Mitral Valve Prolapse

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Mitral Valve Prolapse

T. Sloane Guy1 and Arthur C. Hill2
1
Department of Surgery, Temple University, Philadelphia, Pennsylvania 19140;
email: sloane.guy@tuhs.temple.edu
2
University of California, San Francisco, California 94143; email: ahill@itsa.ucsf.edu
Keywords
myxomatous, regurgitation, leaet coaptation, echocardiography,
remodeling
Abstract
Mitral valve prolapse is dened as abnormal bulging of the mitral valve
leaets into the left atrium during ventricular systole. Mitral valve prolapse is a common condition that is a risk factor for mitral regurgitation,
congestive heart failure, arrhythmia, and endocarditis. Myxomatous degeneration is the most common cause of mitral prolapse in the United
States and Europe, and progression of myxomatous mitral prolapse is
the most common cause of mitral regurgitation that requires surgical
treatment. Myxomatous degeneration appears to have genetic etiology.
The genetics of myxomatous degeneration is complex and not fully
worked out; it appears to be heterogeneous with multi-gene, multichromosomal autosomal dominance with incomplete penetrance. The
molecular disorder of myxomatous degeneration appears to consist of a
connective tissue disorder with altered extracellular matrix status and involves the action of matrix metalloproteinase, cysteine endoproteases,
and tenomodulin. Treatment of mitral prolapse with regurgitation is
complex, and the technological advances that are currently in development will be challenging and controversial.
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INTRODUCTION

Mitral valve prolapse is dened as an abnormal

bulging of the mitral valve leaets into the
left atrium during ventricular systole. Mitral
prolapse can be localized (involving one leaet
or a segment of a leaet) or generalized (involving the entire mitral leaet apparatus). The
presence of anatomic mitral valve prolapse can
be specically dened and characterized using
modern imaging modalities (echocardiography
and cine MRI). Progressive worsening of
mitral prolapse is associated with progressive
mitral regurgitation (1, 2) and the physiologic
consequences of mitral regurgitation, which
can progress to congestive heart failure,
arrhythmia, and/or sudden death (3). Furthermore, mitral valve prolapse is a risk factor
for endocarditis (47). Flail mitral prolapse
is a term applied to the most severe form,
in which a segment or segments of a leaet
protrude into the left atrium during systole.
Flail mitral prolapse is usually localized to one
leaet segment and typically is associated with
torn chordae or ruptured papillary muscle
with complete loss of leaet restraint, allowing
complete dislodgment of the involved segment
into the left atrium during ventricular systole.
Despite the potential to develop clinically
signicant problems, only a small percentage
of patients with mitral prolapse will progress
to the extent that ultimately warrants surgical
or percutaneous intervention.
The incidence of mitral valve prolapse in
the general population has historically ranged
from 5% to 15%, but more recent studies
employing rigid diagnostic criteria suggest
a much lower rate of around 23% (8, 9).
Mitral valve prolapse due to myxomatous
degeneration is the most common cause of
mitral regurgitation requiring surgery in the
Western world. Rheumatic heart disease is
more common as an etiology of mitral regurgitation in the developing world (10). Other
etiologies of mitral valve prolapse include
broelastic deciency, Marfan syndrome,
endocarditis, acute ischemia, chronic ischemic
cardiomyopathy, and papillary muscle rupture.
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Hill
A condition where myxomatous degeneration

is diffuse, with extensive bileaet redundancy,
billowing, and broad bileaet prolapse, is
referred to as a Barlows valve.
A specic gross pathologic and microscopic
pathologic denition of mitral valve prolapse
exists (11, 12). The gross criteria for diagnosing
prolapsing mitral valve are (a) interchordal
hooding of the involved leaets; (b) hooding
or doming of leaets toward the left atrium;
(c) elongation of the involved leaets, resulting
in an increase in valve area; and (d ) dilation of
the valve annulus in patients with severe mitral
regurgitation. Microscopic ndings include
signicant thickening of the spongiosa and
the brosa layers, changes in dense collagen
bers in the atrialis layer, and variable amounts
of brin-platelet deposition. Myxomatous
degeneration has recently been determined to
be, for the most part, a genetic condition that
produces a form of connective tissue disorder.
Myxomatous degeneration is the most common cause of mitral regurgitation in the United
States and Europe. Mitral regurgitation is dened as abnormal backward blood ow through
the mitral valve from the left ventricle into the
left atrium during ventricular systole. Anything
greater than trace mitral regurgitation is considered abnormal, and progressive worsening of
mitral regurgitation leads to adverse anatomic,
cellular, molecular, and electrical remodeling
of the left atrium and left ventriclewith progression to congestive heart failure.
The development of echocardiography
dramatically advanced the ability to diagnose
mitral valve prolapse. Two-dimensional and
three-dimensional echo, including transthoracic and transesophageal approaches, combined with Doppler imaging, have made it easy
to obtain a precise understanding of the structure and function of the valve. It is, however,
not always easy to distinguish moderate from
severe levels of mitral regurgitation, which
can lead to difculties in deciding whether to
recommend surgery.
The clinical entity referred to as mitral
prolapse syndrome is a symptom complex that
is out of proportion to, or unrelated to, the

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magnitude of the mitral valve pathology. Mitral

prolapse syndrome typically consists of one
or more of the following symptoms: atypical
chest pain, palpitations, syncope, dyspnea on
exertion, and anxiety. Other clinical ndings
may include low blood pressure, electrocardiographic abnormalities, and other signs suggestive of autonomic nervous system dysfunction.
Some evidence suggests the presence of abnormalities in the renin-angiotensin system (13,
14), adrenergic hyperfunction (1517), and
hypomagnesemia (18, 19).
P1
A1
A2
P2
A1
P3
ANATOMY
A simplied understanding of mitral prolapse
can be obtained by knowing the basic anatomy
of the mitral valve (Figure 1) and the classication of mitral regurgitation developed by
Carpentier (Figure 2).
The basic anatomy of the mitral valve
(Figure 1) is composed of the following structures: an anterior leaet and a posterior leaet;
chordae tendineae (attaching free edge and
inferior surface of the leaets to papillary muscle and left ventricle); antero-lateral papillary
muscle and posterior-medial papillary muscle;
and mitral annulusconsisting of the circumferential attachment of the leaets at the atrioventricular junction. The three-dimensional
structure of the mitral valve is complex and
includes the well-documented saddle shape of
the mitral valve annulus, with two high points
situated anteriorly (near aortic valve) and posteriorly (posterior left ventricular wall), along
with two low points (troughs) medially and
laterally. Studies have shown that the average
maximum deviation from planarity is 1.4
0.3 cm (20, 21). The annulus-leaet structure approximates the shape of a hyperbolic
paraboloid (22, 23), and this has signicance in
mitral valve repair (2426). The most widely
used classication of leaet anatomy is that of
Carpentier (27), in which the posterior leaet is
composed of segments P1, P2, and P3 from left
to right and the anterior leaet segments are
A1, A2, and A3 from left to right (Figure 1).
Prolapse and regurgitation usually result from
Figure 1
Basic mitral valve anatomy with Carpentier classication of leaet anatomy.
The anterior leaet is divided into three segments (scallops) and the posterior
leaet is divided into three segments. P2 is the most common site of localized
prolapse and ail due to myxomatous degeneration and broelastic dysplasia.
Commissures consist of the two corners at which the anterior and mitral leaet
join posteromedially and anterolaterally.
focal or multisegment leaet prolapse. Typically, leaet tissue becomes lengthened and
redundant with chordal elongation. Chordal
rupture results in segmental leaet ail.
Ruptured chordae tendineae or an acutely
ruptured papillary muscle may result in acute
or subacute congestive heart failure. The most
common scenario resulting in mitral regurgitation is a redundant P2 scallop. It is the most
common site of segmental prolapse and ail
secondary to myxomatous degeneration with
lengthened chords, with or without ruptured
chords. Flail mitral prolapse is characterized by
reversal of the normal convexity of the leaet
towards the left atrium during systole such that
the leaet enters the left atrium; the normally
convex and coapting leaet surface becomes
concave as it enters the left atrium.
As previously stated, mitral prolapse is an
abnormality of leaet motion wherein one
or multiple components of the leaet apparatus protrude into the left atrium during
www.annualreviews.org Mitral Valve Prolapse
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Type I
Type II
Type III
(normal leaflet motion)
(prolapse)
(restricted leaflets)
Figure 2
Carpentiers functional classication of mitral regurgitation (MR). Type I MR has normal leaet motion
(e.g., annular dilatation, leaet perforation); type II has abnormal leaet motion with prolapse or ail (e.g.,
myxomatous degeneration, torn chordae tendineae); type III has restricted leaet motion (e.g., rheumatic
heart disease, ischemic cardiomyopathy).
ventricular systoletype II abnormal leaet

motion according to the Carpentier classication (Figure 2). The most common medical
imaging modality used to demonstrate abnormal mitral leaet motion is echocardiography.
The echocardiographic denition of abnormal
mitral leaet prolapse is any leaet displacement >2 mm above the plane of the mitral valve
annulus into the left atrium during ventricular
systole.
The extent of mitral regurgitation due to
myxomatous degeneration is highly variable.
Mitral regurgitation can vary from none (0) to
severe (4+). Prolapse with 01+ regurgitation
has no signicant hemodynamic consequence.
Prolapse severity can worsen as failure of
leaet coaptation occurs, leading to moderateto-severe (24+) mitral regurgitation. The
amount of mitral regurgitation depends on the
amount of failure of the anterior-to-posterior
leaet coaptation (Figures 3 and 4). Flail mitral prolapse, in which one or multiple torn
leaet chords allow the leaet to dislodge and
protrude completely into the left atrium, typically results in severe (4+) mitral regurgitation. Four fundamental facets of mitral valve
anatomy and function result in mitral competency: stable, sustainable, and consistent closure
along the line of coaptation (zone of coaptation
is roughly 0.8 cm); an adequate surface area
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of coaptation; correct positioning of posteriorto-anterior leaet coaptation (prevents systolic

anterior motion of the mitral valve); and early
valve closure (which can be adversely affected
by conduction abnormalities). Any perturbation of these facets will result in mitral regurgitation. The delicate and intricate suspension apparatus of the leaetchordpapillary
muscleventricular complex is involved in the
disease process, and normal anatomy is difcult
to reestablish in mitral repair.
ETIOLOGY OF MITRAL
PROLAPSE AND MITRAL
REGURGITATION
The etiology of mitral prolapse is complex and
variable, including both acquired and genetic
causes (Table 1). Separate entities with unrelated molecular and histopathologic pathways
can lead to mitral prolapse.
Genetic causes account for the majority
of mitral prolapse in the United States and
Europe. Myxomatous degeneration is considered a genetic disorder of connective tissue, but
its genetic characteristics have only recently
been articulated. It is known that mitral valve
prolapse is genetically heterogeneous with
autosomal dominant and X-linked inheritance
that has variable penetrance and is sex- and

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Figure 3
Sagittal view of the heart with mitral valve
regurgitation due to prolapse of the posterior leaet.
age-dependent. Studies have revealed that

mitral valve prolapse maps to three different
chromosomal loci on chromosomes 16 (24),
11 (25), and 13 (26), and other studies suggest
a locus on the X chromosome (27, 28). No
specic single gene has been implicated (25,
26, 29). It cannot be overemphasized that
the genetics of mitral valve prolapse are in
development (30) and a clearer understanding
of its molecular, histologic, and mechanical
characteristics may lead to improved methods
of treatment and prevention. However, ndings from two animal modelsmouse (28) and
Cavalier King Charles spaniel (29)and from
several human studies (3034) allow preliminary conclusions. Myxomatous degeneration
has been studied with respect to extracellular
matrix (ECM) status and the action of matrix
metalloproteinase (MMP), cysteine endoproteases, and tenomodulin (35, 36). Changes in
MMP expression have also been found at sites
remote from the mitral valve in patients with
myxomatous degeneration of the mitral valve
(37).
Figure 4
Prolapse at A3 and P3 leading to regurgitation.
Mitral valve prolapse is a common condition in Marfan syndrome. It appears that the
genetic pathway for mitral valve prolapse in
Marfan syndrome may be different from that
found in myxomatous degeneration. Denitive
comparisons have not been done; however, for
Marfan syndrome, studies to date implicate mutations in the Fibrillin-1 gene (FBN1) on chromosome 15q21.1 and inactivation mutations in
TGF- receptor 2 (TGFBR2), located at
3p24.2p25 (3133). TGF- regulation may
be a common downstream pathway in both
Marfan syndrome and mitral prolapse.
Myxomatous degeneration of the mitral
valve is associated with distinctive histologic
and mechanical changes. The histologic
characteristics of myxomatous mitral valve
prolapse consist of inammatory cell and
Table 1 Etiology of mitral prolapse
Acquired causes
Genetic causes
Rheumatic
Myxomatous degeneration
Endocarditis
Marfan syndrome
Trauma (penetrating or blunt)
Ehlers-Danlos syndrome
Ischemic (papillary muscle dysfunction or

rupture)
Osteogenesis imperfecta
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broblast proliferation within the spongiosa of

the mitral leaets and mucopolysaccharide acid
replacement of constituent collagen (38, 39).
The leaet tissue also has disorganized collagen
and elastin bers with pools of proteoglycans
in multiple layers, including the load-bearing
brosa layer (21, 40). Progressive histologic
change includes brosis of the leaet surface
and spongiosa. The leaet collagen content
changes, with increased type III collagen and
decreased type I and type V collagen (41).
Myxomatous chordae have been shown to
contain signicantly more glycosaminoglycans
(chondroitin/dermatan 6-sulfate and hyaluron)
(4245), perhaps accounting for observed
leaet over-hydration and poor load-bearing
features. Thinning and elongation of the
leaet tissue and chordae tendineae occur with
resultant failure of coaptation. Further, the
stress-strain relationship of the leaets and
chordae allows weakening and rupture of the
chordae, leaet ail, and mitral regurgitation
in a positive feedback loop.

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PATHOPHYSIOLOGY
Mitral leaet prolapse can exist without
producing signicant pathophysiologic or
hemodynamic consequences. However, the
presence of mitral valve prolapse, and the
underlying disease that produces prolapse, can
lead to progressive adverse tissue change, with
mechanical characteristics that lead to a positive feedback loop of worsening prolapse and
chordal rupture. Myxomatous degeneration of
the mitral leaet and chordal apparatus exists
in a large portion of the population but leaet
coaptation is retained and there is no hemodynamically signicant regurgitation. The leaet
and chordal changes that accompany myxomatous degeneration and its variants can, however,
lead to an abnormal stress-strain relationship
such that leaet injury, chordal injury, and
elongation result in progressive regurgitation
as coaptation becomes compromised.
The mechanical properties of normal versus
myxomatous mitral valves and chordae have
been studied (4650). Valve tissue obtained
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Guy
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from patients with ail mitral leaets were

studied in the biomechanical laboratory at the
Cleveland Clinic (48, 50). This study compared
myxomatous versus normal tissue and veried
that abnormal mitral leaet tissue had less stiff
chordae (23.5 3.6 versus 59.1 11.7 Mpa,
p = 0.006); abnormal tissue had a lower
failure stress (3.8 0.9 versus 9.6 2.2 Mpa,
p = 0.07); and abnormal tissue had more
extensible leaets (56.4% 7.9% versus
42.9% 2.7% strain, p = 0.04). These
changes suggest the mechanism for progressive
mitral regurgitation.
EVALUATION
Patients with mitral valve prolapse present in a
variety of ways. The diagnosis may arise from
incidental echocardiogram ndings, or patients
may present with palpitations related to arrhythmias or other symptoms associated with
mitral regurgitation. The standard evaluation
of these patients includes a complete history
and physical examination. An emphasis should
be placed on determining if there are any signs
and symptoms associated with end-stage disease, including heart failure, and signs related
to mitral regurgitation and heart failure: systolic thrill, displaced apical pulse, systolic murmur, S3, early diastolic rumble, cardiomegaly,
left atrial enlargement (by echocardiography or
other imaging modalities), elevation of B-type
natriuretic peptide (BNP), and atrial brillation
(51).
Any suspicion of a structural cardiac problem should always lead to a transthoracic
echocardiogram. Transesophageal echocardiography yields a clearer visualization, but is generally reserved for cases in which the mitral
valve is difcult to visualize or a complex surgical repair is anticipated (52). Most experienced
mitral valve surgeons will proceed with surgery
without a transesophageal echocardiogram because one will be performed in the operating
room immediately prior to starting the surgery.
This test is not completely accurate, and unexpected ndings upon direct visualization of the
mitral valve during surgery are not uncommon

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even with experienced echocardiographers. 3D

echocardiography may improve the accuracy of
determining exactly what the pathology of the
valve is and predict ease of repair, or suggest
possible repair techniques prior to starting the
surgery. Alternative imaging techniques for visualizing the mitral valve include cardiac MRI,
although this is not in widespread use for this
purpose. Quantitative measurements are possible but not well validated (53).
Doppler echocardiography is essential in determining the severity of mitral regurgitation.
Accepted criteria for severe mitral regurgitation
include a vena contracta width >0.7 cm, large
central mitral regurgitation jet (area >40% of
left atrium), pulmonary vein reversal, effective
regurgitant orice >40 mm2 , regurgitant fraction >50%, regurgitant volume >60 cc (37).
The proximal isovelocity surface area (PISA)
method of regurgitant color ow jet is also used
in echocardiography to estimate the severity of
mitral regurgitation (5457).
It is not uncommon, however, for different cardiologists and centers to disagree on
whether severe regurgitation is present. Additionally, hemodynamic factors such as blood
pressure can inuence the degree of regurgitation. Echocardiography is also used to measure
the structural and functional consequences of
mitral regurgitation and heart failure including
cardiac chamber dimension and volumes. An
EF (ejection fraction) <60% or an end-systolic
diameter >4045 mm is considered severe left
ventricular dysfunction and would generally be
an indication for surgery in the setting of severe mitral regurgitation (58). Clinicians may
mistakenly assume that a patient with mitral regurgitation and an EF of 50% has good function; however, since a signicant portion of the
ejected volume goes into the left atrium, this EF
is clearly abnormal. Elevated BNP level is used
as a marker for severity and duration of cardiac
failure and excess risk (59, 60).
Once a patient has been diagnosed with mitral valve prolapse and severe mitral regurgitation and it is determined that surgery should
be undertaken, other preoperative testing is
usually indicated. This might include cardiac
catheterization for patients over the age of

40 years to identify coronary disease that might
need intervention.
NATURAL HISTORY
Mitral valve prolapse is a disease state that can
exist in stable form without signicant physiologic consequences. If mitral regurgitation
is absent or mild, there may be no need for
treatment. However, the disease can progress
and lead to worsening mitral regurgitation and
congestive heart failure. Once the process is
under way, progression is the usual course,
and clinical surveillance is recommended. If
signicant (moderate to severe) regurgitation
is present, left ventricle pressure-volume work
overload begins to affect circulatory function.
Myocardial and circulatory compensation leads
to adverse remodeling. These changes occur
at rates dependent on the etiology of mitral
prolapse, the amount of mitral regurgitation,
and the degree of pre-existing myocardial
injury. Early in the natural history of the
disease, compensatory cardiac and circulatory
changes occur, consisting of cardiac chamber
enlargement, cardiac muscle hypertrophy,
and development of cardiac murmur. The
compensated phase of mitral regurgitation
usually produces no symptoms or mild symptoms. A neuro-hormonal response becomes
activated and plays a role in the mitral prolapse
syndrome. As the disease progresses, a decompensated phase of congestive heart failure
ensues with cardiac chamber enlargement
and cardiac muscle hypertrophy, and medical
treatment reaches a point of limited effectiveness and diminishing returns. Additional
consequences of adverse remodeling may
occur, including end-organ dysfunction (renal,
gastrointestinal, and neurologic). Of major signicance is the possible development of atrial
brillation with its attendant risks of thromboembolism and decline in cardiac output with
loss of atrial kick. During this late phase of
cardiac decompensation, progressive mitral
regurgitation leads to end-stage congestive
heart failure and irreversible end-organ injury.
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TREATMENT OPTIONS
There is no medical treatment for mitral
prolapse in the absence of mitral regurgitation, although beta blockade may be used
to potentially reduce stress on the valve

Figure 5
(a) Typical anatomy associated with mitral valve regurgitation showing
prolapse of the P2 segment of the posterior leaet. (b) Classic Carpentier mitral
valve repair (P2 quadrangular resection and ring placement).
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Guy
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leaets (61). Antibiotic prophylaxis to prevent

endocarditis is unnecessary in such patients
(62, 63).
The medical treatment of mitral regurgitation entails afterload reduction, diuresis, anticoagulation for associated atrial brillation, and
other medications useful for heart failure. However, once mitral regurgitation becomes severe,
surgery is often indicated. Another option (currently still experimental but under active FDA
consideration) is percutaneous attachment of
the two mitral leaets using a MitraClip device. It is anticipated this device will be mostly
used in high-risk patients who are not optimal
surgical candidates. A recent trial demonstrated
that the MitraClip did not reduce mitral regurgitation as much as surgery but did bring about
similar improvements in clinical outcomes and
reduced complications (64, 65). Percutaneous
methods to reduce annular size with a device
placed in the coronary sinus have been limited
by the distance between the coronary sinus and
the annulus and have not entered the realm
of standard therapy. Ischemic mitral regurgitation is by denition not related to prolapse,
but when present is corrected by percutaneous
revascularization.
The standard surgical approach to severe
mitral regurgitation secondary to prolapse
has been full sternotomy followed by arrest
of the heart and direct repair using a variety
of techniques. The Carpentier methods for
open mitral repair for mitral regurgitation
consist of resection of redundant leaet tissue
[e.g., quadrangular resection of P2 prolapse
or ail (Figure 5) or triangular resection
of P2 (Figure 6)], chordal shortening, and
annuloplasty ring placement. However, mitral
valve repair surgery is currently in the midst
of signicant change. Multiple methods,
concepts, devices, and controversies have
arisen, which can be seen as both enabling
and confusing. Minimally invasive techniques
have evolved over the past 15 years, including
partial sternotomy, right-mini-thoracotomy
(also called port access), robotic mitral valve
repair (either with mini-thoracotomy or totally
endoscopic), and percutaneous methods.
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INDICATIONS AND GUIDELINES

The American College of Cardiology and
the American Heart Association (ACC/AHA)
published detailed guidelines for the management of patients with mitral regurgitation in 2006 (58). Patients with possible indications for surgery are ranked from class I
(surgery is highly recommended) through class
III (surgery is not recommended). Controversies regarding management of these patients
are discussed in the next section. Here we focus on an understanding of the prevalent management styles as codied in these guidelines
(Table 2).
Briey, class I includes patients with severe
mitral regurgitation and one of the following:
signicant heart failure symptoms, an EF 30%
60%, or an end-systolic dimension 4055 mm.
For patients in class IIa, surgery is favored by
a majority but debated. These include asymptomatic patients without altered EF or left ventricular dimensions who can be treated at a
high-volume center with a high likelihood of
repair, asymptomatic patients with atrial brillation or pulmonary hypertension, and patients
with a primary structural valve abnormality and
EF <30% or end-systolic dimension >55 mm
in whom repair is likely.
Class IIb indications (surgery is not favored
by a majority but is debated) include severe
left ventricular dysfunction (EF < 30%) without structural valve problems and with optimal
Figure 6
Triangular resection of prolapsed P2 segment. This is an alternative to the
quadrangular (square-shaped) resection. In this repair, the two sides are
reapproximated and then a ring is placed around the annulus.
therapy including biventricular pacing. It is

worth noting that many such patients will, in
the presence of a prolonged QRS, have resolution of mitral regurgitation when coordinated
conduction is re-established. It is suboptimal
for such a patient to undergo surgery when a
biventricular pacemaker would have eliminated
the issue.
Table 2 Summary of indications for surgery in mitral regurgitation based on 2006 ACC/AHA guidelines
Class I (surgery highly
Class IIa (debated;
Class IIb (debated; minority
majority favors surgery)
favors surgery)
Symptomatic
Asymptomatic, >90% chance

of repair
Severe LV dysfunction (EF < 30%)

and functional mitral regurgitation
Asymptomatic, EF
30%60%
Asymptomatic, new atrial

brillation
Mild mitral regurgitation
Asymptomatic, ESD
4055 mm
Asymptomatic, pulmonary
hypertension
Moderate mitral
regurgitation
Acute onset
Repair preferred over
replacement
EF < 30% or ESD > 55 mm,

mitral valve structural
abnormality, repair likely
recommended)
Class III (surgery not

recommended)
Asymptomatic,
repairability doubtful
Abbreviations: ACC, American College of Cardiologists; AHA, American Heart Association; EF, ejection fraction; ESD, end-systolic diameter; LV, left
ventricle.
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Surgery is not recommended for patients in

class III. Class III indications include absence
of symptoms, normal ventricular size and
function, or signicant doubt about reparability. This is based on the widely accepted
notion that repair is superior to replacement.
Additional class III indications include mild
or moderate mitral regurgitation. It is clear
that surgery is not indicated for mild to moderate mitral-prolapse-related regurgitation,
but there are some cases of ischemic mitral
regurgitation where it may be acceptable
to repair the valve. This question is often
debated and is the basis of a NIH-sponsored
multi-institutional trial currently in progress
(HL088942-01-1, http://clinicaltrials.gov/
ct2/show/NCT00806988).
In our experience, some of the most common mistakes made in the management of patients with mitral regurgitation are failure to
refer asymptomatic patients, failure to refer
patients with clear class I indications, referral
of patients with functional mitral regurgitation
who are too high-risk for surgery (given lack of
solid evidence for clinical value added), failure
to place biventricular pacers for mitral regurgitation related to conduction abnormalities, and
referral to low-volume, inexperienced centers
and surgeons without a good track record for
mitral repair.

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CONTROVERSIES
Signicant developments in the past ve years
have led to controversy in the treatment of
mitral valve prolapse. Three controversies are
worth addressing:
1. Timing of operation for prolapse/ail
with signicant regurgitation
2. Open surgery versus percutaneous repair
3. French Correction versus American
Correction (resect versus respect)
Surgical Prophylaxis Versus

Watchful Waiting
Current ACC/AHA guidelines (58, 6668) for
surgical treatment of mitral regurgitation are
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Guy
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based on timing surgical repair after the appearance of specic clinical and quantiable
echocardiographic triggers. This approach has
been challenged recently based on the idea
that classical guideline-oriented watchful waiting (versus prophylactic surgery) results in
presymptomatic progression of adverse remodeling and, signicantly, results in excess mortality compared to the mortality of the general
population. Those who argue for the prophylactic approach point to data suggesting that
early surgery can restore cardiac mortality risk
to match that of the general population (6971).
This ongoing controversy is well articulated
in recent reviews by Enriquez-Sarano (favoring
prophylactic mitral repair) and Gillam (favoring
watchful waiting) (72, 73). Clinical equipoise is
present and thus a prospective clinical trial is
warranted to address this question. On careful
review of the literature, it is clear that those in
the watchful-waiting camp are accurate when
they claim that the available data support the
policy of watchful waiting until triggers develop. Proponents of watchful waiting claim
that no data have shown restoration of normal
mortality with early prophylactic mitral repair,
and that surgical morbidity/mortality counteracts the gain afforded by preemptive repair (73).
The advocates of watchful waiting also regard
current mitral repair success rates and durability rates as too low to recommend prophylactic
surgery.
However, the merits of arguments by the
advocates of surgical prophylaxis cannot be
ignored. The same data that are used to argue
against prophylactic mitral repair have been
interpreted in favor of early prophylactic repair
(74, 75). Mitral regurgitation secondary to
ail is associated with excess mortality, double
the expected mortality of the population
without mitral regurgitation (74); furthermore,
excess risk worsens as the quantity of mitral
regurgitation worsens (76). Following surgical
correction, reverse remodeling is possible if
irreversible changes have not already occurred
(72, 77). The data show that utilization of new
markersnot currently used in ACC/AHA
guidelinesis useful and relevant for timing

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of mitral repair surgery. Markers suggested by

Sarano and Sundt include EF <60%, effective
regurgitant orice >40 mm2 , elevated BNP,
and atrial brillation (78). Current triggers for
recommendation of mitral repair for mitral regurgitation for ail mitral valve are described in
the Indications and Guidelines section above.
In accordance with the classical recommendations for the timing of operative repair for
mitral regurgitation, patients frequently are
treated with aggressive medical (pharmacologic) management with subsequent delay in
surgical treatment. Longstanding mitral regurgitation has been allowed to exist and progress
as long as symptoms were controlled and as long
as complications were avoided using pharmacologic treatment. Delayed surgical correction is
known to allow anatomic, histologic, cellular,
and molecular adverse remodeling, and pharmacologic treatment produces symptom relief
without reverse remodeling.
Advocates of early prophylactic surgery
also stipulate the following criteria for the
center where the surgery is performed: high
volume of mitral repair; >90% repair rate;
>90% durability of repair with low need for
reoperation and low postoperative recurrence
of mitral regurgitation (72).
Mitral Surgery Versus

Percutaneous Repair
The controversy that will take on increased
signicance over the next ve years is whether
open surgical repair for mitral regurgitation is
better than percutaneous approaches to mitral
repair and replacement. Comparison of the
two methods has just started. The New England
Journal of Medicine article from April 2011 (64)
comparing MitraClip to surgical repair is the
opening move in a complex debate. Currently,
open or minimally invasive surgical correction
of mitral regurgitation secondary to mitral
prolapse/ail is superior to any percutaneous
method. Currently available percutaneous
methods for mitral repair are limited to simple
lesions, and residual mitral regurgitation is
common. Open surgical methods are applica-
ble to complex mitral pathology, and multiple

methods of repair can be applied during a single
operation. As percutaneous methods for repair
and replacement of the mitral valve evolve
and improve, preference for the least invasive
procedure will prevail. Potential developments
are ongoing with respect to percutaneous
mitral replacement and percutaneous repair
using leaet replacement devices. A large part
of the controversy resides in the transfer of
mitral repair and replacement methods from
the surgeon to the nonsurgeon and the effectiveness/durability of repair. As percutaneous
methods become advanced, comparison will
arise between percutaneous methods and minimally invasive/robotic methods. With respect
to the robotic methods of mitral repair (7982),
one center claims a 96.2% robotic repair rate,
0.8% surgical mortality, and echocardiographic
follow-up in 77% of survivors showing 01+
postoperative regurgitation in 96.9% and 2+
in 3.1% of patients (79). We expect that the
demand for high-quality robotic surgical or
percutaneous mitral repair will accelerate and
the use of open mitral repair will decrease or
end. It can also be expected that high-quality
robotic surgical or percutaneous mitral repair
will be limited to a select set of high-volume
medical centers with extensive resources and
reproducible experience and outcomes.
Resect Versus Respect

The methods proposed by Carpentier for
mitral valve repair have been used with considerable success since their original description
in 1983. Mitral repair for mitral prolapse has
consisted of resection of redundant leaet
tissue, chordal shortening, and remodeling
ring annuloplasty. Only recently has the
Carpentier method been challenged. The
deviations consist of the following methods: no
resection of redundant leaet tissue (respect,
dont resect); elimination of chordal adoption
of neo-chordal reconstruction using Gortex
sutures, instead of chordal shortening; and
focus on optimizing leaet coaptation. These
concepts have generated interest, and clinical
287
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12 December 2011
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data have accumulated showing signicant

success and long-term durability of repair (83).
The use of neo-chordal reconstruction (84)
with an emphasis on leaet coaptation has become standard methodology for mitral repair
(83, 8589).
DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.

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Contents
Annual Review of
Medicine
Volume 63, 2012
Huntingtons Disease: Advocacy Driving Science

Nancy S. Wexler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Direct-to-Consumer Genetic Testing: Perceptions, Problems,
and Policy Responses
Timothy Cauleld and Amy L. McGuire p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23
Human Genome Sequencing in Health and Disease
Claudia Gonzaga-Jauregui, James R. Lupski, and Richard A. Gibbs p p p p p p p p p p p p p p p p p p p p p35
The Genetic Architecture of Schizophrenia: New Mutations
and Emerging Paradigms
Laura Rodriguez-Murillo, Joseph A. Gogos, and Maria Karayiorgou p p p p p p p p p p p p p p p p p p p p63
CCR5 Antagonism in HIV Infection: Current Concepts
and Future Opportunities
Timothy J. Wilkin and Roy M. Gulick p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81
New Paradigms for HIV/AIDS Vaccine Development
Louis J. Picker, Scott G. Hansen, and Jeffrey D. Lifson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95
Emerging Concepts on the Role of Innate Immunity in the Prevention
and Control of HIV Infection
Margaret E. Ackerman, Anne-Sophie Dugast, and Galit Alter p p p p p p p p p p p p p p p p p p p p p p p p p 113
Immunogenetics of Spontaneous Control of HIV
Mary Carrington and Bruce D. Walker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131
Recent Progress in HIV-Associated Nephropathy
Christina M. Wyatt, Kristin Meliambro, and Paul E. Klotman p p p p p p p p p p p p p p p p p p p p p p p p 147
Screening for Prostate Cancer: Early Detection or Overdetection?
Andrew J. Vickers, Monique J. Roobol, and Hans Lilja p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161
Targeting Metastatic Melanoma
Keith T. Flaherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Nanoparticle Delivery of Cancer Drugs
Andrew Z. Wang, Robert Langer, and Omid C. Farokhzad p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185
ME63-frontmatter
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12:3
Circulating Tumor Cells and Circulating Tumor DNA

Catherine Alix-Panabi`eres, Heidi Schwarzenbach, and Klaus Pantel p p p p p p p p p p p p p p p p p p p 199
Translation of Near-Infrared Fluorescence Imaging Technologies:
Emerging Clinical Applications
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Familial and Acquired Hemophagocytic Lymphohistiocytosis
G.E. Janka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233

The Management of Gastrointestinal Stromal Tumors: A Model

for Targeted and Multidisciplinary Therapy of Malignancy
Heikki Joensuu and Ronald P. DeMatteo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
Carotid Stenting Versus Endarterectomy
David Doig and Martin M. Brown p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 259
Mitral Valve Prolapse
T. Sloane Guy and Arthur C. Hill p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
Telomeres, Atherosclerosis, and the Hemothelium: The Longer View
Abraham Aviv and Daniel Levy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Aquaporins in Clinical Medicine
A.S. Verkman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 303
Role of Endoplasmic Reticulum Stress in Metabolic Disease
and Other Disorders
Lale Ozcan and Ira Tabas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Role of Fructose-Containing Sugars in the Epidemics of Obesity
and Metabolic Syndrome
Kimber L. Stanhope p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Vaccines for Malaria: How Close Are We?
Mahamadou A. Thera and Christopher V. Plowe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Crisis in Hospital-Acquired, Healthcare-Associated Infections
David P. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Novel Therapies for Hepatitis C: Insights from the Structure
of the Virus
Dahlene N. Fusco and Raymond T. Chung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 373
Multiple Sclerosis: New Insights in Pathogenesis and Novel
Therapeutics
Daniel Ontaneda, Megan Hyland, and Jeffrey A. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 389
Traumatic Brain Injury and Its Neuropsychiatric Sequelae
in War Veterans
Nina A. Sayer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405
vi
Contents
ME63-frontmatter
ARI
20 December 2011
12:3
Eosinophilic Esophagitis: Rapidly Advancing Insights

J. Pablo Abonia and Marc E. Rothenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 421
Physician Workforce Projections in an Era of Health Care Reform
Darrell G. Kirch, Mackenzie K. Henderson, and Michael J. Dill p p p p p p p p p p p p p p p p p p p p p p p 435

Reducing Medical Errors and Adverse Events

Julius Cuong Pham, Monica S. Aswani, Michael Rosen, HeeWon Lee,
Matthew Huddle, Kristina Weeks, and Peter J. Pronovost p p p p p p p p p p p p p p p p p p p p p p p p p p p p 447
Relationships Between Medicine and Industry: Approaches to the
Problem of Conicts of Interest
Raymond Raad and Paul S. Appelbaum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 465
Wireless Technology in Disease Management and Medicine
Gari D. Clifford and David Clifton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479
Geographic Variation in Health Care
Tom Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 493
Deep Brain Stimulation for Intractable Psychiatric Disorders
Wayne K. Goodman and Ron L. Alterman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
Contemporary Management of Male Infertility
Peter J. Stahl, Doron S. Stember, and Marc Goldstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 525
Indexes
Cumulative Index of Contributing Authors, Volumes 5963 p p p p p p p p p p p p p p p p p p p p p p p p p p p 541
Cumulative Index of Chapter Titles, Volumes 5963 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 545
Errata
An online log of corrections to Annual Review of Medicine articles may be found at
http://med.annualreviews.org/errata.shtml
Contents
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