Molecular genetics of mitral valve prolapse

Robert A. Levinea and Susan A. Slaugenhauptb

Purpose of review
Mitral valve prolapse is a common disorder with a strong
hereditary component. It is associated with important mitral
regurgitation requiring surgical repair and other clinical
complications. Genetic studies can provide clues to
mechanism and therapy.
Recent findings
Advances in phenotypic classification have led to linkage to
sites on chromosomes 11, 13 and 16 and identification of
the first mutation in familial mitral valve prolapse not related
to connective tissue syndromes an X-linked filamin A
mutation. New understanding of mechanism based on
studies in a mouse Marfan model emphasize the dynamic
interplay of differentiating cells and growth factors, with
strong potential for therapy.
Summary
This new knowledge brings us closer to the ultimate goal of
preventing the progression of mitral valve disease to the
stage of clinical expression.
Keywords
filamin A, genetics, growth factor, mitral regurgitation,
mitral valve prolapse
Curr Opin Cardiol 22:171175. 2007 Lippincott Williams & Wilkins.
a

Cardiac Ultrasound Laboratory and bCenter for Human Genetics Research,

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,
USA
Correspondence to Robert A. Levine, MD, FACC, Cardiac Ultrasound Laboratory,
Massachusetts General Hospital, 55 Fruit Street, Yawkey 5068, Boston, MA
02114, USA
Tel: +617 724-1995; fax: +617 643 1616; e-mail: rlevine@partners.org
Current Opinion in Cardiology 2007, 22:171175
Abbreviation
MVP

mitral valve prolapse

2007 Lippincott Williams & Wilkins

0268-4705

Introduction
Mitral valve prolapse (MVP, MIM 157700) is a common
disorder with a strong hereditary component. It occurs in
approximately 2.4% of the general population [1,2].
Fibromyxomatous changes in the mitral leaflet tissue
cause superior displacement of the leaflets into the left
atrium [24]. MVP is associated with important mitral
regurgitation, bacterial endocarditis, congestive heart
failure and even sudden death [58], and is the most
common cause of isolated mitral regurgitation requiring
surgical repair [9]
With growing evidence that high-degree mitral regurgitation conveys adverse prognosis, it is important to
determine the mechanisms of MVP to provide clues to
therapy. Genetic mechanisms can provide such clues,
which may have implications even for sporadically
affected patients. Recent advances in phenotypic
classification have led to linkage results, and mechanistic
breakthroughs are promising.
Pathophysiology

MVP is characterized by progressive increases in area and

length of mitral leaflet tissue, and typically progresses
with a multidecade natural history, causing leaflets
to billow backwards during ventricular contraction,
prolapsing superiorly into the left atrium beyond their
normal position of closure at the level of the mitral ring or
annulus (Fig. 1). This causes mitral regurgitation, which
may progress and cause heart failure with limited exercise
tolerance, cardiac chamber dilatation, arrhythmias and
susceptibility to valve infection. Weakening of valvular
and restraining chordal tissue with sudden chordal
rupture causes abrupt clinical deterioration. Expression
is variable within families. The valve tissue itself shows
increased spongiosa, including altered collagen and
increased glycosaminoglycans, and a disrupted fibrous
backbone. Improved techniques, pioneered by Alain
Carpentier, have improved outcomes relative to valve
replacement. An ultimate goal remains understanding the
pathophysiology of the valve disease itself, however,
so that susceptible individuals, identified early, could
potentially receive therapy that would limit or prevent
clinical expression.
Diagnosis and prevalence of mitral valve prolapse

As MVP is defined by the abnormal relationship of the

mitral leaflets to their surrounding structures, cardiac
ultrasound is well suited for its diagnosis. MVP, however,
was originally diagnosed in a surprisingly high proportion
171

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172 Molecular genetics

Figure 1 Mitral valve prolapse with posterior leaflet flail

Leaflet abnormalities and valve development:

clues to a genetic cause?
Myxomatous valves show disorganized collagen and
elastin fibers, with pools of proteoglycans from the
spongiosa layer present in the load-bearing fibrosa
layer [3,15]. Myxomatous chordae contain significantly
more glycosaminoglycans than controls, specifically
chondroitin/dermatan 6-sulfate and hyaluronan [16],
which bind more water, contributing to the enlarged,
gelatinous nature of the chordae and leaflets.

Figure shows mitral valve prolapse in a patient with posterior leaflet (PL)
flail [large visible gap relative to the anterior leaflet (AL)] in a parasternal
long-axis echocardiographic view, with corresponding eccentrically
directed jet of mitral regurgitation (MR) (right). Ao, aorta; LA, left atrium;
LV, left ventricle.

of the general population, often in otherwise normal

individuals without clinical evidence of disease. Early
estimates of MVP prevalence ranged from 5 to 15%, and
were even as high as 35%. These studies relied on
auscultation and single-dimensional M-mode echo techniques. Despite the improved spatial appreciation and
view standardization of two-dimensional echocardiography, similarly high diagnostic rates could still be
obtained based on the assumption that the mitral
annulus, or attachment ring of the valve to the rest of
the heart, is planar, and that leaflet displacement relative
to the annulus in any view is abnormal [1012].
Three-dimensional echocardiographic studies have
shown that the mitral annulus is not a flat plane but
rather has a saddle-like shape with high points
positioned anteriorly and posteriorly and low points
medially and laterally [1114]. Appearances in twodimensional echo views must therefore be interpreted
in the context of this shape. In the long-axis view
through the anterior and posterior high points of the
valve, there is normally no displacement of the leaflets
into the left atrium. A side-to-side or four-chamber
view through such a structure, however, can normally
show leaflets apparently bulging upward relative to the
low points of the valve in the absence of any leaflet
disease or distortion. Eliminating the use of such views
has considerably reduced the frequency of MVP
diagnosis, providing greatly increased specificity
without loss of sensitivity. A recent survey carried
out in conjunction with the Framingham Heart Study
[1,2] has shown that the prevalence of MVP in an
unselected, community-based sample of ambulatory
subjects is 2.4%. This specificity fulfils an important
criterion for successful genetic studies.

Heart valves have a complex layered architecture and a

highly specialized extra-cellular matrix, the turnover of
which depends on a precise balance of synthesis and
degradation by matrix metalloproteinases and cysteine
endoproteases (cathepsins). In myxomatous tissue, the
interstitial cells regulating turnover have features of
activated myofibroblasts and express excessive levels
of catabolic enzymes [4]. Valve plasticity can therefore
continue into adult life.
Clues to pathways involved in abnormal leaflet biology
may be derived from understanding heart valve
development. Early septation of the cardiac tube into
distinct chambers is achieved through regional swellings
of extracellular matrix, known as cardiac cushions, which
form the primordial valves. Reciprocal signaling between
the endocardial and myocardial cell layers in the cushion,
mediated in part by TGF-b family members, induces a
transformation of endocardial cells into mesenchymal cells
[17]. Sox9 is activated when endocardial cells undergo
mesenchymal transformation, and Sox9-deficient mesenchymal cells fail to express ErbB3, which is required for
cushion cell proliferation [18]. The mesenchymal cells
migrate into the cushions and differentiate into the fibrous
tissue of the valves [19]. Several genes have been shown to
play pivotal roles in heart valve formation, including
calcineurin, with signaling and downstream activation of
the NFAT family of transcription factors, the absence of
which leads to fatal defects in valve formation [20,21]; Wnt/
beta-catenin signaling, which determines endocardial cell
fate during valve development [22]; fibroblast growth
factor (FGF)-4, the homeobox gene Sox4, and the
downstream modulator of TGF-b superfamily signaling
Smad6 [2325], the disruption of which leads to abnormally thickened, gelatinous valves. Defects in these genes
and their signaling cascades may also conceivably lead to
myxomatous change and mechanically weakened valves in
adult life. As discussed below, there is growing recognition
of this dynamic interplay of growth factors and cells
in valves, from which mechanistic concepts and therapeutic strategies may emerge [26,27,28,2932].
Genetics of mitral valve prolapse

Familial studies of idiopathic or nonsyndromic MVP

suggest an autosomal dominant mode of inheritance with

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Genetics of mitral valve prolapse Levine and Slaugenhaupt

incomplete penetrance [3335]. Additionally, sex and

age-dependent penetrance has been noted. The clinical
heterogeneity observed within families is often striking,
with severe valvular abnormalities seen in several
patients, while other affected family members show only
moderate or slight changes [36]. MVP has been reported
in association with many genetic connective tissue
disorders, including Marfan syndrome, EhlersDanlos
syndrome, osteogenesis imperfecta, dominant cutis laxa
and pseudoxanthoma elasticum [3743].
Studies have failed to link nonsyndromic familial MVP
with fibrillar or other collagen genes [44,45]. Negative
linkage results may have related to lack of systematic
examination of the entire human genome and phenotypic
uncertainty. More recently, understanding of threedimensional mitral valve shape has improved diagnostic
specificity and provided a sound basis for genetic studies.
Based on this phenotype, linkage of myxomatous MVP to
chromosome 16 (MMVP1) was first reported in two of four
families studied using a conservative model of disease
inheritance by Disse et al. [46]. Autosomal-dominant
familial MVP has also been linked by our group
to MMVP2 on chromosome 11p15.4 in a single large
pedigree and to chromosome 13q31.3q32.1 in another
[47,48]. These family studies by Nesta et al. [48] have
also led to the recognition of an early or prodromal form
without leaflet displacement into the atrium but with
anteriorly shifted leaflet coaptation, indicating posterior
leaflet elongation. The group of Herve Le Marec and
Jean-Jacques Schott in Nantes [49,50] have studied an
X-linked valvular dystrophy affecting both mitral and
aortic valves, which they have now linked to filamin A
mutations. Together, these studies confirm the strength
of the phenotyping and the genetic heterogeneity of
this condition, and suggest that MVP maybe the final
common outcome of multiple genetic defects, analogous
to familial hypertrophic cardiomyopathy [51,52]. Finding
loci containing diverse but functionally related genes
could provide helpful clues for gene identification and
increase our understanding of pathogenesis.
Mechanisms of valve abnormality

The long-held notion that MVP must have its root cause
in abnormalities of structural proteins has had little
confirmation outside the collagen mutations in Ehlers
Danlos syndrome [42]. The finding of mutations in
fibrillin a structural protein, responsible for Marfan
syndrome seemed at first to provide an additional
example of a structural deficiency causing the valve
to become susceptible to the constant buffeting by
myocardial and flow-related forces. A recent landmark
discovery by the laboratory of Harry Dietz [53] has
shown that the picture is far more intricate. The mitral
valve abnormality in mice with a fibrillin-1 mutation can
be rescued by perinatal administration of neutralizing

173

antibodies to TGF-b a growth factor that stimulates

activity and matrix formation by the valvular interstitial
cells. Fibrillin is therefore an important regulator of the
choreographed interplay between growth factors, made
by the interstitial cells, and the cells themselves. The
current proposal is that fibrillin stabilizes a TGF-b
complex, so that fibrillin mutation subjects the valve to
TGF-b overexpression. Along the same lines, valvular
abnormalities also occur in patients with mutated TGF-b
receptors in the LoeysDietz syndrome. Translating this
insight to potential clinical benefit, the same group [54]
has shown that Losartan an angiotensin converting
enzyme receptor (AT1) antagonist that also modulates
the interaction of TGF-b with valves and vascular structures can rescue the lethal aortic aneurysm expression
in the mouse model of Marfan syndrome.
These pathways may also figure in the mechanism of
nonsyndromic familial MVP. Charitakis and Basson
[55], for example, have suggested that the newly
discovered filamin A mutation responsible for X-linked
valvulopathy may also exert its effect through the
interaction of filamin A with molecules in the TGF-b
pathway. The emerging picture presents a unifying
theory of valve biology based on the dynamic interplay
of differentiating cells and growth factors, and highlights
the opportunities for understanding human disease
through animal models, both in mice and in the naturally
occurring King Charles spaniels [56].
Remaining questions

MVP presents enormous opportunities for discovery of

genes, mechanisms and therapies. The leaflet displacement or billowing that characterizes the condition
appears to be the end result of multiple genetic and
molecular pathways, and genetic defects can inform us
regarding the importance of those pathways. Given its
typically late manifestation in life, we do not yet know
how often MVP is familial compared with sporadic.
Phenotypes such as the fibroelastic deficiency described
by Carpentier, in which the leaflets are largely thin
but nevertheless prolapse and fail to coapt properly,
are another unexplored element in the constellation of
excessive leaflet motion, as is the nonmyxomatous leaflet
elongation in patients with hypertrophic cardiomyopathy.
To what extent pathways that allow normal leaflet growth
in the developing heart are activated in a potentially
nonadaptive manner in adult life needs to be explored.
Advances could come from exploring common themes in
the biology of the valvular and vascular endothelium, and
in the mesenchymal and interstitial elements of valves,
cartilage, bones and vascular plaque.

Conclusion
Recent advances have identified multiple genetic
loci associated with the excessive valve motion and

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174 Molecular genetics

regurgitation classified as MVP. These findings have

placed us on the threshold of accelerated discovery of
new genes and mechanisms, and closer to the ultimate
goal of preventing the progression of mitral valve
disease to the stage of severe regurgitation and clinical
complications.

Acknowledgement

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