Contemporary Reviews in Cardiovascular Medicine
Epidemiology and Pathophysiology of Mitral Valve Prolapse
New Insights Into Disease Progression, Genetics, and Molecular Basis
Francesca N. Delling, MD; Ramachandran S. Vasan, MD
M itral valve (MV) prolapse (MVP) is a common disorder,
afflicting 2% to 3% of the general population.1,2 It is
characterized by typical fibromyxomatous changes in the mitral
leaflet tissue with superior displacement of 1 or both leaflets
into the left atrium.3,4 With a prevalence of 2% to 3%, MVP is
expected to affect ≈7.8 million individuals in the United States
and >176 million people worldwide. MVP can be associated
with significant mitral regurgitation (MR), bacterial endocardi-
tis, congestive heart failure, and even sudden death.5–7
MVP is a clinical entity that is not fully understood, despite
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being known for more than a century. A “midsystolic click”
was first described in 1887 by Cuffer and Barbillon.8 In 1963,
Barlow and Pocock9 demonstrated the presence of MR by
angiography in patients with the “click-murmur” syndrome.
Criley et al10 subsequently coined the term MVP.
MVP may be familial or sporadic. Despite being the most
common cause of isolated MR requiring surgical repair,11
little is known about the genetic mechanisms underlying the
pathogenesis and progression of MVP. Studies on the heri-
table features of MVP have been limited by the analysis of
relatively small pedigrees and by self-referral and selection
biases, including a preponderance of data from hospital-based
cohorts.12,13 Nonetheless, the majority of data favor an auto-
somal-dominant pattern of inheritance in a large proportion
of individuals with MVP.12,13 Despite the variability in clini-
cal features, familial MVP might be considered a prevalent
mendelian cardiac abnormality in humans. Although filamin-
A has been identified as causing an X-linked form of MVP,14
the causative genes for the more common form of autosomal-
dominant MVP have yet to be defined. In this review, we sum-
marize our current knowledge of the diagnosis, epidemiology,
prognosis, pathophysiology, and genetics of MVP, with a
focus on potential future research directions.
Diagnosis of MVP
Physical examination and 2-dimensional (2D) echocardiog-
raphy are the diagnostic gold standards for MVP.15,16 Various
symptoms (including atypical chest pain, exertional dyspnea,
palpitations, syncope, and anxiety) and clinical findings (low
blood pressure, leaner build, and electrocardiographic repo-
larization abnormalities) have been associated with MVP, and
their constellation has been called the MVP syndrome.1,17 Of
From the Framingham Heart Study, Framingham, MA (F.N.D., R.S.V.); Department of Medicine (Cardiovascular Division), Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA (F.N.D.); and Cardiology Section, and Preventive Medicine Section, Boston University School of
Medicine, Boston, MA (R.S.V.).
Correspondence to Francesca Nesta Delling, MD, Beth Israel Deaconess Medical Center, Cardiovascular Division, 330 Brookline Ave, E/SH-458,
Boston, MA 02215. E-mail fdelling@bidmc.harvard.edu
(Circulation. 2014;129:2158-2170.)
© 2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
2158
the numerous reported correlates, only the association with
leaner body mass has been reproducibly associated with MVP
in the literature.1 Abnormal autonomic function has been
reported as the mechanism explaining symptoms in patients
with MVP,18 but given its absence in asymptomatic MVP
patients, it remains unclear whether MVP is directly related to
autonomic dysfunction or any reported association is purely
incidental.19 Hypomagnesemia and dysregulation of the renin-
angiotensin-aldosterone system have also been demonstrated
in MVP syndrome, albeit in small patient samples.20,21
The classic auscultatory finding in MVP is a dynamic,
midsystolic to late systolic click frequently associated with a
high-pitched, late systolic murmur. A careful physical exami-
nation is highly sensitive for making a diagnosis of MVP, but
its specificity is limited (with echocardiography used as the
gold standard).22 Redundant leaflets or chordae may produce
an audible click without echocardiographic evidence of leaf-
let prolapse, giving false-positive physical findings. Finally,
echocardiographic prolapse may exist without significant aus-
cultatory findings.22 Patients with physical examination find-
ings that suggest MVP should undergo confirmatory testing
with 2D echocardiography.
In the early days of 2D echocardiography, the diagnosis of
MVP occurred with a prevalence ranging from 5% to 15% and
in as many as 35% of those undergoing imaging.23–25 In part,
this overdiagnosis was the result of the erroneous assump-
tion that the MV was planar; thus, any sonographic view that
showed excursion of the leaflets superior to the mitral annu-
lus was deemed pathological. Pivotal echocardiographic work
in the late 1980s redefined normal mitral anatomy.26 Using
3-dimensional echocardiographic imaging, Levine and col-
leagues26 established that the mitral annulus was in fact saddle
shaped. Therefore, in the anterior-posterior axis, the mitral
annulus is concaved upward, whereas medially to laterally,
the annulus is concaved downward. This mitral geometry cre-
ates the possibility that, in a sonographic 4-chamber view,
the leaflets can appear to “break” the annular plane (creating
the appearance of prolapse) when in reality they are normal.
Echocardiographic MVP has since been defined as single-
leaflet or bileaflet prolapse of at least 2 mm beyond the long-
axis annular plane, with or without mitral leaflet thickening
(Figure 1A). Prolapse with thickening of the leaflets >5 mm is
DOI: 10.1161/CIRCULATIONAHA.113.006702
 Delling and Vasan   Epidemiology and Pathophysiology of MVP   2159
Figure 1. Prolapse of the intermediate posterior mitral valve scal-
lop (P2) shown in a long-axis view of (A) a 2-dimensional (2D)
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transthoracic echocardiogram, (B) a 2D transesophageal echo-
cardiogram (TEE) with (C) associated severe, eccentric, anteriorly
directed mitral regurgitation, and (D) a 3-dimensional TEE surgi-
cal view. AO indicates aorta; LA, left atrium; LV, left ventricle; and
RV, right ventricle.
called classic prolapse, whereas prolapse with lesser degrees
of leaflet thickening is regarded as nonclassic prolapse.26
Transthoracic echocardiography (TTE) may not adequately
visualize the entire MV anatomy. Anatomically, the posterior
and anterior leaflets of the MV each may be divided into 3 sec-
tions. Carpentier’s widely recognized nomenclature describes
3 posterior leaflet scallops, the lateral (P1), middle (P2), and
medial (P3), and 3 anterior segments, the lateral (A1), middle
(A2), and medial (A3; Figure 1D).27,28 Most cases of prolapse
involve the posterior middle scallop, which is easily identi-
fied on long-axis TTE images (Figure 1A). However, the
posterior lateral scallop (P1) is not clearly seen on long-axis
images but is best visualized in the apical 4-chamber view.
As noted above, superior leaflet displacement in a 4-chamber
view should not be regarded as diagnostic of prolapse. Thus,
TTE can confirm the diagnosis of MVP but may not be able
to exclude prolapse of all scallops. Although the Carpentier
nomenclature is based on leaflet indentation, in the Duran
classification, scallops are grouped on the basis of chordal
attachments.29 Specifically, the anterior leaflet is divided into
2 segments (A1 and A2) and the posterior into 4 segments (P1,
PM1, P2, and PM2). Segments A1, P1, and PM1 attach to the
anterolateral papillary muscle, and segments A2, P2, and PM2
attach to the posteromedial papillary muscle. The modified
Carpentier classification30 is a combination of the Carpentier
and Duran nomenclatures. Although the Duran and modified
Carpentier classifications are anatomically more precise than
the classic Carpentier scheme, they are less widely used.
By taking into account several planes of imaging, 2D
transesophageal echocardiography (TEE) is more effective
in identifying prolapsing MV segments (Figure 1B).28 Three-
dimensional TEE has the additional advantage of simulating
the surgeon’s view of the MV, with the aortic valve at the 11
o’clock position (Figure 1D), and has become an essential tool
in the intraoperative setting.31
Cardiac magnetic resonance (CMR) represents a novel,
albeit still not widely used, noninvasive imaging method that
identifies MVP with a sensitivity and specificity of 100%
with 2D TTE used as the gold standard (Figure 2A).32 In
addition, CMR can quantify MR using phase-contrast veloc-
ity mapping.33 Because CMR can reliably provide quantita-
tive determination of ventricular volumes and function, it is
becoming an important clinical tool for following up patients
with MVP-related moderate to severe MR and for surgical
decision making.34 Finally, CMR provides novel insight into
the biology of the MV and its linked myocardium through
improved spatial resolution provided by 3-dimensional
acquisition of images with delayed gadolinium enhance-
ment.32 Such enhancement occurs when the kinetics of gado-
linium excretion is different in 2 adjacent compartments so
that over time 1 compartment enhances more than the other.
This has been a powerful tool for delineating infarcted and
scarred myocardium, which excrete gadolinium more slowly
than viable tissue. The presence of gadolinium enhancement
has been shown in both the MV and in papillary muscle
tips in patients with MVP but not in normal control sub-
jects (Figure 2B).32 It has been speculated that the papil-
lary muscle is altered in MVP by repetitive traction exerted
by the prolapsing leaflets,35 which has been shown experi-
mentally to lower the threshold for arrhythmias.36 Although
more frequent complex arrhythmia on 24-hour ambulatory
Holter monitor has been demonstrated in MVP patients with
scarring of the papillary muscles,32 its clinical significance
remains to be established.
Clinical Classification and Prevalence of MVP
MVP can be distinguished into primary or nonsyndromic
MVP and secondary or syndromic MVP. In the latter case,
MVP occurs in the presence of connective tissue disorders
such as Marfan syndrome (MFS), Loeys-Dietz syndrome,
Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudo-
xanthoma elasticum, and the recently reported aneurysms-
osteoarthritis syndrome.37–42 MVP has also been observed
in hypertrophic cardiomyopathy (HCM) and may con-
tribute to the pathophysiology of obstruction typical of
this myopathy.43
Figure 2. Cardiac magnetic resonance steady state free pro-
cessing long-axis view of bileaflet mitral valve prolapse (A).
Short-axis view with 3-dimensional late-gadolinium enhance-
ment (3D-LGE) showing fibrosis of the papillary muscle tips.
Adapted from Han et al32 with permission from the publisher.
Copyright © 2008 Elsevier B.V. Authorization for this adaptation
has been obtained both from the owner of the copyright in the
original work and from the owner of copyright in the translation
or adaptation.
 2160  Circulation  May 27, 2014
Nonsyndromic MVP
Based on revised echocardiographic diagnostic criteria, the
26
prevalence of MVP and its clinical associations were examined
in the community-based Framingham Heart Study (FHS).1
The sample analyzed consisted of 3491 participants in whom
routine 2D echocardiograms were available and adequate for
the evaluation of the MV. Forty-seven individuals (1.3%) had
classic and 37 (1.1%) had nonclassic MVP, yielding an esti-
mated overall prevalence of 2.4%. The prevalence of MVP was
distributed fairly evenly among individuals in each decade of
age from 30 to 80 years of age. With respect to sex, MVP was
equally distributed between men and women. These findings
differed from older studies based on M-mode diagnostic cri-
teria or observations of pedigrees12,13 that reported that MVP
preferentially afflicted women and older individuals. Although
the genetic predisposition to develop MVP may be present at
birth, MVP is not found in newborns,44 and its prevalence is
low among children (0.3%)45 and young adults (0.6%).46 These
findings suggest that MVP is a progressive disease affecting
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predominantly middle-aged individuals.1 Participants with
MVP in FHS were leaner compared with those without MVP.1
An important limitation of the FHS sample is that it is pre-
dominantly white. A similar prevalence of MVP was described
in a population-based sample of American Indians (the Strong
Heart Study),2 and in a different sample of Canadians of South
Asian, European, and Chinese descent (the SHARE study).47
Although these recent studies were based on revised echocar-
diographic criteria, the prevalence of MVP in blacks was based
on older M-mode criteria and nonstandard 2D echocardio-
graphic views.48 A systematic review of the published literature
did not reveal prior studies that have evaluated the prevalence
of MVP in Hispanic samples.
Tricuspid valve prolapse has been observed in up to 40%
to 50% of patients with primary or nonsyndromic MVP,49 but
isolated tricuspid prolapse has rarely been reported.
Syndromic MVP: MFS and Other Connective
Tissue Disorders
The prevalence of at least mild MV pathology in MFS has been
estimated to be ≈75%, whereas the prevalence of more severe
myxomatous MV thickening with prolapse is closer to 25% in
these individuals.50 The prevalence of MVP in patients with
Ehlers-Danlos syndrome using standard echocardiographic
criteria appears to be much lower (6%).37 The prevalence
of MV disease also appears to be lower in patients with the
Loeys-Dietz syndrome (relative to MFS).51 One group reported
a direct comparison of MVP prevalence in 71 individuals with
transforming growth factor-β (TGF-β) receptor 2 (TGFBR2)
mutations (characteristic of Loeys-Dietz syndrome) with that
in 243 people with fibrillin-1 (FBN1) mutations (typical of
MFS) and in 50 unaffected family members.51 The investiga-
tors observed a substantially higher prevalence of both MVP
and MR in the cohort with FBN1 mutations than in the group
with TGFBR2 mutations (45% and 56% versus 21% and 35%,
respectively). Among affected individuals with the aneurysms-
osteoarthritis syndrome, MV abnormalities were common and
ranged from mild to severe; 10 of 22 (45%) had MVP and 6
of 22 (27%) had MR.42 The presence of MVP has also been
described in osteogenesis imperfecta and pseudoxanthoma
elasticum,38,52 although the true prevalence of the disease is
unclear because standard diagnostic criteria were not used in
the initial imaging studies performed on these patients.
Hypertrophic Cardiomyopathy
The largest study assessing the prevalence of MVP in HCM
observed it in 3% (of 528 people with HCM), which might
suggest that HCM and MVP are 2 distinct conditions that may
coexist in some cases.53 However, the prevalence of other MV
abnormalities (leaflet elongation and increased thickness) is
much higher in HCM, estimated at 66% in 1 study.54 This sug-
gests that MV abnormalities are intrinsic to HCM,54 either as
a primary trait or as a secondary adaptive response to shear
stress in a turbulent outflow tract or paracrine effects arising in
the adjacent hypertrophic ventricle (see below).55
Prognosis of MVP
A Controversial Past
The prognosis of MVP has varied in the published literature.
In the community-based FHS sample, MVP was described as
a benign entity with a low occurrence of adverse sequelae.1
Specifically, none of the individuals with MVP had a his-
tory of heart failure, 1 patient (1.2%) had atrial fibrillation,
1 patient (1.2%) had cerebrovascular disease, and 3 patients
(3.6%) had syncope. The prevalence of these outcomes in the
subjects without prolapse was 0.7%, 1.7%, 1.5%, and 3.0%,
respectively. The frequencies of chest pain, dyspnea, and elec-
trocardiographic abnormalities were similar among individu-
als with and without MVP. Individuals with MVP had a greater
degree of MR than those without prolapse, but typically the
valvular regurgitation was classified as trace or mild.1 In prior
studies,5,6 MVP was portrayed as a disease with frequent and
serious complications, including stroke, atrial fibrillation,
heart failure, and MR requiring surgery. These discrepancies
may be due to selection biases inherent in evaluating symp-
tomatic patients at referral tertiary care centers compared with
observations made on healthier asymptomatic volunteers.1,5,6
Changes in diagnostic criteria for MVP over time may have
further exacerbated these differences in the prevalence of
MVP.26 Subsequently, a community-based study from the
Mayo Clinic conducted in a primary care setting has under-
scored the clinical heterogeneity of MVP, including a widely
varying prognostic spectrum.56 Based on primary (depressed
left ventricular ejection fraction, moderate/severe MR) and
secondary (age >50 years, mild MR, left atrial enlargement,
atrial fibrillation, and flail leaflet) risk factors, different groups
of MVP with varying prognoses were identified with regard
to cardiovascular morbidity and mortality.56 Overall, young
(<50 years of age), medically treated patients presenting with
normal left ventricular function and no symptoms have excel-
lent survival, even with severe MR.56,57 The benefit of early
surgery (ie, valve repair in asymptomatic patients) versus a
watchful wait was suggested in observational studies58 but
remains controversial.57
Impact of MR
The common denominator of the studies evaluating prog-
nosis of MVP is the role of MR at the time of diagnosis in
 Delling and Vasan   Epidemiology and Pathophysiology of MVP   2161
determining the risk for adverse events (such as congestive
heart failure, atrial fibrillation, ischemic neurological event,
and endocarditis) and the need for surgery on follow-up.1,5–7,59,60
The Mayo Clinic series highlighted that over a follow-up
period of 1.5 years, MR volume increased >8 mL in 51% of 74
individuals with MVP. In this clinical series, the progression
of the valvular lesion (particularly a new flail leaflet) and an
increase in the mitral annular diameter were the 2 independent
predictors of an increase in the regurgitant volume over time.60
Although mitral leaflet thickness >5 mm on M-mode echocar-
diography has been associated with increased risk for sudden
death, endocarditis, and MR in patients with classic prolapse
in some series,5,6 a more recent larger series using 2D echo-
cardiography reported that mitral leaflet thickness was not an
independent predictor of mortality and valvular morbidity.7
In this community-based study of 833 individuals diagnosed
with asymptomatic MVP and followed up longitudinally in
Olmsted County, cardiac mortality was best predicted by the
presence of MR and left ventricular dysfunction at the time of
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diagnosis. Risk factors for cardiac morbidity (defined as the
occurrence of heart failure, thromboembolic events, endocar-
ditis, atrial fibrillation, and need for cardiac surgery) included
age ≥50 years, left atrial enlargement, MR, the presence of a
flail leaflet, and prevalent atrial fibrillation at the time of the
baseline echocardiogram.7
Impact of a Flail Leaflet
The presence of a flail MV leaflet has been associated with
a widely varying prognosis.61 Survival in medically treated
asymptomatic patients with MVP presenting with a flail leaflet
and normal left ventricular function is excellent.61 Thus, such
patients are at relatively low risk of cardiovascular morbidity.
The indications for valve surgery in this group include the devel-
opment of atrial fibrillation (4%/y) and heart failure (5.7%/y).
Older age, the presence of symptoms, and a left ventricular
ejection fraction <60% at the time of initial diagnosis increase
the risk of developing heart failure and atrial fibrillation and
are markers of the need for valve surgery and mortality.61,62 As
for chronic severe MR in general, management decisions for
patients with flail leaflet are based largely on the presence or
absence of clinical symptoms, the functional state of the left
ventricle, and the feasibility of successful MV repair.16
Sex-Related Differences in Outcomes
As noted, the prevalence of MVP was similar in the 2 sexes in
the FHS, a referral-free, community-based sample.1 Conversely,
in the Olmsted County population, characterized by a mixed
spectrum of community-dwelling and referred patients, with
the use of similar echocardiographic criteria, women were
diagnosed with MVP more often than men and at a younger
age.56 However, complications (such as the development of a
flail leaflet) have been reported more frequently in men.62 The
Mayo Clinic group also underscored the anatomic and func-
tional differences between the 2 sexes in the context of MVP.
Women present with more anterior and bileaflet prolapse, more
thickened leaflets, fewer flail leaflets, and less MR compared
with men.63 These milder clinical features in women have led
to the speculation that an interplay may exist between load-
ing conditions on the valve (such as higher blood pressure in
men) and the development of complications in MVP. However,
women represent a large proportion of patients with moderate
or severe MR. In these severe forms, the assessment of left ven-
tricular enlargement in women is challenged by the differences
in weight and height between the 2 sexes and the frequent use
of an absolute rather than a body size–adjusted left ventricular
size measurement. Consequently, for the same degree of MR,
women undergo mitral surgery less frequently and later than
men. As a consequence, women exhibit excess long-term mor-
tality but equivalent survival after valve surgery compared with
men.63 Thus, there are important sex-related differences in the
morphology, presentation, and prognosis of MVP.
Pathology and Pathophysiology
Myxomatous Valve Degeneration
MVP is characterized by progressive increases in the area and
length of the MV tissue and typically progresses with a natu-
ral history spanning decades, causing leaflets to thicken ana-
tomically and prolapse superiorly into the left atrium beyond
the mitral annulus in systole, leading to MR (Figure 1C).
Histologically, the mitral leaflets in MVP are characterized by
myxomatous degeneration. A detailed explanation of myxo-
matous changes requires an understanding of the histology
and the development of the normal MV.
Normal MV Histology and Alterations in MVP
The extracellular matrix (ECM) constitutes the fibroskeleton
of a normal MV. Normal valve tissue is divided into 3 layers:
the atrialis on the atrial side; the spongiosa, which is the mid-
dle layer; and the fibrosa on the ventricular side (Figure 3).64
The atrialis, a dense sheet of elastic fibers, provides elasticity
to the valve leaflet. The spongiosa is rich in glycosaminogly-
cans and proteoglycans within a fine, interweaving, spongy
elastin network. It functions to resist compression between the
outer layers, gives flexibility to the valve leaflet, and dampens
the vibrations resulting from valve closure. The fibrosa, which
is the thickest part of the leaflet, is made up primarily of orga-
nized collagen fibers that give the valve its tensile strength.64
Figure 3. Schematic of normal mitral valve histology. ECM indi-
cates extracellular matrix; GAG, glycosaminoglycans; VEC, val-
vular endothelial cells; and VIC, valvular interstitial cells. Adapted
from Bischoff and Aikawa66 with permission from the publisher.
Copyright © 2011 Springer. Authorization for this adaptation
has been obtained both from the owner of the copyright in the
original work and from the owner of copyright in the translation or
adaptation.
 2162  Circulation  May 27, 2014
Valvular leaflets are populated on the surface by endothelial
cells (VECs) and by interstitial cells (VICs) within the valve
(Figure 3). VICs, which originate from endothelial progenitor
cells, are considered the principal initiators of collagen synthe-
sis and degradation in the valve leaflets.65 Quiescent VICs are
noncontractile, α-smooth muscle actin–negative, fibroblast-
like cells that can synthesize and degrade matrix enzymes.65
Enzymes secreted by the VICs include matrix metalloprotein-
ases (MMPs) such as collagenase (MMP-1) and gelatinases
(MMP2 and MMP9), as well as tissue inhibitors of MMPs.65
Quiescent VICs maintain a tight balance between degradation
and synthesis of the matrix proteins, thus allowing normal
valve leaflet strength and function.
Myxomatous degeneration is characterized by the expansion
of the middle spongiosa layer of the valve (resulting from an
accumulation of proteoglycans), structural alterations of colla-
gen in all components of the leaflet, and structurally abnormal
chordae.3,4 Dysregulation of ECM components plays a key role
in mediating these changes. In MVP, the VICs acquire proper-
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ties of activated myofibroblasts characterized by the expression
of vimentin and α-smooth muscle actin but not SM1 or SM2
(markers of differentiated smooth muscle cells).3,66 Activated
myofibroblasts are responsible for increased concentrations of
various proteolytic enzymes, including MMPs, which degrade
collagen and elastin at a rate exceeding the rate of production
seen in quiescent VICs.67 In addition, cells staining for the
pan-hematopoietic marker CD45+ can also be found in myxo-
matous valve tissue66 and may represent fibrocytes capable of
differentiating into myofibroblasts that can both secrete matrix
and degrade collagen and elastin.
The chordae tendineae in myxomatous valves do not appear
to have increased cellularity, although they contain increased
amounts of glycosaminoglycans.68 In a study by Grande-Allen
et al,68 myxomatous chordae contained significantly more
chondroitin/dermatan 6-sulfate and slightly more hyaluronan
than control chordae. In contrast to leaflets, which contained
predominantly hyaluronan, the predominant glycosamino-
glycan class in chordae was chondroitin/dermatan sulfate.
Myxomatous chordae contained more water and less col-
lagen than control chordae. These findings may account for
the reduced tensile strength at which the valve leaflets, and
especially the chordae, fail in MVP.69 Chordal rupture is a
frequent pathological finding in MVP and may be secondary
to mechanical weakening of the chordae, combined with the
abnormal hemodynamic stresses arising from the redundancy
of the valve leaflets.68,69
Finally, degenerative processes have 2 main histological
phenotypes recognized in the surgical literature70: diffuse
myxomatous degeneration (or Barlow’s disease) and fibroelas-
tic deficiency. Barlow’s disease is characterized by thickened
and diffusely redundant myxomatous leaflet tissue with dis-
rupted collagen and elastic layers, leading to prolapse of most
of the mitral leaflet segments, severe mitral annular enlarge-
ment, and elongated (rarely ruptured) chordae.70 Patients usu-
ally present young or are middle-aged at the time of surgery
after a long history of murmur or MR. Fibroelastic deficiency
is characterized by decreased connective tissue deficient in
collagen, elastin, and proteoglycans; thin, smooth, translu-
cent leaflets without excess tissue and only moderate annulus
dilatation; and thin, slightly elongated chordae. Patients fre-
quently present at an older age with chordal rupture and flail
leaflet after a shorter (if any) clinical history. Although most of
the mitral leaflet is thin, localized myxomatous degeneration
and thickening occur within the flail scallop, mainly of the
posterior leaflet.70 Although Barlow’s disease and fibroelastic
deficiency are treated with very different surgical approaches,
it is unclear whether they represent 2 histopathological fea-
tures of the same syndrome or 2 genetically distinct entities.
Molecular Biology of Valve Changes in MVP
Some clues to the various signaling pathways involved in
abnormal valve biology in MVP can be gleaned from our
understanding of normal heart valve development. Early sep-
tation of the cardiac tube into distinct chambers is achieved
through regional swellings of the ECM, known as cardiac
cushions, which form the primordial valves.66 Reciprocal sig-
naling between the endocardial and myocardial cell layers in
the cardiac cushion (mediated in part by members of the TGF-
β family) induces a transformation of the endothelial cells
(VECs) into interstitial or mesenchymal cells (VICs).71 This
transformation is also known as endothelial to mesenchymal
transition.66 Sox9 is a transcription factor activated when the
endothelial cells undergo mesenchymal transformation, and
Sox9-deficient mesenchymal cells fail to express ErbB3, an
enzyme required for the proliferation of cardiac cushion cells.72
The mesenchymal cells then migrate into the cardiac cushions
and differentiate into the fibrous tissue of the valves.72
Several genes have been shown to play pivotal roles in the
formation of the heart valves: calcineurin, with the signaling
and downstream activation of a family of transcription factors
called nuclear factor of activated T cells (the absence of acti-
vation of the nuclear factor of activated T cells leads to fatal
defects in cardiac valve formation)73; Wnt/β-catenin signal-
ing, which determines the fate of the endocardial cells during
valve development;74 fibroblast growth factor-4 (FGF-4); the
homeobox gene Sox4; and the downstream modulator of TGF-
β superfamily signaling SMAD6,67,75 the disruption of which
leads to abnormally thickened, gelatinous valves. Defects in ≥1
of these genes and their signaling cascades may also conceiv-
ably lead to myxomatous change and mechanically weakened
valves in adult life.66 Similar to syndromic MVP (see below),
TGF-β upregulation appears to have a pivotal role in various
biological pathways in the pathogenesis of primary or nonsyn-
dromic MVP. Specifically, TGF-β is known to activate VICs
toward a pathological synthetic phenotype, as shown both in
animal models76 and in human in vitro studies. Geirsson et al77
demonstrated TGF-β signaling dysregulation in clinical speci-
mens of sporadic MVP cases undergoing MV repair. TGF-
β–induced ECM production in cultured valvular interstitial
cells was dependent on SMAD2/3 and p38 signaling and was
inhibited by angiotensin II receptor blockers. In another study
of human MVP surgical specimens by Hulin et al,78 upregula-
tion of TGF-β2 was secondary to the reduced expression of
metallothioneins, genes involved in the response to oxidative
stress. In turn, TGF-β2 upregulation led to downregulation of
genes of the ADAMTS family (responsible for degradation
of proteoglycans), ultimately causing excessive ECM remod-
eling. Finally, upregulation of bone morphogenetic protein
 Delling and Vasan   Epidemiology and Pathophysiology of MVP   2163
has also been shown to mediate the activation of VICs from
healthy quiescent cells to a pathological synthetic phenotype
in microarray data of clinical MVP specimens.79
Endothelial to mesenchymal transition can be induced
in vitro and is increased in vivo in response to mechanical
stretch, suggesting that endothelial to mesenchymal transition
not only occurs in normal valve development but also plays a
role in adaptation to pathophysiologic conditions.66 The abil-
ity of valves to remodel and “reset the clock” in response to a
reduction in mechanical stretch can be derived from the clini-
cal context: MV repair is typically very durable, suggesting
that an annuloplasty ring, by reducing the mechanical load on
the valves and chordae, improves long-term valve function.
The mesenchymal differentiation potential of the VECs can
be directed toward their transformation into osteogenic and
chondrogenic phenotypes, reflecting an ability of these cells
to generate VICs that reside in specific regions of the valve.66
The multilineage differentiation potential of the VECs, com-
bined with a robust capacity for self-renewal, strongly sug-
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gests that at least a subset of the VECs are likely progenitor
cells.66 Such progenitor cells may be essential for the health
and longevity of the valve and may become activated during
the disease process. Whether these cells can be harnessed or
manipulated to prevent or limit valve disease is an exciting
direction for future translational research.
Altered ECM turnover is also crucial in the pathogenesis
of ruptured chordae tendineae in MVP. Although the heart is
a vascular-rich organ, most of the cardiac valve complex is
avascular (similar to cartilage and tendons).80 Work by Kimura
et al81 showed a differential local expression of tenomoduline
(a recently isolated antiangiogenic factor) measured in the
chordae tendinae. Specifically, tenomoduline is locally absent
in the ruptured zones of the chordae, favoring abnormal vessel
formation also in combination with enhanced expression of
vascular endothelial growth factor-A. Moreover, in contrast
to what was observed in normal or nonruptured areas, higher
numbers of inflammatory cells positive for CD11b, CD14, and
vimentin and with an augmented expression of MMP-2 and
-13 were detected in association with the downregulation of
tenomoduline.81
Molecular Biology of Syndromic MVP
Syndromic MVP associated with connective tissue disorders
has been shown to manifest myxomatous changes similar
to primary or nonsyndromic MVP.82 MFS is associated with
mutations in the FBN1 gene (chromosome 15q15-q21).83 It
can also be caused by inactivating mutations of the TGFBR2
gene, located on chromosome 3p24.2-p25.84 A recent study
addressed the importance of TGF-β dysregulation in the con-
nective tissue for the development of MVP in MFS. Ng et
al85 tested the hypothesis that the FBN1–TGF-β pathway is
implicated in the pathogenesis of MVP in a murine model of
MFS. Increased TGF-β signaling was observed in the prolaps-
ing valves of FBN1-deficient mice. Treatment with a TGF-β–
neutralizing antibody successfully normalized both the length
and the thickness of the MV leaflets in these mutant mice,
further supporting the hypothesis that the valve abnormalities
in this mouse model were caused by increased TGF-β lev-
els.85 The responsiveness of the MV length and thickness to
excess TGF-β activity has implications for the identification
of novel genes that may be implicated in the pathogenesis of
MV disease. Furthermore, these findings raise the possibil-
ity that myxomatous MV disease could potentially be treated
with therapies that reduce TGF-β overexpression. Although
treatment with TGF-β–neutralizing antibodies successfully
improves many phenotypic manifestations of MFS in murine
models, this therapy cannot be readily translated to the treat-
ment of the human form of the disease in the absence of US
Food and Drug Administration–approved “humanized” anti-
bodies that block TGF-β. Because of the extensive interac-
tions between angiotensin II and TGF-β signaling pathways,
mice with a FBN1 mutation were treated with losartan, a selec-
tive angiotensin II type 1 receptor antagonist, in an attempt
to reduce TGF-β signaling.86 Remarkably, the mutant mice
treated with losartan had dramatic improvement in their rate
of aortic root growth compared with mutant mice treated with
β-adrenergic receptor blockers in doses with similar hemody-
namic effects.86 In the recently published Cozaar in Marfan
Patients Reduces Aortic Enlargement (COMPARE) trial,87
losartan reduced aortic root dilatation rate compared with pla-
cebo in adult humans with MFS. Another trial comparing the
effect of losartan and atenolol on aortic dilatation and MVP in
children and young adults with MFS is ongoing.88,89
Among other connective tissue disorders commonly asso-
ciated with MV disease, the Loeys-Dietz syndrome typically
involves marked arterial tortuosity and distinct craniofacial
abnormalities such as hypertelorism and cleft palate. It is
caused by heterozygous mutations in either the TGFBR1 gene
or the TGFBR2 gene that encode subunits of the TGF-β recep-
tor.39 Immunostaining of diseased tissues from affected indi-
viduals with the syndrome shows evidence of increased TGF-β
activity such as increased nuclear accumulation of phosphory-
lated SMAD2 and increased connective tissue growth factor,
which is induced by TGF-β.39 In the aneurysms-osteoarthritis
syndrome, characterized by aortic aneurysms, arterial tortu-
osity, craniofacial features (similar to the Loeys-Dietz), and
early-onset osteoarthritis,42 inactivating heterozygous muta-
tions in MADH3 encoding SMAD3 (positive regulator of
TGF-β signaling) have been identified, once again pointing
to the link between TGF-β overexpression and myxomatous
MV disease.
Nonmyxomatous Valve Elongation: HCM and
MV Disease
Elongation and pathological thickening of the MV are com-
monly seen in HCM, a genetic disorder typically caused by
mutations in sarcomere genes and characterized by unex-
plained thickening of the LV walls and by LV outflow tract
obstruction.55 For years, it has been recognized that the sim-
ple impingement of the MV on the interventricular septum
(resulting from high systolic velocities in the vicinity of the
leaflets generated by the predominant upper septal hypertro-
phy) contributes to systolic anterior motion of the MV or SAM
(Venturi effect).55 Whereas the Venturi effect likely contributes
to the propagation and worsening of SAM, it is not adequate
to initiate SAM, indicating that complementary mechanisms
centered on structural MV abnormalities likely contribute
to SAM.55 Experimental in vitro studies and computational
 2164  Circulation  May 27, 2014
models have demonstrated that isolated anterior and internal
displacement of the papillary muscles, combined with leaflet
elongation (especially of the posterior leaflet), is able to rec-
reate SAM.55 The degree of SAM is related to leaflet length,
even in the absence of septal hypertrophy. Typically, basal and
midanterior MV leaflet elongation causes SAM with prolapse,
whereas distal anterior leaflet elongation creates SAM with
a mobile flap. Leaflet elongation without papillary muscle
displacement creates prolapse.55 Several mechanisms may
contribute to MV disease in HCM, including the primary sar-
comeric gene mutation, the response to shear stress in a tur-
bulent outflow tract, and concomitant but unrelated familial
MV disease.55 Paracrine factors such as periostin have also
been implicated in the pathogenesis of MV disease in HCM.90
Periostin is a TGF-β1–inducible secreted protein origi-
nally identified in mouse osteoblasts.91 In the heart, perios-
tin is expressed physiologically in embryonic cardiac valves,
whereas it is re-expressed abundantly in the adult left ventricle
after pressure overload or myocardial infarction.91 Markedly
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elevated levels of periostin are indeed secreted by nonmyocyte
elements in the left ventricular walls and expressed in HCM
mice.90 Periostin promotes VIC proliferation, differentiation,
and matrix production, therefore potentially driving leaflet
elongation in HCM.55,90
Genetics of Nonsyndromic MVP
A familial basis for MVP has long been recognized, with an
autosomal-dominant mode of inheritance, a variable pen-
etrance influenced by age and sex, and a marked heterogene-
ity of clinical presentation even among the affected members
within a family.12,13,92
Because MVP is found in many but certainly not all patients
with MFS, it was suggested that primary MVP may be due
to a mutation of FBN1. However, studies have failed to link
nonsyndromic familial MVP with variants in fibrillar or other
collagen genes.93,94 Negative genetic linkage results may have
been related to a lack of systematic examination of the entire
human genome and to phenotypic ambiguity. More recently,
our understanding of the 3-dimensional shape of the MV has
improved the specificity of MVP diagnosis and in turn the
Table 1.  Summary of Linkage Studies of Nonsyndromic MVP
MMVP1
Probands, n 17
Pedigrees, n 4 1
Total subjects in pedigrees with 79
echocardiography+DNA, n
Affected individuals, n 25
Ethnicity Ashkenazi Jewish (pedigree 1),
western France (pedigrees 2,4),
eastern France (pedigree 3)
LOD score >5
Chromosome 16
Gene map locus 16p12.1-p11.2
MMVP indicates myxomatous mitral valve prolapse; MVP, mitral valve prolapse; N/A, non applicable; and XMVD, X-linked
myxomatous valvular dystrophy. Adapted from Grau et al.8 Copyright © 2007 John Wiley & Sons, Inc. Authorization for this
adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the
translation or adaptation.
yield of genetic studies.26 On the basis of this newer MVP
phenotype, 3 loci for autosomal-dominant, nonsyndromic
MVP have been identified on chromosomes 16, 11, and
13.95–97 Although filamin-A has been identified as causing an
X-linked form of MVP,14 the genes for the more common form
of autosomal-dominant MVP have yet to be defined (Table 1).
In 1999, the first genetic locus for MVP was mapped to
chromosome 16p11.2-p12.1 (MMVP1) in a family with the
trait segregating in an autosomal-dominant fashion.95 Genetic
linkage studies yielded maximum multipoint LOD scores of
5.4 and 5.6. This was confirmed by haplotype analysis dem-
onstrating that a chromosomal region of ≈5 cM containing the
locus (a genetic distance equivalent to 5 million DNA base
pairs) was present in all affected individuals.95 In 2003, Freed
et al96 identified a second locus for MVP (MMVP2) at chromo-
some 11p15.4. The risk haplotype comprised a 4.3-cM region
on this chromosome. In 2005, a new locus for autosomal-
dominant MVP was mapped to chromosome 13q31.3-q32
with a multipoint LOD score of 3.17 (MMVP3).97 Haplotype
analysis showed that a portion of the chromosome contain-
ing the locus was present in all affected members of the fam-
ily. The discovery of MMVP3 not only confirmed the genetic
heterogeneity of MVP but also provided important clinical
lessons. Specifically, phenotyping of the chromosome 13 ped-
igree revealed a spectrum of expression that included valve
morphologies previously considered to be normal variants
but now for the first time were recognized as having the same
genetic substrate in the familial context.97 Prodromal mor-
phologies shared 2 salient features with fully diagnostic MVP:
an anteriorly displaced coaptation point and posterior leaflet
asymmetry (Figure 4). The term prodromal used in the initial
literature may not be ideal outside the familial context because
its prognostic significance is unclear at this time. Therefore,
these morphologies are better defined as abnormal anterior
coaptation (AAC) to underline their similarity with fully diag-
nostic MVP. Individuals with minimal systolic displacement
shared the posterior leaflet asymmetry with individuals with
full-blown MVP, but their coaptation point was posterior (as
in normal individuals). Individuals with AAC and minimal
systolic displacement shared either the complete or a major
MMVP2 MMVP3 XMVD
1 1 N/A
1 1
28 47 92
12 9 21
Western European Western European French origin
descent descent
>3 >3 >6
11 13 X
11p15.4 13.q31.3-q32.1 Xq28
 Delling and Vasan   Epidemiology and Pathophysiology of MVP   2165
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Figure 4. Two-dimensional parasternal long-axis images of posteriorly coapting leaflets (anterior leaflet [AL]; posterior leaflet [PL]) in a
normal individual (A) vs increased coaptation height and an elongated posterior leaflet in an individual with abnormal anterior coapta-
tion (AAC) features (B) and in a patient with bileaflet mitral valve prolapse (MVP) into the left atrium (LA; C). Schematics (D) showing the
projections of anterior (A) and posterior (P) leaflets onto the mitral annular diameter (D). C indicates the coaptation height relative to the
annulus and is calculated as P/D or C/LVID, where LVID is left ventricular internal diameter. AO indicates aorta; LV, left ventricle; and RV,
right ventricle.

portion of the at-risk haplotype with fully diagnostic MVP.
This same AAC morphology was also observed in the fam-
ily linked to chromosome 11.97 Quantitatively, the height of
coaptation relative to the annulus or left ventricular diameter
(Figure 4) correlated well with the ratio of posterior to ante-
rior leaflet length (r=0.83–0.85) in the members of the family
with a genetic linkage signal on chromosome 11. Thus, the
spectrum of valvular abnormalities (AAC or minimal systolic
displacement) may represent, in the familial context, early dis-
ease expression in gene carriers, a stage of progression, or the
result of disease-modifying factors.
Recognizing early forms of MVP may be important because
the condition often manifests clinically in the fifth or sixth
decade of life as a severe cardiac event.5,6 It is conceivable that
earlier targeted intervention to reduce hemodynamic stresses
on the MV leaflets in genetically susceptible individuals (as
shown in a murine model of MFS with aortic dilatation and in
surgical specimens of nonsyndromic MVP)77,85,86 may poten-
tially prevent the progression of MVP and severe MR requir-
ing surgery, although this premise remains to be tested.
A rare form of myxoid heart disease, X-linked myxomatous
valvular dystrophy, was first described >3 decades ago.14,98 It
is characterized by multivalvular myxomatous degeneration,
although the histopathological features of the MV do not dif-
fer significantly from the severe form of autosomal-dominant
MVP. In 1 large family, X-linked myxomatous valvular dys-
trophy cosegregated with hemophilia A.98 This relatively large
familial study that included >92 individuals over 4 genera-
tions, with a full penetrance for men (men were either clearly
affected or not), was the first investigation that mapped this
rare clinical dystrophy to a sex chromosome, Xq28. Thus, the
genetic linkage analysis, facilitated by the X-linked mode of
inheritance and by the linkage with a mild form of hemophilia
A in this pedigree, permitted rapid mapping of this X-linked
myxomatous valvular dystrophy gene, with a highly informa-
tive LOD score of 6.57 (Table 1). Coupling genealogical sur-
veys of the larger family with linkage analyses, Kyndt et al14
refined the previously mapped locus on chromosome Xq28
to a 2.5-Mb region. Screening of candidate genes revealed a
P637Q missense mutation in the filamin-A gene in the affected
members of the larger family.14 Mutational analyses of the
filamin-A gene in the other families identified 3 additional fila-
min-A gene mutations: 2 more missense mutations (G288R,
V711D) and a 1944–base pair in-frame deletion.14 Both male
and female carriers were affected, but the affected female car-
riers had a less severe phenotype.
Filamins are large cytoplasmic proteins that play an
important role in cross-linking cortical actin filaments into a
dynamic 3-dimensional structure and thereby transmit extra-
cellular signals through their interactions with the integrin
receptors.99 These proteins not only serve a structural role in
cytoskeletal organization but also appear to serve as hubs or
docking platforms for second messengers important in signal
transduction. The filamin group of proteins contains 3 mem-
bers: A, B, and C. Filamin-A and filamin-B are reported as
ubiquitously expressed in tissues, whereas filamin-C expres-
sion is restricted to the cardiac and the skeletal muscle.99
The filamins are present as homodimeric or heterodimeric
Y-shaped proteins with each chain consisting of an actin-
binding region at the amino terminus. The core of the pro-
tein consists of 24 highly homologous immunoglobulin-like
repeats followed by a carboxyl integrin binding domain.99
Gene knockout studies have indicated the importance of these
proteins in diverse developmental processes, and filamin-A
appears to be the major family member responsible for car-
diac and vascular development.100 Hemizygous mice for the
filamin-A–null allele show embryonic lethality and a wide
range of cardiovascular malformations, including incomplete
 2166  Circulation  May 27, 2014
septation of the outflow tract that leads to a common arterial
trunk and double outlet, abnormally thickened and malformed
outflow tract valves, atrial and ventricular septal defects, type
B interruption of the aortic arch, abnormal endothelial organi-
zation in blood vessels, abnormal vascular permeability, and
thickening of the MV.100 Compensation of the other filamin
genes does not seem to occur, nor have cardiovascular defects
been described in mouse mutants for either the filamin-B or
the filamin-C gene.101,102 Filamin-A appears as a functional
hub in many signaling pathways that may contribute to the
development of valvular disease. Filamin-A coordinates local-
ization and activation of TGF-β receptor–activated SMADs,
particularly SMAD2, to act as a positive regulator of TGF-
β signaling.103 One potential mechanism underlying cardiac
valvular dystrophy could involve increased TGF-β signaling
secondary to perturbed filamin-A–SMAD interactions with
consequent dysregulation of endothelial-to mesenchymal
transition.104 Filamin-A mutations may provide a link between
MFS and nonsyndromic MVP, conditions that are character-
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ized by increased TGF-β signaling. Specifically, myxomatous
MVs found in fibrillin-1–deficient mice (which model MFS)
display excessive TGF-β activation and upregulated expres-
sion of filamin-A.85,105
Remaining Questions
MVP Pathophysiology and Genetics
In this review, we present a unifying theory for the pathogen-
esis of MVP based on our knowledge of the biology of valves
and the dynamic interplay of differentiating cells and growth
factors. However, a full understanding of the molecular basis
of MVP requires 2 additional steps (Table 2): identification of
the genetic variants responsible for nonsyndromic autosomal-
dominant MVP, including the role of both susceptibility and
modifier genes, and functional studies with animal models to
corroborate the clinical relevance of identified mutations.
MVP appears to be the result of multiple genetic pathways,
as illustrated by the identification of several genes in syndromic
MVP83,84 and 3 loci for nonsyndromic MVP.95–97 The identifica-
tion of filamin-A mutations in an X-linked form of valvular
dystrophy14 highlights the importance of the cytoskeleton not
only in providing structural integrity but also in critical cellular
signaling pathways, specifically the TGF-β pathway. Advances
in DNA sequencing technologies may lead to the identifica-
tion of the MMVP1, MMVP2, and MMVP3 genes in the near
future. Large-scale collections of MVP patients and genome-
wide association studies will allow identification of additional
MVP genes and will finally elucidate the pathways leading to
the occurrence of MVP. Identification of the genes involved
in the development of MVP is important because the disease
typically manifests later in life, and earlier intervention in sus-
ceptible individuals may potentially prevent progression to a
clinically severe stage, a premise that remains to be tested. In
vitro studies of surgical specimens have shown for the first time
that the myxomatous changes characteristic of MVP are phar-
macologically preventable,77 which offers great hope for the
development of therapies based on future genetic discoveries.
Mouse models have proved to be essential for demon-
strating the importance of filamin-A mutations in cardiac
Table 2.  Summary of Future Research Directions
MVP pathophysiology and genetics
 Identify the genetic variants responsible for nonsyndromic autosomal-
dominant MVP
 Develop functional studies with animal models to corroborate the clinical
relevance of identified genetic variants
 Develop new nonsurgical therapies based on a better understanding of
genetic determinants of MVP and related biochemical pathways
MVP epidemiology
 Better characterize the natural history of nondiagnostic MVP morphologies
 Identify genetic and environmental risk factors responsible for accelerated
MVP progression
 Examine whether specific risk factors act differently at different stages of
MVP progression
 Evaluate the duration of the different stages of MVP progression
 Assess whether response to future nonsurgical therapies (losartan?) varies
on the basis of different MVP stages (nondiagnostic MVP morphologies vs
full-blown MVP)
MVP indicates mitral valve prolapse.
valve development.100 Further opportunities for understand-
ing human MV disease may derive from a study of the King
Charles Spaniel, a species in which MVP naturally occurs
with a frequency of 1% to 5%, similar to that in humans.106 In
addition, the zebrafish has recently been identified as an ideal
model for genetic knockdown experiments and understanding
of valve development.107 Although zebrafish display differ-
ences in atrioventricular canal and valve morphology com-
pared with other model organisms (such as mice and chicken),
they share the same molecular and cellular mechanisms for
valve development with humans.107 Thus, several signaling
pathways implicated in MVP also contribute to atrioven-
tricular canal formation in zebrafish (eg, the TGF-β/SMAD,
Notch1b, and vascular endothelial growth factor/calcineurin/
nuclear factor of activated T cells signaling pathways).107
Identification of the mutations responsible for autosomal-
dominant MVP and their corroboration through functional
studies will provide a potential screening tool to help clini-
cians identify asymptomatic patients who may progress to
significant MR, perhaps among the individuals with diagnos-
tic MVP without MR or among AAC individuals who do not
meet standard diagnostic criteria but share features of exces-
sive leaflet motion with the fully affected family members
(Figure 5).97 Advances in the understanding of MVP patho-
physiology outlined in this review may lead to new medical
therapies aimed at preventing the progression of disease by
targeting different cells and signaling pathways (Figure 5):
from excessive TGF-β signaling (similar to what has been
shown in the MFS and in cultured human MV cells of non-
syndromic MVP, in which angiotensin I receptor blockade
leads to regulation of TGF-β and limitation of clinical disease
progression) to manipulation of progenitor cells (among the
endothelial cells responsible for both valvular embryogen-
esis and response to hemodynamic stress in adult life) to the
development of tissue-engineered heart valves. Such medical
interventions may hold the potential for limiting disease pro-
gression at an early stage in nondiagnostic MVP phenotypes
or avoiding surgical treatment and clinical complications in
fully diagnostic MVP individuals (Figure 5).
 Delling and Vasan   Epidemiology and Pathophysiology of MVP   2167
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Progression of MVP
Although the natural history of MVP has been studied since
the 1980s, these investigations have focused on individuals
with fully diagnostic MVP and its clinical outcomes, includ-
ing cardiac death, heart failure, endocarditis, or severe MR
requiring surgery.5,6 The natural history of early echocar-
diographic stages of MVP leading to diagnostic MV leaflet
displacement and to subsequent clinical outcomes has yet
to be described in both tertiary care and community-based
studies (Table 2). In the familial context, previously non-
diagnostic morphologies that share features of excessive
leaflet motion with fully diagnostic MVP have been shown
to represent mild or early stages of phenotypic expression
in gene carriers.97 The existence of early MVP morpholo-
gies in the general population would raise the possibility of
echocardiographic screening and provide an opportunity for
potential intervention at an early phase of disease. As sug-
gested in Figure 5, the progression of MVP may occur in
stages over a lifetime, beginning with a genetic substrate,
leading to mild, nondiagnostic valve morphologies, develop-
ing into full expression of the MVP phenotype, and culmi-
nating in severe MR requiring valve surgery. The duration of
the individual stages of the disease can range from months to
years, the shorter progression duration being a consequence
of the development of a flail mitral leaflet. Various risk fac-
tors, including genetic modifiers, environmental factors
(smoking, diet, body mass index, hypertension), and non-
modifiable characteristics such as race or sex, may influence
the progression from one stage of MVP to the other and the
duration of the different stages.
Several questions about the epidemiology of MVP remain
unanswered (Table 2). Specifically, it is unknown whether
early, nondiagnostic MVP morphologies progress within or
outside the familial context; whether some risk factors more
than others contribute to progression and at which stages; and
whether the response to future nonsurgical therapies varies as
MVP progresses from early disease to significant MR. Further
longitudinal studies with a focus on specific clinical, demo-
graphic, and ethnic subgroups are needed to answer these
important questions.
Figure 5. Proposed temporal spectrum of mitral
valve (MV) prolapse (MVP) progression with poten-
tial interventions/nonsurgical therapies depending
on progression stage (bottom). A and P indicate
projections of anterior and posterior leaflets onto
the mitral annulus; C; mitral leaflet coaptation
height; MR, mitral regurgitation; MSD, minimal sys-
tolic displacement; and TGF-β, transforming growth
factor-β.
Conclusions
MVP is a common clinical phenotype and remains the most
common valvular pathology requiring surgery. Multiple loci
for autosomal-dominant nonsyndromic MVP and a gene
responsible for a rare X-linked form of MVP have been dis-
covered. Studies in a mouse MFS model and in clinical speci-
mens of excised myxomatous MVs have underlined the role
of excessive TGF-β signaling in the development of degen-
erative MV disease and the potential of angiotensin I recep-
tor blockade in limiting MVP progression. These discoveries
overall have exponentially accelerated our understanding of
MVP. However, many questions remain unanswered in rela-
tion to both MVP pathophysiology and epidemiology, and
future studies are needed to address these important issues.
Sources of Funding
This work was supported by the Founders Affiliate American Heart
Association Clinical Research Program, by the National Institute
of Health K23HL116652 (Dr Delling) and by the National Heart,
Lung, and Blood Institute’s Framingham Heart Study (contract
N01-HC-25195) R01HL080124 and RO1HL0107385 (Dr Vasan).
Disclosures
None.
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Key Words: mitral valve ◼ mitral valve insufficiency ◼ mitral valve
prolapse
 Epidemiology and Pathophysiology of Mitral Valve Prolapse: New Insights Into Disease
Progression, Genetics, and Molecular Basis
Francesca N. Delling and Ramachandran S. Vasan

Circulation. 2014;129:2158-2170
doi: 10.1161/CIRCULATIONAHA.113.006702
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