been made through the unraveling of gene network and molecular mechanisms regulating
normal valve development. Important progress has also arisen
from a series of elegant studies that have focused on linkage analyses of large families with VHD, transgenic animal
models, in vitro studies, and, more recently, microRNA and
transcriptomic assessment of diseased tissues. Identification
of the genes and molecular pathways responsible for the
development of VHD has important implications in terms of
improving current therapeutic strategies, as well as guiding
the management of at-risk family members, with the ultimate aim to reduce the health burden of VHD. This article
will summarize the current state of knowledge regarding the
genetic basis of 2 common familial VHDs, namely mitral
valve prolapse and bicuspid aortic valve, and highlight some
of the recent findings that shed light on the pathogenesis of
these diseases.
Valvular heart disease (VHD) is a major cause of disability, diminished quality of life, and premature death from cardiovascular disease,1 making it an important clinical entity.
Despite a dramatic decline in the incidence of rheumatic
heart disease in industrialized countries, VHD remains highly
prevalent.2 Although many VHDs are acquired during adult
life, congenital forms present with abnormal valve structures at birth, yet may not manifest as valvular dysfunction
and disease until later in life.3,4 Furthermore, familial clustering and heritability have been noted for common heart valve
defects, such as bicuspid aortic valve (BAV) and myxomatous
mitral valve prolapse (MVP), implying an underlying genetic
basis.3,5,6 These familial VHDs can occur in isolation (nonsyndromic) or present as part of a clinical genetic syndrome, such
as Marfan, Turner, and Noonan syndromes.7
Traditionally, well-characterized multigeneration families
have been invaluable for determining the genetic basis of
disease, because they are amenable to marker-based genomewide linkage analysis. However, the identification of causal
genes in VHD has been hampered by complex genetic and
phenotypic heterogeneity, incomplete penetrance, and the
likely contribution of genetic modifier loci. Although in vitro
studies and transgenic animal models that recapitulate the
human phenotype have provided insights into the genetic basis
of VHD, these findings do not always translate to humans.
Therefore, concurrent studies on the molecular pathways regulating valvulogenesis have sought to highlight gene networks
relevant to VHD.
This review article will focus primarily on the 2 most common isolated VHDs, ie, MVP and BAV. The review will summarize the current knowledge regarding the genetic basis of
MVP and BAV and highlight some of the recent findings that
shed light on the pathogenesis of these diseases. Although
there is much more to discover about the genetic causes of
VHD, it is timely to review the current state of knowledge in
these important cardiovascular genetic disorders.
Overview of Development of Cardiac Valves
A key aspect of cardiac development is the formation and
function of the cardiac valves. Cardiac valve development
begins immediately after cardiac looping, at embryonic
days 31 to 35 in humans, with the formation of endocardial
cushions in the atrioventricular canal and outflow tract.8,9
Normal uridine diphosphate glucose dehydrogenase gene
activity to synthesize glycosaminoglycan is critical for the
early cell signaling events that establish the boundaries of
these cushion-forming regions.10 Cardiac cushion formation
involves the transformation of a subset of endothelial cells
into mesenchymal cells in the cushion-forming area, which
is induced by bone morphogenetic protein-2 (BMP-2) signals
derived from adjacent myocardial cells.8 The mesenchymal
progenitor cells migrate into the intervening cardiac jelly
and proliferate to form swellings of valve primordial, which
eventually give rise to valvuloseptal structures and adult
valvular interstitial cells.8,11–13 The atrioventricular cushions
contribute to atrioventricular (mitral and tricuspid) valve
leaflets, whereas the outflow tract cushions contribute to
From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia (R.P., R.D.B., C.S.); Sydney Medical School, University
of Sydney, Sydney, Australia (R.P., C.S.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (R.P., C.S.).
Correspondence to Christopher Semsarian, MBBS, PhD, FRACP, Agnes Ginges Centre of Molecular Cardiology, Centenary Institute, Camperdown,
NSW 2050, Australia. E-mail [email protected]
(Circ Cardiovasc Genet. 2012;5:569-580.)
© 2012 American Heart Association, Inc.
Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org
569
DOI: 10.1161/CIRCGENETICS.112.962894
570 Circ Cardiovasc Genet October 2012
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semilunar (aortic and pulmonary) valve leaflets.3,8 The
development of the outflow tract and semilunar valve is
complex and involves coordinated interactions between the
endocardial-derived mesenchyme, cardiac, and smooth muscle
progenitors from the anterior or secondary heart field and
the cardiac neural crest.14 Whereas the secondary heart field
progenitor cells contribute to the outflow tract myocardium, a
population of neural crest-derived cells migrate into the distal
(truncal) part of the outflow tract cushions, which subsequently
divide the outflow tract into aortic and pulmonary trunks, and
differentiate into the vascular smooth muscle layer of the aortic
arch.9,14, 15 A number of signaling pathways including Wnt/βcatenin, NOTCH, transforming growth factor β receptor
(TGF-β), BMP, vascular endothelial growth factor, NFATc1
and MAPK, and transcription factors, including Twist1,
Tbx20, Msx1/2, and Sox9, are active during this early stage of
valvulogenesis. These pathways are collectively important in
the regulation of cell migration, proliferation, and extracellular
matrix expression in the developing valves.8,13,16,17
Later in embryonic valve development, cell proliferation decreases and the fused endocardial cushions remodel
and thin out to form mature valve leaflets, which are characterized by increasing complexity and organization of the
extracellular matrix, and compartmentalization of valvular
interstitial cells.8,13 The molecular pathway that regulates
this later stage of valvulogenesis is less well understood,
but it involves periostin, a component of the extracellular
matrix protein.18 The periostin gene has been identified as a
molecular switch that promotes the differentiation of endocardial cushion cells into a fibroblastic cell lineage, rather
than into myocardial or osteochondral cell lines, and regulates cushion remodeling, separation of the developing atrioventricular valve from the underlying myocardium, and its
transformation into mature valve leaflet and the supporting
apparatus.9,18 The mature valve leaflets are stratified into 3
layers with distinct mechanical properties arranged in orientation to the blood flow: a flexible, elastin-rich atrialis/ventricularis layer, a central shock-absorbing proteoglycan-rich
spongiosa layer, and a tensile, collagen-rich fibrosa layer.19
The process of valve compartmentalization and remodeling
occurs at late gestation and continues into postnatal life,
suggesting that mechanisms of prenatal valve development
persist during postnatal valve growth and maintenance.6,11
Furthermore, evidence suggests that developmental signaling pathways are shared between heart valves and the precursors of cartilage, tendon, and bone, playing a critical role
at this later stage of valve maturation/remodeling.19 These
pathways include BMP-2–mediated induction of Sox9 and
aggrecan, receptor activator of NFκB ligand–mediated
induction of NFATc1, and FGF4-mediated induction of
scleraxis and tenascin.17,19,20
Cardiac valve development during embryogenesis is therefore complex, with an integrated mechanism of genetic factors, activation of signaling pathways, as well as external
environmental factors, such as the physical forces of blood
flow. Because many of the signaling pathways and transcription factors responsible for valve development are reactivated
in pediatric and adult valve diseases,3,21 the insights gained
from understanding normal valvulogenesis have provided
a platform to identify potential candidate genes involved in
familial VHDs.
Mitral Valve Prolapse
Clinical Significance
MVP is a common disorder, which affects 2.4% of the general population and exhibits strong heritability.22-24 Because
MVP is defined by the abnormal relationship of mitral leaflets to their surrounding structures, echocardiography has
become a diagnostic standard to confirm its presence. In a
pivotal 3D echocardiographic study in the late 1980s, Levine
et al25 demonstrated that the mitral annulus was in fact saddle
shaped, with the most superior aspects positioned anteriorly and posteriorly and the most inferior aspects positioned
medially and laterally. This improved understanding of normal mitral valve anatomy has greatly enhanced the diagnostic specificity for MVP without loss of sensitivity.22 Because
successful genetic studies rely on accurate phenotypic definition, the increased diagnostic specificity for MVP has been
central in enabling the advances to be made in MVP genetics
over the past few years.
MVP is characterized by fibromyxomatous degeneration of
the mitral valve, leading to progressive thickening and expansion of the leaflet(s) and lengthening of the chordae tendineae, which results in superior displacement of the leaflet(s)
into the left atrium during systole.23,24,26 The clinical phenotype of MVP is widely heterogeneous,24,27,28 ranging from a
benign clinical course with normal life expectancy to adverse
outcomes with significant morbidity and mortality resulting
from the development of valvular insufficiency. Although
most patients are asymptomatic, up to 13% of affected subjects develop serious MVP-related complications,28 attributed
to significant mitral regurgitation, congestive heart failure,
infective endocarditis, arrhythmias, and, in worst cases, sudden cardiac death.22,23,27 MVP is the leading cause of isolated
mitral regurgitation, requiring surgical intervention in developing nations.12,22,27
Pathogenesis of MVP
Histological examination of myxomatous MVP leaflets charac­
teristically demonstrates activated interstitial myofibroblastlike cells, disorganized fragmentation of collagen and
elastin fibers, and expansion of the spongiosa layer that
have resulted from the accumulation of proteoglycans and
glycosaminoglycans, which extend into the load-bearing
fibrosa.22,29 This alteration of extracellular matrix synthesis
and maladaptive remodeling by activated valvular interstitial
cells result in a disruption in the mechanical integrity of the
leaflet(s) which, together with normal wear and tear, leads to
leaflet(s) stretching and expansion.12
Although the pathological features of MVP are well
known, the precise cellular and molecular mechanisms
that contribute to the development of MVP are less clear.
Isolated MVP is absent in newborn babies,30 suggesting
that it may develop from a combination of genetic variation
with age-dependent penetrance, postnatal disruption of cellular signaling, and environmental factors, including repetitive mechanical stress from normal physiological wear and
tear (Figure 1).27,31 It is postulated that hemodynamic shear
Padang et al Genetics of Familial Valve Disease 571
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Figure 1. Factors contributing to MVP
development and progression. MVP indicates mitral valve prolapse; BP, blood
pressure; Fbn, fibrillin; and MMP, matrix
metalloproteinases.
stress and impact-induced damage to the superficial lining layer of valvular endothelial cells leads to the release
of proinflammatory cytokines, such as TGF-β and vasoactive substance; eg, endothelin-1 and prostanoids.11,32–35
This then activates the residing valvular interstitial cells,
which transform into myofibroblast-like cells and secrete
excessive levels of catabolic enzymes, including the collagenases MMP-1 and MMP-13, the gelatinases MMP-2
and MMP-9, cysteine proteases cathepsin C and M, and
interleukin-1β, a cytokine that induces the secretion of
proteolytic enzymes.34 Moreover, a proportion of valvular
interstitial cells transform toward a hyperplastic CD34+
fibrocyte phenotype, which synthesizes MMP-9 and collagen-III, and seem to take part in leaflet remodeling (Figure
2).31,36 Together, these changes alter the metabolism and
composition of the extracellular matrix and, although most
pronounced in the spongiosa layer, also affect the fibrosa
backbone layer, hence compromising the leaflet structural
integrity and biomechanics. Ultimately, remodeling of the
extracellular matrix and excessive glycosaminoglycan and
water accumulation, give the diseased leaflets their classical
myxomatous appearance.22
Genetic Basis of MVP
MVP can be sporadic, familial, or occur in the context of a
syndrome, the latter occurring as part of heritable connective
tissue disorders, which are often attributed to specific
mutations in extracellular matrix genes. A summary of the
genetic factors in MVP is provided in Table 1.
Mutations in fibrillin-1 (FBN-1) and, less commonly,
in TGF-β receptor-2 (TGFBR2), cause Marfan syndrome
Type I and Type II, respectively, in which MVP is common.
Advances in understanding MVP pathogenesis have been
made using an FBN1-deficient mouse model that recapitulates human Marfan syndrome in a landmark study by Dietz
and colleagues.32 Fibrillin-1 is a major structural component
of the extracellular matrix microfibrils and a key regulator
of TGF-β availability.37 TGF-β regulates extracellular matrix
content and remodeling, as well as valvular interstitial cell
differentiation and activity, via autocrine signaling.11,34,37,38
TGF-β isoforms are synthesized in the intracellular compartment as large precursors that are cleaved into mature TGF-β
and its propeptide, called latency-associated peptide, which
are covalently bound to form inactive small latent complexes.38 This complex remains intracellular until it is bound
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Figure 2. Schematic representation of postulated pathogenesis of mitral valve prolapse
(MVP). MVP is believed to
be the consequence of a
maladaptive response of a
genetically predisposed mitral
valve to repetitive mechanical stress. As well as having
a possible direct effect of
shear stress on the residing
valvular interstitial cells (VICs),
this impact-induced damage
to the superficial lining layer
of valvular endothelial cells
(VEC) leads to the release of
proinflammatory cytokines
and vasoactive substances.
This, in turn, stimulates transformation of VICs to an active
myofibroblast-like cells. The
activated VICs then secrete
excessive levels of catabolic
enzymes, which result in collagen degradation, deposition
of proteoglycans, extracellular
matrix (ECM) disarray and
remodeling, ultimately leading
to disruption in the mechanical integrity of the leaflet and leaflet prolapse. MMP indicates matrix metalloproteinases; BMP, bone morphogenetic protein; TGF-β, transforming growth factor type β.
to latent TGF-β–binding protein, forming a large latent
complex. Fibrillin-1 has been shown to bind to latent TGFβ–binding protein and the large latent complex, thus allowing fine control of TGF-β levels and activity by sequestering
biologically active TGF-β into the extracellular matrix.37,38
Therefore, deficiency of fibrillin-1 results in increased TGFβ signaling within the extracellular matrix, as demonstrated
by the increased levels of phosphorylated Smad2 and the
expression of TGF-β–responsive extracellular matrix genes,
such as Tgfbi, endothelin-1 (Edn1), and tissue inhibitor of
metalloproteinase1 (Timp1).32 It is remarkable that TGF-β
antagonism in vivo using neutralizing antibodies was able
to rescue the valve phenotype of FBN1-deficient mice.32
Furthermore, Losartan, an angiotensin II type 1 receptor
antagonist, prevents and possibly reverses the aortic root dilatation and MVP in mice with Marfan syndrome, probably
by decreasing TGF-β–mediated ERK1/2 activation, a principal effector of disease in FBN1-deficient mice.37,39 These
insightful findings suggest that myxomatous MVP may
result from dysregulation of conserved signaling pathways
and be amenable to therapeutic intervention. Although linkage between FBN1 and several of the collagen genes have
not been demonstrated in autosomal dominant MVP,40,41 the
established role of TGF-β in the pathogenesis of MVP in
Marfan syndrome suggests that it may be relevant in nonsyndromic forms of MVP.12
The contribution of genetic factors in nonsyndromic MVP
is supported by family studies, which indicate genetic heterogeneity with autosomal dominant and X-linked modes
of inheritance.22 Incomplete penetrance with age- and sexdependent expressivity further contributes to the striking
clinical heterogeneity even within the same family.22,24,27,42
X-linked myxomatous valvular dystrophy is a rare form of
familial multivalvular myxomatous degeneration caused by
mutations in the filamin A (FLNA) gene located on chromosome Xq28, in which MVP is a frequent manifestation.43,44
FLNA encodes a large cytoskeletal actin-binding protein that
directly coordinates the localization and activation of Smad
proteins, especially Smad2, and serves as a positive regulator of TGF-β signaling.43 Although defective Smad signaling
caused by FLNA mutation has not been shown, understanding
the role of FLNA in modulating TGF-β signaling has provided
another clue toward an improved understanding of myxomatous MVP pathogenesis. Furthermore, genome-wide linkage
analyses in large families have mapped MVP loci to chromosomes 16p11.2-p12.1 (MMVP1),45 11p15.4 (MMVP2),46
and 13q31.3–31.2 (MMVP3),42 although the causative genes
remain to be identified.
In sporadic MVP, where family studies are not informative,
associations with single-nucleotide polymorphisms in genes
implicated in extracellular matrix remodeling, collagen
metabolism, and the renin–angiotensin–aldosterone system
(RAAS) have been examined (Table 1). The association of
sporadic MVP with the G/G genotype of a polymorphism
in exon 31 of the collagen IIIα1 gene (COL3A1)47 and 3
polymorphisms in the FBN1 gene have been reported.38,39
However, the generalizability of these results is restricted
by the small number of patients, and is in contrast with the
previously mentioned linkage analyses on several pedigrees
that showed no linkage of these genes to autosomal dominant
MVP. A polymorphism in the 3’ untranslated region of the
urokinase–plasminogen activator gene, which plays a role
in the pathogenesis of elastin and collagen degradation in
arterial aneurysms, was also reportedly associated with
MVP.48 It is interesting that in another study of MVP patients,
an MMP-3 promoter haplotype-1612 5A/5A polymorphism
was associated with severe mitral regurgitation and more
pronounced left ventricular remodeling.49 It is speculated
Padang et al Genetics of Familial Valve Disease 573
Table 1. Summary of Gene Anomalies and Polymorphisms Associated With the Development of Mitral Valve Prolapse
Study Cohorts
Genetic Anomalies and Polymorphisms Associated With
MVP Development
Reference
Animal study
Mice
Cavalier King Charles Spaniels
FBN1-deficient mouse model
32
Cardiac-specific MMP-2 transgenic mouse model
54
Adamts9 haploinsufficient mice
53
Locus on CFA13 and CFA14
92
Locus on Chr 16p11.2-p12.1 (MMVP1)
45
Locus on Chr 11p15.4 (MMVP 2)
46
Human study
Familial MVP
Families with idiopathic autosomal
dominant pattern of inheritance for
MVP
Locus on Chr 13q31.3-q31.2 (MMVP3)
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Families with X-linked form of MVP
(myxomatous valvular dystrophy)
42
Filamin A gene mutation (Chr Xq28)
43, 44
PLAU gene T4065C polymorphisms
48
Sporadic MVP
Chinese Han population cohort living
in Taiwan
Collagen IIIα1 exon 31 G2209A polymorphisms,
particularly with GG genotype
FBN1 exon 15 TT and exon 27 GG polymorphisms
47, 93
51
Angiotensinogen gene M235T polymorphisms, particularly
with TT genotype and T allele
ACE-I gene (Chr 17q23) insertion /deletion polymorphisms
affecting intron 16
50
White population
Angiotensin II type 1 receptor gene A1166C polymorphism,
particularly with C allele
52
Pediatric cohort in Turkey
FBN1 56GC intronic polymorphism
94
Syndromic MVP
Marfan syndrome
FBN1 (Chr 15q21.1) and TGFβR2 (Chr 3p24.2-p25)
mutations
Loeys–Dietz syndrome
TGFβR1 and TGFβR2 mutations
Ehler–Danlos syndrome
Collagen type I, III, V, XI ,and tenascin mutations
Stickler syndrome
Collagen type II and XI mutations
Williams–Beuren syndrome
Elastin gene mutation
Osteogenesis imperfecta,
Collagen type I mutation
Pseudoxanthoma elasticum
ATP-binding cassette protein ABCC6 mutation
3, 26
MVP indicates mitral valve prolapse; FBN, fibrillin; MMP, matrix metalloproteinases; CFA, canine chromosome; MMVP, myxomatous mitral valve prolapse;
Chr, chromosome; PLAU, urokinase–plasminogen activator; ACE-I, angiotensin-converting enzyme inhibitor; and TGFβR, transforming growth factor β receptor.
that the MMP-3 promoter 5A/5A polymorphism may result
in increased MMP-3 expression in the myocardium, which
then accentuates the adaptive response of the myocardium to
the volume overload of mitral regurgitation and hence more
adverse disease course.49 This suggests that genetic variation
influences the disease course in MVP.
A subset of MVP patients present with a variety of symptoms
that seem to be independent from their underlying valve
disease, including chest pain, dyspnea, dysrhythmia, anxiety,
and syncope, and this is collectively termed MVP syndrome.
The misperception that these symptoms frequently occur
concomitantly with MVP has led to the practice of obtaining
screening echocardiograms on patients with atypical or
nonspecific cardiovascular symptoms.27 Thus, MVP syndrome
may be overdiagnosed as a result of 2 common things
occurring together, without necessarily bearing any patho­
physiological relationship. It is interesting that perturbations
in autonomic, neuroendocrine, and renin–angiotensin–
aldosterone system regulation have been reported among
symptomatic patients with MVP.31 A number of studies have
subsequently demonstrated genetic association between MVP
syndrome and the components of the renin–angiotensin–
aldosterone system, namely an angiotensin I–converting
enzyme insertion/deletion polymorphism in intron 16,50 the TT
genotype of the angiotensinogen Met235Thr polymorphism,51
and the C allele of the angiotensin II type 1 receptor A1166C
polymorphism,52 although these studies are limited by the
relatively small cohort of patients with MVP syndrome.
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However, further studies of asymptomatic patients with MVP
have failed to show evidence of abnormal autonomic or
neuroendocrine function, either at rest or during tilt testing.27
Therefore, although abnormal autonomic function might
be responsible for symptoms in some patients with MVP,
it remains unclear whether their MVP is directly related or
incidental.27
Furthermore, studies in animal models have also highlighted genetic factors involved in MVP pathogenesis.
Proteoglycan accumulation is a hallmark of MVP,34 and mice
haploinsufficient for the versican-specific protease, Adamts9,
display abnormal valve morphogenesis and subsequently
develop myxomatous mitral valve leaflets during adulthood
as a result of versican accumulation.53 In addition, enzymes
that degrade the extracellular matrix, such as the gelatinase
MMP-2, may mediate myxomatous degeneration of the mitral
valve leaflet, and the cardiac-specific transgenic expression of
MMP-2 in mice reproduces many of the pathological features
of MVP.54
Recently, gene expression microarray technology was used
to gain a more unbiased, global view of the genetic signature
of prolapsed mitral valve tissue from patients with idiopathic
MVP, compared with control valve tissue from transplant
donors. The study identified decreased expression of the
metallothioneins 1 and 2 (MT1/2), which protect against oxidative stress, and ADAMTS-1, an abundant aggrecanase in the
mitral valve leaflets that is implicated in proteoglycan degradation.55 Subsequent in vitro silencing of the expression of
metallothioneins 1 and 2 in valvular interstitial cells culture
resulted in the upregulation of TGF-β2 activity and TGF-β2
secretion, with consequent downregulation of ADAMTS-1,
leading to versican accumulation and remodeling of the extracellular matrix, recapitulating the features of human MVP.55
Collectively, these findings provide an insight into the
genetic basis of MVP, which is complex, highly heterogeneous, and most likely involves causative gene mutations with
genetic modifier loci that influence the disease course.
Bicuspid Aortic Valve
Clinical Significance
BAV occurs when the aortic valve has 2 cusps, rather than 3,
and represents the most common form of congenital cardiac
malformation, affecting ≈1.4% of the general population.56,57
BAV has a male predominance of ≈3:1,58 and at least 35% of
those affected develop serious complications including aortic
stenosis and regurgitation requiring valve replacement, endocarditis, ascending aortic aneurysm, and dissection.59 BAV
underlies 70% to 85% of stenotic aortic valve in children and
at least 50% of aortic stenosis in adults.12,60 Furthermore, BAV
carries an 8-fold increased risk of aortic dissection, and over
a 25-year period, the risk of valve replacement is 53%, aneurysm formation is 26%, and aortic surgery is 25%.56 As such,
BAV represents a greater burden of disease than all other congenital heart diseases combined.58,61
Disorders of aortic valvulogenesis tend to be regarded in
the context of a phenotypic continuum, ranging from aortic
valves with a single leaflet to those with 4 leaflets.59 Within
this continuum, BAV exists and demonstrates a wide morphological variation, as seen in human cases of BAV (Figure 3)
and observed in BAV of Syrian hamsters.62 BAV morphological phenotypes range from the typical form with 2 unequalsized leaflets and the larger leaflet having a central raphe
that has resulted from commissural fusion (ie, functionally
bicuspid), to the less common form with 2 approximately
symmetrical leaflets without a raphe (ie, anatomically bicuspid).58,63 Fusion of the right and left coronary cusps is the most
common pattern of BAV and is associated with the coarctation
of the aorta, whereas the fusion of the right and noncoronary
cusps, the second commonest form, is associated with more
cuspal pathology.58
Like MVP, BAV can occur sporadically as an isolated
birth defect, can be familial, and can occur as part of a
syndrome with more global clinical manifestations, such
as Turner, Williams-Beuren, and Andersen syndromes.
Furthermore, BAV is also recognized to coexist with other
congenital cardiovascular malformations, most commonly
Figure 3. Different phenotypic spectrum
of BAV morphology. A, Trileaflet aortic
valve with complete fusion of the right and
left (R-L) coronary cusps; B, Trileaflet aortic valve with complete fusion of the R-L
coronary cusps and partial fusion of the
right and noncoronary cusps; (C) and (D)
Bileaflet aortic valve with extensive raphe
in the fused leaflet; E, Bileaflet aortic valve
with a vestigial raphe; F, True bicuspid
aortic valve without raphe. Figures A and
B are classified as functionally bicuspid
and the remaining are classified as anatomically true bicuspid.
Padang et al Genetics of Familial Valve Disease 575
with coarctation of the aorta, and with cardiac septal
defects or the genetically related hypoplastic left heart
syndrome.58,64 This suggests that BAV is not only a disorder of valvulogenesis, but it also represents a more complex coexistent genetic disease of the aorta and cardiac
development.58,60
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Pathogenesis of BAV
Despite its high prevalence, the pathogenesis of BAV is largely
undetermined, although gene mutations leading to alterations
in cell migration and signal transduction, in conjunction with
nongenetic factors such as blood flow during valvulogenesis,
may contribute to its formation prenatally.3 Because the relationship of the individual valve cusps to specific endocardial
cushion progenitors is not known,8 BAV could result from
a failure of separation of primordial cusps.3 Meanwhile, the
pathogenesis of aortic valve dysfunction in BAV is thought
to be the result of dysregulation in the complex molecular
hierarchies controlling late valve development, which continues into the postnatal life and results in the chronic process of valve tissue remodeling, leading to abnormal leaflet
architecture, valvular thickening, and abnormal biomechanics
(Figure 4).6,65,66 With increasing age, BAV leaflets are prone
to develop premature fibrosis and calcification in response to
hemodynamic shear stress,67,68 an active process that involves
inflammation, endothelial dysfunction, and lipoprotein and
calcium deposition, and results in the ossification of the leaflets and valvular stenosis.58 Meanwhile, the pathogenesis of
aortic regurgitation in BAV patients is more complex. It is
often a consequence of an intrinsic leaflet(s) redundancy or
prolapse of the larger of the unequal-sized cusps; however,
it can also occur secondary to other external factors, such as
endocarditis after balloon valvuloplasty, or concomitant dilatation of the aortic root.58,65,67
Histological examination of BAV tissue from pediatric
patients revealed excessive extracellular matrix production
and trilaminar matrix disorganization, with fragmentation and
reduction in elastin content, and accumulation of collagen and
proteoglycan.6 BAV leaflets also show valvular interstitial cell
disarray and varying degrees of inflammatory cell infiltrates,
which secrete proteolytic enzymes implicated in collagen and
elastin degradation in abdominal aortic aneurysm, such as
MMP-2 and MMP-9.65 Supporting this, tissue microarray and
immunohistochemical analysis of BAV leaflets demonstrated
higher levels of MMP-2 and MMP-9, and lower level of the
MMP inhibitor, TIMP1.65 The increased MMP activity extends
to the aortic annulus and ascending aorta and may contribute
to the related aortopathy.69
Over 50% of individuals with BAV also present with
dilatation of the proximal aorta.59,67 Some controversies exist
in the literature regarding the underlying pathogenesis of BAVrelated aortopathy.70 These are of major clinical relevance
because they will have an influence on the surgical management
of the valve and the ascending aorta. One proposition is that
aortic dilatation in BAV is a hemodynamic phenomenon,
because the structurally defective valve alters blood flow within
the aortic root, producing abnormal biomechanics inside the
proximal aorta.71 The resulting shear stress and friction on the
aortic endothelium subsequently lead to increased expression
of MMPs and growth factors that regulate matrix degradation
and vascular smooth muscle apoptosis. This proposition is
supported by the increased expression of MMP-2 and a higher
ratio of MMP-2 to TIMP1 activity in the tissue samples from
aortic aneurysms in BAV patients.59,69 An alternate proposition
is based on the observation that aortic dilatation can occur
in patients with normally functioning BAV or after valve
replacement.69,71 Moreover, an inherent structural alteration has
also been described in the ascending aorta of BAV patients.69,71
The dilated aortas of BAV patients demonstrate degeneration
of the aortic media with focal matrix disruption, fragmented
elastic lamellae, and higher rates of vascular smooth muscle
cell loss, which is also present in the no dilated aortas of
BAV patients.56,58 This cell loss is similar to that observed in
the aortas of Marfan syndrome patients, which may involve
Figure 4. Proposed pathogenetic
mechanism of bicuspid aortic valve (BAV).
Although BAV is largely genetically determined, both environmental and stochastic
factors play a contributory role in the
determination of BAV morphogenesis and
later manifestation of valve dysfunction
and complication. It is likely that different
BAV morphology have different etiologic
entities. R-N indicates right and noncoronary; R-L, right and left coronary; L-N, left
and noncoronary; A-P, anterior to posterior; and miRNA, microRNA.
576 Circ Cardiovasc Genet October 2012
the Bcl-2 mediator of apoptosis.67,69 Deficiency of fibrillin-1
has also been reported in BAV aortic tissue, and this may result
in increased TGF-β signaling, as seen in Marfan syndrome.69
This suggests an underlying genetic defect in the pathogenesis
of aortic dilatation in BAV, although both genetic and
hemodynamic factors likely contribute to the development of
osteopathy and subsequent disease progression.
Genetic Basis of BAV
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Familial clustering demonstrates that BAV is heritable,
with 9% prevalence in first-degree relatives of patients with
BAV, and up to 24% in families with >1 person affected.58,61
Table 2 summarizes the key genetic findings in BAV identified
to date. Genetic heterogeneity in BAV is demonstrated by the
involvement of mutations in diverse genes encoding transcription factors, extracellular matrix proteins, and signaling pathways that regulate cell proliferation, differentiation, adhesion,
or apoptosis.61,66,72
To date, only the transcriptional regulator NOTCH1 gene
at chromosome 9q34.3 has been linked to the development
and calcify progression of nonsyndromic BAV in humans,
in a limited number of familial cases and ≈4% of sporadic
cases.5,73 The Notch signaling pathway is highly conserved
and plays a critical role in cell fate determination and differentiation during organogenesis.72 NOTCH1 transcripts
are abundant in the mesenchyme of the outflow tract and the
developing aortic valve leaflets, which probably underlie the
role of notch signaling in aortic valve development.5 There
are 4 notch proteins in mammals (NOTCH1–4), which are
large single-pass Tran membrane receptors that are activated
upon binding with legends expressed on neighboring cells,
egg, Delta-like proteins (DLL1, DLL3, and DLL4) and jagged proteins (JAG1 and JAG2). The ligand–receptor interaction results in 2 independent proteolytic cleavages of the
notch receptor, first, by a metalloprotease followed by a presenilin, which releases the notch intracellular domain.74 The
notch intracellular domain then translocates to the nucleus
where it, together with its cofactors, activates transcription
of downstream target genes, including members of the hairy/
enhancer of split (Hes/Hey) family of transcription factors.74
NOTCH1 signaling also represses BMP-2 and the downstream osteogenic gene, RUNX2, a central transcriptional
regulator of osteoblast cell fate.5,75 Recently, NOTCH1
signaling has been shown to regulate the expression of
Sox9, a key chondrogenic transcription factor and regulator of extracellular matrix genes that is required for normal
valve development and maintenance.76 Although inhibition
of NOTCH1 signaling downregulates Sox9 expression and
promotes valvular calcification in vitro, overexpression of
Sox9 markedly attenuates the calcific process that occurs
with NOTCH1 inhibition.76 NOTCH1 mutations are therefore associated with both defective development of the aortic
valve and, later, derepression of an osteoblast gene program
and dysregulation of valvular extracellular matrix genes, via
a Sox9-dependent mechanism, leading to accelerated aortic
valve calcification.
Further evidence of specific gene mutations as a cause
of BAV has come from genome-wide marker-based linkage
analyses. Families showing autosomal dominant inheritance
of BAV and associated cardiovascular malformations have
shown linkage to chromosomes 18q, 5q, and 13q, whereas
families with BAV and ascending aortic aneurysms have
shown linkage to chromosome 15q25-26.59,66 The causal
gene(s), however, are yet to be identified. Furthermore,
mutations in ACTA2 gene on chromosome 10q, which encode
smooth muscle α-actin, cause thoracic aortic aneurysm and, in
some instances, BAV.58 It has been suggested that the different
phenotypes of BAV-associated aortopathy may be caused by
unique pathogenetic mechanisms.77 A missense mutation in
the TGFBR2 gene, c.1159G>A, which destabilizes the protein
structure, was segregated in a family with nonsyndromic
BAV with proximal aortic involvement,77 although the true
incidence of TGFBR mutation in the overall BAV population
is probably very low.78 Associations have also been reported
between aneurysm risks in BAV patients with polymorphisms
in eNOS, angiotensin I-converting enzyme, and MMP-9
and MMP-2 genes.79,80 Furthermore, downregulation of the
ubiquitin fusion degradation 1–like gene, which is highly
expressed in the cardiac outflow tract during embryogenesis,
has also been noted in BAV, and may represent a candidate
gene.81
In addition to the above studies in humans, animal studies
have shed light on the genetic basis of BAV. In mice, homozygous deletion of the endothelial NO (eNOS) synthase gene
Table 2. Gene Mutations in Human and Animal Models of Bicuspid Aortic Valve
Human
Mouse
Nonsyndromic (familial and sporadic) BAV:
NOS3 (eNOS) deficiency
NOTCH1 missense and frame shift mutations
Nkx 2.5 haploin sufficiency
Linkage to locus on Chr 5q, 13q, 18q
Targeted deletion of GATA5
GATA5 missense mutations
Syndromic BAV or BAV with other cardiovascular malformation:
Andersen syndrome—KCNJ2 mutation (Chr 17q)
Thoracic aortic aneurysm and dissection syndrome (TAAD)—ACTA2 mutation (Chr 10q)
Marfan syndrome—Fibrillin1 mutation (Chr 15q)
William Beuren syndrome—Elastin mutation (Chr 7q)
Turner syndrome (45XO karyotype)
BAV indicates bicuspid aortic valve; eNOS, endothelial NO synthase; ACTA2, α-actin-2; and Chr, chromosome.
Padang et al Genetics of Familial Valve Disease 577
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and haploinsufficiency in the cardiac homeobox gene Nkx2-5,
are associated with a higher incidence of BAV.82,83 However,
neither of these genes have been associated with BAV in
humans.84,85 Furthermore, targeted deletion of the transcription factor Gata5 in mice leads to partially penetrant BAV
with fusion of the right and noncoronary cusps.84 An essential role of GATA5 in cardiac morphogenesis and aortic valve
development has only recently been reported, whereby it
regulates several pathways involved in endocardial cell differentiation, including those directed by Bmp4, Tbx20, and,
notably, eNOS and NOTCH1.84 Downregulation of eNOS
expression and attenuation of the notch pathway are observed
in Gata5−/−mice,84 which may underlie the development of
BAV as mutations in eNOS, and NOTCH1 are associated with
BAV in mice and humans, respectively. It is interesting that a
number of rare nonsynonymous variations within the highly
conserved and functionally important GATA5 transcriptional
activation domains have recently been reported in up to 4% of
sporadic cases of human BAV.86 This provides support for the
role of GATA5 as a potential candidate gene in modulating the
pathogenesis of BAV disease in humans.
Animal studies are also at the forefront of research into the
hypothesis that the different BAV morphologies have a different etiologic basis. Gata5−/− mice, eNOS knockout mice, and
inbred Syrian hamsters each display a high incidence of BAV,
but with different valve morphologies. BAV with fusion of
the right coronary and noncoronary leaflets may result from
morphogenetic defects that happen before outflow tract septation, which probably relies on an exacerbated NO-dependent
endothelial-to-mesenchymal transformation. BAV with
fusion of right and left coronary leaflets may result from the
anomalous septation of the proximal portion of the outflow
tract, because of the distorted behavior of neural crest cells
(Figure 4).62 This anomalous behavior of the cardiac neural
crest is believed to explain the association of the right and left
coronary leaflet fusion BAV morphology with coarctation of
the aorta and the more pronounced aortic wall degeneration,
compared with BAV with fusion of the right and noncoronary
leaflets.62
It is interesting that Sans-Coma et al87 recently demonstrated that BAV in Syrian hamsters express a quantitative
trait, subject to polygenic inheritance, with reduced penetrance and variable expressivity. Furthermore, examination
of aortic valve morphology in virtually isogenic Syrian
hamsters produced by systematic inbreeding through fullsib mating, with the probability of homozygosity being
0.999 or higher, demonstrated the presence of BAV in up to
five sixths of the hamsters studied, whereas the remaining
one sixth had a trileaflet aortic valve. No significant association was noted between the valvular phenotype in the
parents and the offspring produced by crossing genetically
alike hamsters, with the probability of homozygosity of at
least 0.989. This suggests that a single underlying genotype
may predispose to BAV and account for the whole range
of valve morphology, and implies that nongenetic factors
are acting during embryonic life, creating “developmental
noise,” to influence the definitive anatomic configuration
of the valve.87 This finding supports a complex inheritance
pattern, as seen in human BAV, and may explain the relatively low recurrence rate of BAV in first-degree relatives,
despite its common prevalence within the general population.87 The findings also provide a potential explanation
regarding aortic valve anatomy in monozygotic twins
where BAV was present in 1 twin, but tricuspid aortic valve
in the other.88
Although specific gene mutations can cause BAV in
mice and humans, the variability in BAV morphology and
its disease manifestations cannot be entirely explained.
MicroRNAs (miRNAs) are a class of evolutionarily conserved small, noncoding RNAs that regulate gene expression
in development and disease. Reduced expression of miR-26a,
miR-30b, and miR-195 in stenotic BAV associated with calcification, compared with a regurgitant phenotype, has been
reported.89 In vitro transfection of each of these miRNAs into
human aortic valvular interstitial cells indirectly modulated
the expression of several calcification-related genes, including RUNX2, BMP-2, alkaline phosphatase (ALPL), SMAD1,
and SMAD3.89 Patients with BAV-associated aortic stenosis
have also been shown to have attenuated the expression of
miRNA-141, a repressor of BMP-2.90 Together, these studies suggest that miRNA dysregulation contributes to aortic
stenosis in BAV, and that miRNAs represent a potential new
therapeutic target to limit progressive aortic valve calcification and dysfunction.
Most recently, global gene expression levels have been
compared in aortic tissue from patients with a bicuspid or
tricuspid aortic valve, with and without thoracic aortic aneurysm.91 Only 7 genes were differentially expressed between
the nondilated BAV and nondilated tricuspid groups; the 4
upregulated genes were: left–right determination factor 2,
a TGF-β family member; Fraser syndrome 1, a member of
the extracellular matrix family of protein; Src homology 2
domain containing family, member 4;and death-associated
protein kinase 3, a proapoptotic gene; and the 3 downregulated genes were: VEGFC (a member of the vascular
endothelial growth factor family); NFASC (neurofascin
homolog, a member of the L1 family of cell adhesion molecule); and LSP1 (lymphocyte-specific protein 1). Given the
possible shared genetic underpinnings of BAV and related
aortopathy, an investigation of these genes in BAV is warranted. The study also showed that immune responsive
genes were upregulated in patients with tricuspid valve and
with a dilated aorta, compared with those with a dilated
aorta and BAV, suggesting that immune response genes are
not directly involved in BAV-related aneurysms. Rather,
BAV patients with aortic dilation showed an almost exclusive expression of the TGF-β–binding proteins LTBP3/4,
ADAMTSL1, and an alternatively spliced isoform of fibronectin-1 (FN1).91
Collectively, these findings support a genetic basis for
BAV, the pathogenesis of which involves a complex interplay between specific gene mutations, environmental
influences, and stochastic factors. The balance of this interaction is likely to have major influence on disease progression and severity, including valve dysfunction and aortic
complications.
578 Circ Cardiovasc Genet October 2012
Conclusions and Future Directions
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Current evidence points to heritable and familial VHD being a
final common pathway for a wide variety of altered molecular
and genetic defects. Determination of the genetic basis
underlying these disorders is complex. Not only that there
are large number of genes involved in valvulogenesis (genetic
heterogeneity) but epigenetic, environmental, and stochastic
factors are also important in modulating phenotype expression
and thus contributing to the wide spectrum of disease
manifestations (clinical heterogeneity). Recent advances in
the fields of valve development and familial VHD, combined
with major developments in genetic analysis technologies,
place the field at the precipice of accelerated discovery into
the causative and pathogenetic mechanisms responsible for
common heart valve defects.
Furthermore, the present limitation of pharmacological
therapy in delaying or stopping disease progression has left
surgical therapies as the most effective cure for many cases of
familial VHD. Improved understanding of the genetic basis,
molecular pathways, and cellular mediators involved in the
pathogenesis of VHD will create great opportunities for the
development of novel pharmacological treatment and prevention strategies in VHD. This knowledge has the potential
to also be used to stratify treatment modalities, time surgical intervention, and guide management of at-risk family
members, in terms of diagnostic, therapeutic, and prevention
strategies, with the overall aim of reducing the health burden
of VHD. With the advancement of genetic technologies, the
increasing availability of next-generation sequencing, coupled
with well-characterized families with VHD, we are hopeful
that many of the key genes and elusive pathways in VHD will
be identified in coming years.
Acknowledgments
Dr Padang is supported by a cofunded Postgraduate Scholarship (PC
10S 5530) from the National Health and Medical Research Council
(NHMRC) and the National Heart Foundation of Australia (NHFA),
Australia. Dr Semsarian is the recipient of a National Health and
Medical Research Council (NHMRC) of Australia Practitioner
Fellowship. This work was supported by a research project grant from
NHMRC (No. 1023318). We thank our surgical colleagues from the
Cardiothoracic Department of Royal Prince Alfred Hospital, Sydney,
Australia, for their support.
Disclosures
None.
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KEY WORDS: aortic valve ◼ genes ◼ genetic heart disease ◼ mitral valve
◼ valves
Genetic Basis of Familial Valvular Heart Disease
Ratnasari Padang, Richard D. Bagnall and Christopher Semsarian
Downloaded from http://circgenetics.ahajournals.org/ by guest on June 17, 2017
Circ Cardiovasc Genet. 2012;5:569-580
doi: 10.1161/CIRCGENETICS.112.962894
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