Series
Valvular heart disease 2
Lancet 2016; 387: 1324–34
See Editorial page 1252
This is the second in a Series of
three papers about valvular heart
disease
Mayo Clinic, Rochester, MN,
USA (R A Nishimura MD,
M F Eleid MD); Hospital Bichat,
Paris, France (A Vahanian MD);
and Baylor Scott and White
Health, Plano, TX, USA
(M J Mack MD)
Correspondence to:
Dr Michael J Mack, Baylor Scott
and White Health, Plano,
TX 75093, USA
michael.mack@baylorhealth.
edu
1324
Mitral valve disease—current management and future
challenges
Rick A Nishimura, Alec Vahanian, Mackram F Eleid, Michael J Mack
The field of mitral valve disease diagnosis and management is rapidly changing. New understanding of disease
pathology and progression, with improvements in and increased use of sophisticated imaging modalities, have led to
early diagnosis and complex treatment. In primary mitral regurgitation, surgical repair is the standard of care.
Treatment of asymptomatic patients with severe mitral regurgitation in valve reference centres, in which successful
repair is more than 95% and surgical mortality is less than 1%, should be the expectation for the next 5 years.
Transcatheter mitral valve repair with a MitraClip device is also producing good outcomes in patients with primary
mitral regurgitation who are at high surgical risk. Findings from clinical trials of MitraClip versus surgery in patients
of intermediate surgical risk are expected to be initiated in the next few years. In patients with secondary mitral
regurgitation, mainly a disease of the left ventricle, the vision for the next 5 years is not nearly as clear. Outcomes
from ongoing clinical trials will greatly inform this field. Use of transcatheter techniques, both repair and replacement,
is expected to substantially expand. Mitral annular calcification is an increasing problem in elderly people, causing
both mitral stenosis and regurgitation which are difficult to treat. There is anecdotal experience with use of
transcatheter valves by either a catheter-based approach or as a hybrid technique with open surgery, which is being
studied in early feasibility trials.
Introduction presentation, diagnosis, and current and future
Mitral valve disease is the most common of the valvular management for patients with primary mitral regurgitation,
heart disorders, particularly in ageing populations, with secondary mitral regurgitation, and mitral stenosis due to
a prevalence of more than 10% in people aged older than annular calcification. A separate report on rheumatic heart
75 years.1 Mitral regurgitation is divided into either disease will cover rheumatic mitral stenosis.5
primary (a structural or degenerative abnormality of the
mitral valve apparatus) or secondary (a disease of the left Primary mitral regurgitation
ventricle, which interferes with the function and Causes, pathophysiology, and natural history
integrity of the mitral valve apparatus) mitral The most common cause of primary mitral regurgitation
regurgitation (table).2,3 Mitral stenosis is usually due to is degenerative mitral valve disease, in which there is
rheumatic disease, but heavy calcification of the mitral myxomatous degeneration of the mitral valve leaflets
annulus with extension into the leaflets might cause and elongated and redundant chordal apparatus.6
obstruction to left ventricular inflow, particularly in the Thickened redundant leaflets will prolapse back into the
elderly population.2,4 left atrium causing malcoaptation of leaflet edges and
Treatment of these various valve disorders is dependent subsequent regurgitation. Rupture of chordal structures
on the underlying cause, pathophysiology, and natural is not uncommon in patients with mitral regurgitation,
history of each disorder. This Review highlights the clinical especially in older men, which will then cause a further
increase in the severity of mitral regurgitation because
of unsupported segments of the mitral valve leaflets.
Search strategy and selection criteria Other causes of primary mitral regurgitation include
We searched Embase, PubMed, MEDLINE, and the Cochrane rheumatic disease, with rare causes being drug-induced
Library for reports published between Jan 1, 2005, and mitral valve disease, healed infective endocarditis, and
Feb 15, 2016. We used the search terms “mitral valve”, “mitral mitral regurgitation associated with systemic disease.
regurgitation”, “mitral annular calcification”, “mitral valve A diagnosis of severe mitral regurgitation is made if
repair”, “mitral valve replacement”, and “mitral stenosis”, 50% of the total stroke volume is diverted to regurgitant
which we combined with many search terms for flow.7 The compensatory response to this volume
“pathophysiology”, “epidemiology”, “natural history”, overload is a progressive increase in left ventricular
“diagnosis”, “management”, and “current issues”. We focused volume with a normalisation of wall stress, resulting in a
on the latest publications, but did not exclude highly regarded chronic asymptomatic stage of mitral regurgitation.7,8
older publications. In addition to the search results, we However, long-standing volume overload can result in
searched the references of relevant articles retrieved by the progressive left ventricular enlargement and stretching
search strategy. of the myocytes beyond their normal contractile length.
This stretching will lead to a decreased contractile state
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 Series

from reduced myofibre content and interstitial fibrosis
with an increase in left atrial and left ventricular diastolic
pressures, producing symptoms of dyspnoea.7–9 The left
ventricular dysfunction might occur before the onset of
symptoms, might not be identified by conventional
measurements of ejection fraction, and portends a poor
prognosis.
Patients presenting with severe primary mitral
regurgitation have an excess mortality rate of 6·3% per
year7 compared with the expected survival rate. This
disease is associated with a high morbidity, with 10-year
incidence of atrial fibrillation of 30% and heart failure
(36% vs 63%). During 10 years, 90% of patients with
severe mitral regurgitation will have died or undergone
surgical repair because of developing mitral regurgitation
symptoms.10,11 Sudden death might also occur and is
responsible for about a quarter of deaths in patients
receiving medical treatment.12 However, so-called
watchful waiting of patients with asymptomatic severe
mitral regurgitation has been shown to be a reasonable
therapeutic strategy if meticulous regular follow-up for
symptoms and changes in left ventricular performance
are completed.13
Presentation and diagnosis
Most patients with severe, chronic, primary mitral
regurgitation remain asymptomatic for many years due
to compensatory ventricular dilation. Symptoms of
exertional dyspnoea and exercise intolerance will slowly
develop as the compensatory mechanisms are over-
whelmed by the volume overload, and irreversible left
ventricular dysfunction occurs. However, if an inter-
vention can be undertaken before or at the onset of
symptoms or at the onset of left ventricular dysfunction,
there is an excellent chance of improved survival for
patients. Thus, it is important to diagnose mitral
regurgitation, establish its severity, and document the
effect of the volume overload on the left ventricle.
Two-dimensional and Doppler echocardiography have
become standard for the assessment of patients
presenting with mitral regurgitation2,3 (figure 1). In
patients with the primary form of this disease, the
morphology of the mitral valve and its pathoanatomic
abnormalities (eg, presence and location of prolapse and
unsupported segments of the mitral valve) will establish
the feasibility of valve repair. Other anatomical abnor-
malities should be assessed because heavy calcification

Primary mitral regurgitation Secondary mitral regurgitation

Causes
Medical therapy
Indications for intervention (accepted)
Indications for intervention (controversial)
Type of intervention (surgical)
Type of intervention (current catheter based)
Type of intervention (future catheter based)
Disease of the valve (degenerative or rheumatic) Disease of the ventricle (ischaemic or functional)
None GDMT for left ventricle dysfunction (ACE inhibitors,
β blockers, aldosterone antagonists, resynchronisation
if appropriate)
Symptoms (any extent of severity); left ventricle Severe symptoms unresponsive to optimum GDMT
dysfunction (ejection fraction <60%, end systolic
dimension >40 mm)
Repairable valve* NA
Repair if possible Replacement†
MitraClip MitraClip‡
Annuloplasty, chordae replacement, mitral valve Annuloplasty, chordae replacement, left ventricle
replacement remodelling devices, mitral valve replacement

GDMT=guideline-directed medical therapy. ACE=angiotensin converting enzyme. NA=not applicable. *>95% probability of durable repair with <1% operative risk.
†Replacement over repair if inferobasal aneurysm, severe leaflet tethering, or severe left ventricle dilatation. ‡Currently in Europe but not in the USA.

Table: Summary of primary and secondary mitral regurgitation

A B C

Figure 1: Transoesophageal echocardiogram and operative photo of a patient with primary mitral regurgitation
(A) Two-dimensional still frame image during systole, showing a flail posterior leaflet (arrow) resulting in non-coaptation of the mitral leaflets. (B) Colour flow
imaging shows severe mitral regurgitation with a large colour jet coursing anteriorly. Quantitative analysis revealed an effective orifice area of 0·6 cm². (C) Flail
posterior leaflet portion of the posterior mitral leaflet. LA=left atrium. LV=left ventricle.

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 Series
of the mitral annulus, as well as calcification, thickening,
and retraction of the mitral valve leaflets might preclude
a successful and durable repair of the mitral valve. Size
and function of the left ventricle is important to obtain by
use of measurements of ejection fraction and end systolic
and end diastolic dimensions. The severity of mitral
regurgitation needs to be able to be established since an
intervention could be considered for severe mitral
regurgitation, even for patients who are asymptomatic.2,3
Quantitative assessment with proximal isovelocity
surface area has become the standard to establish mitral
regurgitation severity and provides measures of effective
orifice area, regurgitant volume, and regurgitant
fraction.14 In patients in whom a discrepancy exists
between the mitral regurgitation severity (based on the
clinical presentation and echocardiography results),
further evaluation with other methods (eg, volume
quantitation by echocardiography, MRI, CT, or cardiac
catheterisation with left ventriculography) might be
needed.15
Current treatments
Medical therapy
No known medical therapy has altered the natural history
of patients with severe primary mitral regurgitation.
For patients who are symptomatic with severe primary
mitral regurgitation, diuretics and afterload reduction
might relieve signs and symptoms of heart failure, but
the ultimate treatment is intervention.2,3
Surgical repair or replacement
Surgical intervention with repair or replacement is
indicated in patients with severe mitral regurgitation and
symptoms or left ventricular dysfunction (ejection
fraction of <60% or end systolic diameter >40 mm).2,3
Surgical repair is the preferred treatment for patients
with primary mitral regurgitation and is associated
with better outcomes than mitral replacement.16–18 The
spectrum of disease ranges from fibroelastic deficiency—
resulting in leaflet prolapse or a flail leaflet segment due
to ruptured chordae tendinae, most commonly of the
middle portion of the posterior leaflet—to Barlow’s
disease with excessive tissue and prolapse of both anterior
and posterior leaflets.19 Mitral regurgitation can usually be
repaired by either resection of the flail and prolapsing
leaflet segment or by reconstructive techniques using
artificial polytetrafluoroethylene chords.20 Annular dilation
occurs secondary to the mitral regurgitation caused by
the leaflet pathology and is most commonly corrected
with a complete or partial annuloplasty ring. Posterior
leaflet prolapse is the most common problem, causing
severe mitral regurgitation and has higher success of
durable repair than anterior leaflet disease or severe
bileaflet disease.21 Success of durable repair should exceed
95%. A clear relationship has been documented between
volume of procedures completed and success of durable
repair.22,23
1326
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The most important factor of long-term durable success
for mitral repair is the experience and expertise of the
surgeon. This has led to the establishment of reference
centres for mitral valve surgery in which successful
repairs exceed 95%, and have an operative mortality of
less than 1%.3,19 The definition of what a reference centre
is was detailed in a multistakeholder consensus by
Bridgewater.24 Criteria include that surgeons should have
specialised training in mitral surgery, intraoperative
transoesophageal echocardiography be completed by
echo accredited anaesthesiologists and cardiologists,
surgeons should do more than 25 mitral operations a
year, and centres have more than 50 operations a year.
Referring physicians should have access to a transparent
audit of patient outcomes. Many reports from reference
centres show repair rates exceeding 95% with operative
mortality of less than 1%. Castillo and colleagues25
reported a 99·9% successful repair rate and 0·8%
mortality in 743 patients with mitral regurgitation during
2002–10. Johnston and colleagues26 reported a 97% repair
rate and 0·07% in-hospital mortality in 3074 patients who
had posterior leaflet repair from 1995 to 2008. Several
other similar series have been reported.27,28 Studies from
the Society of Thoracic Surgeons database indicate that
the repair rate increases if the number of individual
surgeons do more than 25–40 mitral valve operations per
year.22,29 On the basis of these studies,22,25–29 physicians
should consider patient referral to a reference centre for
an operation, especially for patients with complex
bileaflet disease.30
Besides standard surgical approaches of a median
sternotomy, standard minimally invasive techniques now
represent 21% of surgical procedures.29 In a review29 of
61 201 patients undergoing mitral valve surgery in the
USA, 14% were done by a minimally invasive approach
and 7% by a robotic approach. Both these approaches
included partial sternotomies and restricted or mini-right
thoracotomies.31,32 Although concerns were raised about
additional vascular complications and an increased risk
of stroke with the minimally invasive approaches, many
series now exist attesting to the safety of these less
invasive techniques with preservation of the high
percentage of successful repairs.32,33 Although it is hard to
show improved patient outcomes with a less invasive
approach, a reduction in time to recovery, use of
resources, and blood transfusion have been noted. All
other things being equal, minimally invasive surgical
techniques are becoming more widely available with
equivalent outcomes with open approaches.
Transcatheter mitral valve repair
Although surgery is the gold standard intervention in
patients with severe primary mitral regurgitation, a
rationale exists for the use of transcatheter mitral valve
therapies. Many patients who need treatment are elderly
with several comorbidities, so surgery is high risk or
even contraindicated, leading to its underuse in clinical
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 Series

practice.34 However, transcatheter mitral valve therapy is

much more complicated than transcatheter aortic valve
replacement, because of the complexity and heterogeneity
of mitral valve disease, a more difficult valve delivery is
needed, and use of enhanced imaging modalities are
required.
In current practice, transcatheter mitral valve
intervention is mainly limited to the edge to edge
repair technique with MitraClip (Abbott Vascular Inc,
Santa Clara, CA, USA) therapy (figure 2). This technique
reproduces the surgical Alfieri technique of edge to edge
leaflet repair by clipping together the free edges of valve
leaflets at the mid-portion of the leaflets. The procedure
is completed with the patient under general anaesthesia,
using fluoroscopic and most importantly trans-
oesophageal echocardiographic guidance.35 More than
30 000 patients worldwide have been treated with this
procedure to date. The randomised EVEREST II trial36
compared MitraClip to surgery and showed a higher
percentage of patients with significant residual mitral
regurgitation in those who had received MitraClip
compared with surgery (mitral regurgitation grade ≥2:
57% vs 24%, p<0·001).36 Results of 5-year follow-up
showed that the need for surgery was higher in those
after having MitraClip (27·9% vs 8·9%).37
Worldwide multicentre registries of high-risk or
inoperable patients report a high success, good safety,
and functional improvement after MitraClip procedures
in patients with primary and secondary mitral
regurgitation, despite incomplete relief of this disease.38–41
The technique is more challenging in cases of primary
mitral regurgitation, but long-term survival and need for
those who are readmitted to hospital seem to be better in
primary than in secondary forms of this disease,
probably due to the better cardiac and extra-cardiac
conditions patients receive.39,40 The MitraClip is only
approved for use in patients with primary mitral
regurgitation who have severe symptoms and are at high
or prohibitive risk of surgery in the USA, but is approved
for clinical use for both primary and secondary mitral
regurgitation in Europe.
In the past 5 years two transcatheter techniques of
placing artificial chords by a transapical approach have
been developed. Neochord (St Louis Park, MN, USA)42
has received CE Mark approval, and Harpoon Medical
(Baltimore, MD, USA) has started early human feasibility
studies (ClinicalTrials.gov number NCT02432196).
Treatment controversies
When to operate on asymptomatic patients with severe mitral
regurgitation
Patients with severe primary mitral regurgitation and
symptoms or left ventricular systolic dysfunction should
undergo mitral valve intervention.2,3 However, these
symptoms define a subset of patients in whom an
operation is too late, because irreversible left ventricular
dysfunction has already occurred. With the advent of
A B
C D
Figure 2: MitraClip device (A) and transoesophageal echocardiogram of a patient after MitraClip procedure (B)
(B) Three-dimensional image of the mitral valve from the left atrial view showing the clip bringing together the
mid-portion of the anterior and posterior leaflet, resulting in a double orifice during diastole. The catheter used for
insertion is still attached to the clip. (C) Two-dimensional image during systole showing the clip (arrow) bringing
together the anterior and posterior leaflet. (D) Colour-flow imaging during systole showing a thin jet of mitral
regurgitation (red) indicating mild residual regurgitation. LA=left atrium. LV=left ventricle.
mitral valve repair and its excellent short-term and
long-term outcomes, a proposal was made that patients
with severe primary mitral regurgitation should
undergo early operation if they have a high probability
of a successful durable repair with a low operative
risk—before the onset of symptoms or decrease in
ejection fraction.16,43–45 Others have proposed the pathway
of watchful waiting, in which patients with mitral
regurgitation are medically followed up until they reach
the criteria of left ventricular dysfunction.13 After
reaching these criteria, no patients developed residual
left ventricular dysfunction after an operation, although
a substantial percentage of patients eventually needed
an operation.
Non-randomised studies46,47 showed improved out-
comes in patients undergoing early surgery compared
with a similar group undergoing medical management.
However, the benefit from early operation is dependent
on a successful, durable mitral valve repair, and being of
an extremely low operative risk. The clinician should
have the benefit of transparency of surgical results to
know the feasibility of a successful durable repair in
each institution. Referral to so-called valve centres of
excellence that report surgical success in mitral valve
repair was recommended if early operation was to be
undertaken.2,3 If a conservative approach is undertaken,
the patient and physician must be willing to complete
meticulous and frequent follow-up, with operation done

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 Series
Panel 1: Current controversies in mitral valve disease
treatment
• The timing of surgery in asymptomatic severe primary
mitral regurgitation
• Does correction of secondary mitral valve repair impact
survival and quality of life?
• Should all mitral valve surgery be performed in reference
centres?
• Do minimally invasive approaches offer a significant
advantage over open approaches?
• The efficacy and durability of MitraClip for treatment of
intermediate and high-risk patients with primary mitral
regurgitation
• The role of MitraClip in the treatment of secondary mitral
regurgitation
• The feasibility and effectiveness of novel transcatheter
mitral annuloplasty techniques
• The feasibility and effectiveness of transcatheter mitral
valve replacement
• The feasibility and effectiveness of balloon expandable
valve replacement in non-rheumatic mitral stenosis due to
mitral annular calcification
at the onset of symptoms or changes in left ventricular
function. In an asymptomatic patient, of crucial
importance is for the clinician to accurately assess the
severity of the mitral regurgitation and consider all other
available factors, such as an objective measurement of a
patient’s functional capacity and of parameters of left
atrial size, diastolic function, and pulmonary pressure.48
The final treatment of each patient should be a shared
decision making process, with the heart team describing
the risks and benefits of early operation versus watchful
waiting, and the patient sharing their individual needs
and preferences (panel 1).
Surgery versus MitraClip
The European Society of Cardiology and the European
Association of CardioThoracic Surgeons (ESC/EACTS),2
and the American College of Cardiology and the
American Heart Association (ACC/AHA)3 guidelines
state that MitraClip therapy can be considered in patients
with symptomatic, severe, primary mitral regurgitation
who fulfil the echocardiography criteria of eligibility, are
judged inoperable or at high surgical risk by a heart team
(who have particular expertise in valvular heart disease,
including cardiologists, cardiac surgeons, imaging
specialists, anaesthetists, and, if needed, general
practitioners, geriatricians, or intensive care specialists),2
and have a life expectancy of longer than 1 year. Further
evidence should be accumulated in randomised studies
comparing MitraClip with surgery. Ongoing studies
include the HiRiDE (High and Intermediate Risk
Degenerative Mitral Regurgitation Treatment;
NCT02534155) randomised trial that will enrol
1328
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intermediate-risk and high-risk patients, aiming to show
superiority for safety and non-inferiority for efficacy
between these two treatments.49
Treatment in the next 5 years
In parallel with developments in the field of aortic
stenosis since the advent of transcatheter aortic valve
replacement, the introduction of MitraClip has led to a
large increase in patient referrals for treatment of mitral
regurgitation. As an indirect effect, the number of
patients undergoing surgery, especially for mitral valve
repair, has also increased.50
Surgery will probably remain the standard treatment in
low-risk or intermediate-risk patients with primary
mitral regurgitation in the next 5 years. Transcatheter
intervention will provide a satisfactory palliation in high-
risk or inoperable patients. In primary, degenerative
mitral regurgitation it is expected that there will be the
ability to combine repair techniques to try to mimic
surgical techniques by adding catheter delivered
annuloplasty51 to chordal replacement or the MitraClip.52
Transcatheter valve implantation is being developed for
primary mitral regurgitation due to more complex
disease.53
Secondary mitral regurgitation
Causes, pathophysiology, and natural history
Secondary mitral regurgitation is mainly a disease of
the left ventricle. Mitral regurgitation occurs when the
mitral valve leaflets are normal, but left ventricular
dilation results in leaflet tethering and annular dilation
that prevents coaptation.54 Secondary mitral regurgitation
includes both ischaemic and non-ischaemic functional
mitral regurgitation causes. Studies54,55 have shown
adverse outcome at a smaller calculated regurgitation
orifice area than for primary mitral regurgitation.
A dysfunctional cycle of volume overload occurs, leading
to progressive annular dilation, myocardial thinning,
cavity dilation, increased left ventricular wall stress, and
increased leaflet tethering, resulting in progressive
further loss of leaflet coaptation.54,56
Presentation and diagnosis
As left ventricular dysfunction usually precedes the onset
of substantial mitral regurgitation, symptoms of exertional
dyspnoea and exercise intolerance are initially present but
might progressively worsen as the cycle of volume
overload and progressive mitral regurgitation continues.
Identification of the mechanism of secondary mitral
regurgitation by echocardiography is essential to
understand potential therapies for which a patient could
be a candidate for (figure 3). In ischaemic mitral
regurgitation, there is tethering of the posterior leaflet
which is associated with an akinetic or hypokinetic
posterolateral segment of the left ventricular myocardium,
resulting in a posteriorly directed jet of mitral regurgitation
into the left atrium. In non-ischaemic functional mitral
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 Series

regurgitation, tethering of both the posterior and anterior

A B
leaflets is often present due to global myocardial systolic
dysfunction, with a resulting central jet of mitral
regurgitation due to loss of leaflet coaptation.

Current treatment
Medical therapy
First-line treatment for patients with chronic secondary
mitral regurgitation consists of guideline-directed
medical therapy for left ventricular dysfunction, including
angiotensin converting enzyme inhibitors, angiotensin-
receptor antagonists, β blockers, and aldosterone
antagonists.2,3 For patients with chronic secondary mitral C D
regurgitation and conduction system abnormalities
(eg, left-bundle branch block), cardiac resynchronisation
therapy with biventricular pacing might improve left
ventricular function and reduce mitral regurgitation
severity.2,3

Surgical valve replacement and repair

Secondary mitral regurgitation is a disease of the left
ventricle, therefore intervention should be undertaken
only if severe continued symptoms are unresponsive to
optimum medical therapy. Correction of secondary
mitral regurgitation by repair techniques with an
undersized annuloplasty was first described in the
1990s.54 The principle underlying the procedure was that
annular dilation is a late event occurring secondary to the
leaflet tethering from ventricular dilation. By over-
correction of the annular dilation the leaflet coaptation
can be restored and mitral regurgitation corrected.
Although this technique can abolish mitral regurgitation
acutely with short-term symptomatic improvement, the
recurrence rate is high (about 33% of patients in a year)
and improvement in long-term survival has not been
shown. These figures have led to wider use of valve
sparing mitral valve replacement.57 In the past 2 years
randomised trials58,59 assessing mitral valve repair versus
replacement in secondary mitral regurgitation showed
equivalent clinical outcomes but a lower recurrence of
mitral regurgitation with replacement after 2 years.
Additionally, these studies58,59 clarified predisposing
factors for recurrence with repair, which included
inferobasal aneurysm or dyskinesis, severe leaflet
tethering, significant ventricular dilation, or depressed
ejection fraction. Hence, patients with these factors
should have replacement surgery.60
Transcatheter mitral valve repair
Secondary mitral regurgitation is currently the most
common indication for MitraClip use in Europe. Many
registries show the safety of this procedure and
improvements in patient symptoms and quality of life
after 1 year, but most patients still have some residual
mitral regurgitation.39–41 However, the fundamental
question remains about the efficacy of any valve
intervention for patients with secondary mitral
E F
Figure 3: Transoesophageal echocardiogram of a patient with secondary (ischaemic) mitral regurgitation
(A) Two-dimensional image during systole showing retraction and tenting of the posterior leaflet (arrows),
resulting in non-coaptation of the mitral leaflets. (B) Colour-flow imaging showing severe mitral regurgitation
with a large colour jet coursing posteriorly; quantitative analysis showed an effective orifice area of 0·5 cm².
(C) Operative appearance of undersized annuloplasty and its (D and E) replacement. (F) Three-dimensional
echocardiorgam of two MitraClip devices placed for secondary mitral regurgitation. LA=left atrium.
LV=left ventricle.
regurgitation. European guidelines2 both on manage-
ment of heart failure and valvular heart disease state that
the MitraClip procedure can be considered as an
option—mostly to improve symptoms—in patients who
are symptomatic despite optimum medical therapy, fulfil
the echocardiography criteria of eligibility, are judged to
be inoperable or at high surgical risk by a team of
cardiologists and cardiac surgeons, and have a life
expectancy of more than 1 year.2,61 In the ACC/AHA Heart
Failure guidelines62 transcatheter mitral valve repair is
deemed to be of uncertain benefit.
Other techniques to treatment secondary mitral
regurgitation are at an early phase of development. These
include coronary sinus annuloplasty (with the Carrillon
device [Cardiac Dimensions, Kirkland, WA, USA])63 or
direct annuloplasty (with a Cardioband [Valtech Cardio, Or
Yehuda, Israel]),51,53,64 which better reproduces a surgically
effective technique. More than ten other repair techniques
are currently at the experimental or first-in-human stages.

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 Series
Panel 2: Expectations during the next 5 years
• Increase in worldwide prevalence of degenerative mitral
regurgitation and non-rheumatic mitral stenosis
• Increased knowledge of the epidemiology of secondary
mitral regurgitation
• Progress in multimodality imaging for pre-procedural
screening and procedural performance of transcatheter
mitral valve repair and replacement
• Increasing rates of durable surgical mitral valve repair
versus replacement at low operative mortality
• Continued growth in minimally invasive surgical mitral
valve repair techniques
• Continued development of new transcatheter mitral valve
repair technologies
• Investigation of hybrid transcatheter repair combining
annuloplasty with MitraClip
• Ongoing study of transcatheter mitral valve implantation
for native mitral valve disease and secondary mitral
regurgitation
Current trials and controversies
MitraClip in secondary mitral regurgitation—does correction
make a difference?
Non-randomised comparisons with historical controls
have suggested that in patients with severe secondary
mitral regurgitation and left ventricular dysfunction,
MitraClip might have a benefit (compared with medical
therapy) at reducing the need for readmission to hospital
and improve patient survival.65,66 However, data from
randomised trials is needed to show that any intervention
to correct secondary mitral regurgitation and interrupt
the dysfunctional cycle of volume overload from
mitral regurgitation thus causing more mitral
regurgitation, results in improved long-term outcome.
Several ongoing randomised trials (ie, COAPT
[NCT01626079], RESHAPE-HF 1 [NCT02444286],
MITRA-FR [NCT01920698])67 are comparing only optimal
medical management with MitraClip therapy and
optimal medical management, using the primary
endpoint of death or admission to hospital for heart
failure. Of importance will be to establish the short-term
and long-term effects of optimum medical therapy,
including resynchronisation therapy if indicated, because
many patients with secondary mitral regurgitation will
show substantial symptomatic improvement and
decrease in mitral regurgitation severity, obviating the
need for interventional therapy. Results from these trials
will help identify the clinical efficacy and applicability of
MitraClip in patients with secondary mitral regurgitation.
Transcatheter mitral valve replacement early feasibility trials
The feasibility of transcatheter mitral valve replacement
has been reported in a small number of patients at extreme
risk (<100 patients) with native, mitral valve disease, but
does not allow for any firm conclusions. On the one hand,
1330
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implantation of a valve in a non-calcified mitral valve raises
several important challenges: its positioning and
anchoring, causing obstruction of the left ventricular
outflow tract, or coronary circumflex artery or paravalvular
leak. On the other hand, transcatheter mitral valve
replacement has several theoretical advantages, compared
with valve repair, because it is versatile and durably
eliminates mitral regurgitation.53 Of the ten ongoing
studies, four are early feasibility trials in the USA (Neovasc
Tiara Mitral Valve System [TIARA-I; NCT02276547],
Tendyne Mitral Valve System [NCT02321514], CardiAQ
TMVI System [Transfemoral and Transapical DS;
NCT02515539], and Twelve Transcatheter Mitral Valve
Replacement [TMVR; NCT02428010]).
Treatment in the next 5 years
A combination of percutaneous techniques—eg,
MitraClip plus annuloplasty—could be considered for
patients with secondary mitral regurgitation in the future
(panel 2). Further developments in technology will refine
transcatheter mitral valve replacement devices. As with
surgery, the two techniques will probably be comple-
mentary: repair being preferred at an early stage of the
mitral regurgitation and in the case of less complex
anatomy and replacement in those with more advanced
and greater leaflet tethering and ventricular dilation.
Additional evidence should be accumulated by
randomised studies comparing these new techniques
with medical therapy or possibly surgery or MitraClip
when indicated. The usefulness of left ventricular
remodelling devices should also be evaluated.
Non-rheumatic mitral stenosis
Causes, pathophysiology, and natural history
Mitral annular calcification is a chronic degenerative
condition of the fibrous mitral annulus, resulting in
progressive calcification, particularly involving the
posterior annulus.68 The estimated prevalence of mitral
annular calcification is 10% of elderly patients, with 1–2%
of whom develop stenosis.68–70 Risk factors for mitral
annular calcification include older age, being a woman,
having chronic kidney disease, and diseases predisposing
to left ventricular hypertrophy (ie, hypertension and
aortic stenosis).4 Mitral annular calcification seems to be
a multifactorial condition resulting from a varying
combination of abnormal calcium and phosphorus
metabolism,71 increased mitral valve haemodynamic
stress,72 and atherosclerotic processes.73–76
Presentation and diagnosis
Patients with isolated mitral annular calcification are
typically asymptomatic for many years, but then develop
symptoms of dyspnoea and exercise intolerance, similar
to rheumatic mitral stenosis. Although severe mitral
annular calcification can often be seen on chest
radiograph and cinefluoroscopy during cardiac
catheterisation, echocardiography and CT are the imaging
www.thelancet.com Vol 387 March 26, 2016

tests of choice for diagnosis. With two-dimensional
transthoracic echocardiography, mitral annular cal-
cification is seen as a bright echo-dense, band-like
structure located at the junction of the atrioventricular
groove and the posterior mitral leaflet74,77 (figure 4). Severe
mitral annular calcification has been defined as a
substantial echodensity, involving more than a half of the
circumference of the mitral annulus or with intrusion
into the left ventricular outflow tract.74 CT allows for
quantitation and detailed spatial assessment of the extent
of mitral annular calcification (figure 4).78 Mitral annular
calcification can be quantified by the Agatston method.79
Specific data regarding the extent of mitral annular
calcification, obtained from CT, is useful in procedural
planning for potential interventions, particularly if a
transcatheter valve implantation is being considered.
Mitral stenosis due to mitral annular calcification might
become haemodynamically substantial (eg, cause valve
dysfunction, either stenosis or regurgitation) if cal-
cification extends beyond the annulus and into the mitral
leaflets, resulting in restricted leaflet motion in the
absence of commissural fusion. Although the transmitral
gradient can be accurately assessed by non-invasive
Doppler echocardiography, the use of pressure half time
for calculation of mitral valve area might not be accurate
for non-rheumatic mitral stenosis because of mitral
annular calcification.69 Thus, alternative echocardiographic
techniques to calculate mitral valve area, such as
planimetry or continuity equation, are preferred. Although
no universally accepted criteria exist for severe mitral
stenosis due to mitral annular calcification, a mitral valve
area of 1·5 cm² or smaller has been used in initial, early-
phase trials (eg, MITRAL [Mitral Implantation of
TRAnscatheter vaLves; NCT02370511]).80
Current treatment
Surgery
Open surgical techniques to address mitral annular
calcification range from extensive debridement of
annular calcium to replacement of the valve and leaving
the calcium generally intact to place balloon expandable
transcatheter aortic valve replacement valves under direct
vision during open surgery.81–83 Although reports showed
good results with extensive surgical debridement and
complex reconstructive techniques with autologous and
bovine pericardium and other materials, the procedure is
fraught with neurological complications due to calcium
embolisation and with the devastating complication of
atrioventricular disruption, which is often fatal.
Therefore, extensive surgical debridement of annular
calcification is not used frequently by most surgeons.83
Placement of stented bioprostheses with techniques
using large sutures and excising the anterior leaflet is
possible, but the mitral annular calcification frequently
restricts the procedure to placement of only small-sized
prosthetic valves.84 Case reports and investigative studies
are now examining the technique of placement of balloon
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Series
expandable transcatheter aortic valve replacement valves
under direct vision with minimal native valve excision
and supporting surgical sutures to prevent embolisation.85
Balloon valvotomy
In the absence of commissural fusion, balloon valvulo-
plasty is not indicated in patients with degenerative
mitral stenosis and mitral annular calcification.
Transcatheter valve implantation
Case reports and case series presented preliminary
experience of implantation of transcatheter aortic valve
replacement devices in patients with severe mitral
annular calcification who were deemed inoperable or at
high risk.86–89 Although the procedural success is high
(90%) the 30-day mortality is 35%, occurrence of left
ventricular outflow tract obstruction is 11%, and valve
embolisation is 7%.80 Experience and procedural and
device refinements will be key in patient selection and
procedural performance90 and further studies are needed.
In this respect, the MITRAL (NCT02370511) trial is a
pilot study assessing the results of a transcatheter balloon
expandable prosthesis in patients with severe mitral
annular calcification who were deemed inoperable.
Conclusions
The field of mitral valve disease diagnosis and
management is rapidly developing. New understanding of
disease pathological changes, improvements, and wider
uptake of sophisticated imaging modalities (including
three-dimensional echo, four-dimensional CT, and cardiac
magnetic resonance) are providing new insights leading
A B
C D
Figure 4: Mitral annular calcification (MAC)
Top row: two-dimensional echocardiographic parasternal short-axis views of two patients with mild (A) and
severe (B) MAC (arrows). Bottom row: corresponding gated cardiac CT angiography studies provide more detailed
information regarding the density and circumferential extent of calcification in the same patients with
mild (C) and severe (D) MAC.
1331
 Series
to early diagnosis and complex treatment. In primary
mitral regurgitation, surgical repair—often through
minimally invasive approaches—is becoming the more
commonly used treatment. Treatment of even
asymptomatic patients with severe mitral regurgitation in
valve reference centres that have high success for repairs
and low surgical mortality should be patients’ expectations
during the next 5 years. Transcatheter mitral valve repair
with MitraClip is also producing excellent outcomes in
patients who are of high surgical risk. Clinical trials of
MitraClip versus surgery in intermediate risk patients
should be expected to begin in the next few years.
In patients with secondary mitral regurgitation, the
vision for the next 5 years is not as clear. Outcomes
from the clinical trials in progress, especially the
COAPT trial (NCT01626079), will greatly inform this
field of research. If findings from these trials show
MitraClip is better than medical therapy regarding
patient death and readmission to hospital 1 year after
treatment, the use of transcatheter techniques (both
repair and replacement) is expected to greatly increase.
However, if findings from these trials are not positive,
use of these techniques for secondary mitral
regurgitation will be slowed. With four early feasibility
trials on transcatheter mitral valve replacement
underway in the USA, we are likely to see pivotal trials
of one or more of these devices in 2017.
Mitral annular calcification is an increasing problem in
elderly people and is difficult to treat. Use of transcatheter
valves by either a catheter-based approach or as a hybrid
technique with open surgery are now being assessed in
early feasibility trials.
Contributors
All authors equally contributed to the scientific literature search, writing,
editing, and final analyses.
Declaration of interests
AV reports personal fees from Edwards Life Sciences and Abbott
Vascular and grants from Valtech, during the conduct of the study; and
reports personal fees from Medtonic, outside the submitted work. RAN,
MFE, and MJM declare no competing interests.
References
1 Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG,
Enriquez-Sarano M. Burden of valvular heart diseases:
a population-based study. Lancet 2006; 368: 1005–11.
2 Vahanian A, Alfieri O, Andreotti F, et al, and the Joint Task Force on
the Management of Valvular Heart Disease of the European Society
of Cardiology, European Association for Cardio-Thoracic Surgery.
Guidelines on the management of valvular heart disease
(version 2012). Eur Heart J 2012; 33: 2451–96.
3 Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC
guideline for the management of patients with valvular heart
disease: a report of the American College of Cardiology/American
Heart Association Task Force on practice guidelines. Circulation
2014; 129: e521–643.
4 Abramowitz Y, Jilaihawi H, Chakravarty T, Mack MJ, Makkar RR.
Mitral annulus calcification. J Am Coll Cardiol 2015; 66: 1934–41.
5 Remenyi B, ElGuindy A, Smith SC Jr, Yacoub M, Holmes DR Jr.
Valvular heart disease 3. Valvular aspects of rheumatic heart
disease. Lancet 2016; 387: 1335–46.
6 Olson LJ, Subramanian R, Ackermann DM, Orszulak TA,
Edwards WD. Surgical pathology of the mitral valve: a study of
712 cases spanning 21 years. Mayo Clin Proc 1987; 62: 22–34.
1332
Downloaded for Renato Melendez (renatom@ufm.edu) at Francisco Marroquín University from ClinicalKey.com by Elsevier on
May 18, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
7 Carabello BA. Mitral regurgation: basic pathophysiologic principles.
Mod Concepts Cardiovasc Dis 1988; 57: 53–58.
8 Gaasch WH, John RM, Aurigemma GP. Managing asymptomatic
patients with chronic mitral regurgitation. Chest 1995; 108: 842–47.
9 Wisenbaugh T. Does normal pump function belie muscle
dysfunction in patients with chronic severe mitral regurgitation?
Circulation 1988; 77: 515–25.
10 Ling LH, Enriquez-Sarano M, Seward JB, et al. Early surgery in
patients with mitral regurgitation due to flail leaflets: a long-term
outcome study. Circulation 1997; 96: 1819–25.
11 Tribouilloy C, Grigioni F, Avierinos JF, et al. Survival implication of
left ventricular end-systolic diameter in mitral regurgitation due to
flail leaflets a long-term follow-up multicenter study.
J Am Coll Cardiol 2009; 54: 1961–68.
12 Grigioni F, Enriquez-Sarano M, Ling LH, et al. Sudden death in
mitral regurgitation due to flail leaflet. J Am Coll Cardiol 1999;
34: 2078–85.
13 Rosenhek R, Rader F, Klaar U, et al. Outcome of watchful waiting
in asymptomatic severe mitral regurgitation. Circulation 2006;
113: 2238–44.
14 Enriquez-Sarano M, Tribouilloy C. Quantitation of mitral
regurgitation: rationale, approach, and interpretation in clinical
practice.[comment]. Heart 2002; 88 (suppl 4): iv1–03.
15 Nishimura RA, Carabello BA. Hemodynamics in the cardiac
catheterization laboratory of the 21st century. Circulation 2012;
125: 2138–50.
16 Enriquez-Sarano M, Schaff HV, Orszulak TA, Tajik AJ, Bailey KR,
Frye RL. Valve repair improves the outcome of surgery for mitral
regurgitation. A multivariate analysis. Circulation 1995;
91: 1022–28.
17 Jokinen JJ, Hippelainen MJ, Pitkanen OA, Hartikainen JE.
Mitral valve replacement versus repair: propensity-adjusted survival
and quality-of-life analysis. Ann Thorac Surg 2007; 84: 451–58.
18 Moss RR, Humphries KH, Gao M, et al. Outcome of mitral valve
repair or replacement: a comparison by propensity score analysis.
Circulation 2003; 108 (suppl 1): II90–97.
19 Adams DH, Rosenhek R, Falk V. Degenerative mitral valve
regurgitation: best practice revolution. Eur Heart J 2010;
31: 1958–66.
20 Seeburger J, Falk V, Borger MA, et al. Chordae replacement versus
resection for repair of isolated posterior mitral leaflet prolapse:
a egalite. Ann Thorac Surg 2009; 87: 1715–20.
21 Suri RM, Clavel MA, Schaff HV, et al. Effect of recurrent mitral
regurgitation following degenerative mitral valve repair: long-term
analysis of competing outcomes. J Am Coll Cardiol 2016;
67: 488–98.
22 Bolling SF, Li S, O’Brien SM, Brennan JM, Prager RL, Gammie JS.
Predictors of mitral valve repair: clinical and surgeon factors.
Ann Thorac Surg 2010; 90: 1904–11.
23 Vassileva CM, Boley T, Markwell S, Hazelrigg S. Impact of hospital
annual mitral procedural volume on mitral valve repair rates and
mortality. J Heart Valve Dis 2012; 21: 41–47.
24 Bridgewater B, Hooper T, Munsch C, et al. Mitral repair best
practice: proposed standards. Heart 2006; 92: 939–44.
25 Castillo JG, Anyanwu AC, Fuster V, Adams DH. A near 100% repair
rate for mitral valve prolapse is achievable in a reference center:
implications for future guidelines. J Thorac Cardiovasc Surg 2012;
144: 308–12.
26 Johnston DR, Gillinov AM, Blackstone EH, et al. Surgical repair of
posterior mitral valve prolapse: implications for guidelines and
percutaneous repair. Ann Thorac Surg 2010; 89: 1385–94.
27 Gammie JS, O’Brien SM, Griffith BP, Ferguson TB, Peterson ED.
Influence of hospital procedural volume on care process and
mortality for patients undergoing elective surgery for mitral
regurgitation. Circulation 2007; 115: 881–87.
28 Goldstone AB, Cohen JE, Howard JL, et al. A “repair-all” strategy for
degenerative mitral valve disease safely minimizes unnecessary
replacement. Ann Thorac Surg 2015; 99: 1983–90.
29 Badhwar V, Rankin JS, He X, et al. The Society of Thoracic Surgeons
mitral repair/replacement composite score: a report of The Society
of Thoracic Surgeons Quality Measurement Task Force.
Ann Thorac Surg 2015; published online Dec 28. DOI:10.1016/
j.athoracsur.2015.11.049.
www.thelancet.com Vol 387 March 26, 2016

30 Seeburger J, Borger MA, Doll N, et al. Comparison of outcomes of
minimally invasive mitral valve surgery for posterior, anterior and
bileaflet prolapse. Eur J Cardiothorac Surg 2009; 36: 532–38.
31 Davierwala PM, Seeburger J, Pfannmueller B, et al. Minimally
invasive mitral valve surgery: “The Leipzig experience”.
Ann Cardiothorac Surg 2013; 2: 744–50.
32 Mihaljevic T, Jarrett CM, Gillinov AM, et al. Robotic repair of
posterior mitral valve prolapse versus conventional approaches:
potential realized. J Thorac Cardiovasc Surg 2011; 141: 72–80, e1–4.
33 Umakanthan R, Leacche M, Petracek MR, et al. Safety of minimally
invasive mitral valve surgery without aortic cross-clamp.
Ann Thorac Surg 2008; 85: 1544–49.
34 Mirabel M, Iung B, Baron G, et al. What are the characteristics of
patients with severe, symptomatic, mitral regurgitation who are
denied surgery? Eur Heart J 2007; 28: 1358–65.
35 Wunderlich NC, Siegel RJ. Peri-interventional echo assessment for
the MitraClip procedure. Eur Heart J Cardiovasc Imaging 2013;
14: 935–49.
36 Feldman T, Foster E, Glower DD, et al. Percutaneous repair or
surgery for mitral regurgitation. N Engl J Med 2011; 364: 1395–406.
37 Feldman T, Kar S, Elmariah S, et al. Randomized comparison of
percutaneous repair and surgery for mitral regurgitation: five year
results of Everest II. J Am Coll Cardiol 2015; 662: 844–54.
38 Eggebrecht H, Schelle S, Puls M, et al. Risk and outcomes of
complications during and after MitraClip implantation:
experience in 828 patients from the German TRAnscatheter mitral
valve interventions (TRAMI) registry. Catheter Cardiovasc Interv
2015; 86: 728–35.
39 Maisano F, Franzen O, Baldus S, et al. Percutaneous mitral valve
interventions in the real world: early and 1-year results from the
ACCESS-EU, a prospective, multicenter, nonrandomized
post-approval study of the MitraClip therapy in Europe.
J Am Coll Cardiol 2013; 62: 1052–61.
40 Nickenig G, Estevez-Loureiro R, Franzen O, et al. Percutaneous mitral
valve edge-to-edge repair: in-hospital results and 1-year follow-up of
628 patients of the 2011–2012 Pilot European Sentinel Registry.
J Am Coll Cardiol 2014; 64: 875–84.
41 Schillinger W, Hunlich M, Baldus S, et al. Acute outcomes after
MitraClip therapy in highly aged patients: results from the German
TRAnscatheter Mitral valve Interventions (TRAMI) Registry.
EuroIntervention 2013; 9: 84–90.
42 Colli A, Manzan E, Fabio FZ, et al. TEE-guided transapical
beating-heart neochord implantation in mitral regurgitation.
JACC Cardiovasc Imaging 2014; 7: 322–23.
43 Adams DH, Anyanwu AC, Rahmanian PB, Filsoufi F.
Current concepts in mitral valve repair for degenerative disease.
Heart Fail Rev 2006; 11: 241–57.
44 Enriquez-Sarano M, Orszulak TA, Schaff HV, Abel MD, Tajik AJ,
Frye RL. Mitral regurgitation: a new clinical perspective.
Mayo Clin Proc 1997; 72: 1034–43.
45 Enriquez-Sarano M, Schaff HV, Frye RL. Early surgery for mitral
regurgitation: the advantages of youth. Circulation 1997;
96: 4121–23.
46 Kang D-H, Kim JH, Rim JH, et al. Comparison of early surgery
versus conventional treatment in asymptomatic severe mitral
regurgitation. Circulation 2009; 119: 797–804.
47 Suri RM, Vanoverschelde J-L, Grigioni F, et al. Association between
early surgical intervention vs watchful waiting and outcomes for
mitral regurgitation due to flail mitral valve leaflets. JAMA 2013;
310: 609–16.
48 Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al.
Quantitative determinants of the outcome of asymptomatic mitral
regurgitation. N Engl J Med 2005; 352: 875–83.
49 Mihos CG, Santana O, Lamelas J. Intermediate results of transaortic
edge-to-edge repair of the mitral valve in patients undergoing aortic
valve replacement. J Heart Valve Dis 2014; 23: 91–96.
50 Conradi L, Lubos E, Treede H, et al. Evolution of mitral valve
procedural volumes in the advent of endovascular treatment
options: experience at an early-adopting center in Germany.
Catheter Cardiovasc Interv 2015; 86: 1114–19.
51 Maisano F, Taramasso M, Nickenig G, et al. Cardioband, a
transcatheter surgical-like direct mitral valve annuloplasty system:
early results of the feasibility trial. Eur Heart J 2015; published
online Nov 18. DOI:10.1093/eurheartj/ehv603.
www.thelancet.com Vol 387 March 26, 2016
Downloaded for Renato Melendez (renatom@ufm.edu) at Francisco Marroquín University from ClinicalKey.com by Elsevier on
May 18, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
Series
52 Seeburger J, Rinaldi M, Nielsen SL, et al. Off-pump transapical
implantation of artificial neo-chordae to correct mitral regurgitation:
the TACT Trial (Transapical Artificial Chordae Tendinae) proof of
concept. J Am Coll Cardiol 2014; 63: 914–19.
53 Maisano F, Alfieri O, Banai S, et al. The future of transcatheter
mitral valve interventions: competitive or complementary role of
repair vs. replacement? Eur Heart J 2015; 36: 1651–59.
54 Bolling SF, Pagani FD, Deeb GM, Bach DS. Intermediate-term
outcome of mitral reconstruction in cardiomyopathy.
J Thorac Cardiovasc Surg 1998; 115: 381–86.
55 Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ.
Ischemic mitral regurgitation: long-term outcome and prognostic
implications with quantitative Doppler assessment. Circulation
2001; 103: 1759–64.
56 Beaudoin J, Handschumacher MD, Zeng X, et al. Mitral valve
enlargement in chronic aortic regurgitation as a compensatory
mechanism to prevent functional mitral regurgitation in the dilated
left ventricle. J Am Coll Cardiol 2013; 61: 1809–16.
57 Magne J, Girerd N, Senechal M, et al. Mitral repair versus replacement
for ischemic mitral regurgitation: comparison of short-term and
long-term survival. Circulation 2009; 120 (suppl 11): S104–11.
58 Acker MA, Parides MK, Perrault LP, et al. Mitral-valve repair versus
replacement for severe ischemic mitral regurgitation. N Engl J Med
2014; 370: 23–32.
59 Goldstein D, Moskowitz AJ, Gelijns AC, et al. Two-year outcomes of
surgical treatment of severe ischemic mitral regurgitation.
N Engl J Med 2016; 374: 344–53.
60 Kron IL, Hung J, Overbey JR, et al. Predicting recurrent mitral
regurgitation after mitral valve repair for severe ischemic mitral
regurgitation. J Thorac Cardiovasc Surg 2015; 149: 752–61e1.
61 McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for
the diagnosis and treatment of acute and chronic heart failure 2012:
the Task Force for the Diagnosis and Treatment of Acute and
Chronic Heart Failure 2012 of the European Society of Cardiology.
Developed in collaboration with the Heart Failure Association
(HFA) of the ESC. Eur J Heart Fail 2012; 14: 803–69.
62 Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline
for the management of heart failure: a report of the American
College of Cardiology Foundation/American Heart Association Task
Force on practice guidelines. Circulation 2013; 128: e240–327.
63 Siminiak T, Wu JC, Haude M, et al. Treatment of functional mitral
regurgitation by percutaneous annuloplasty: results of the TITAN
Trial. Eur J Heart Fail 2012; 14: 931–38.
64 Maisano F, Taramasso M. The Cardioband transcatheter direct
mitral valve annuloplasty system. EuroIntervention 2015;
11 (suppl W): W58–59.
65 Van den Branden BJ, Swaans MJ, Post MC, et al. Percutaneous
edge-to-edge mitral valve repair in high-surgical-risk patients:
do we hit the target? JACC Cardiovasc Interv 2012; 5: 105–11.
66 Velazquez EJ, Samad Z, Al-Khalidi HR, et al. The MitraClip and
survival in patients with mitral regurgitation at high risk for
surgery: A propensity-matched comparison. Am Heart J 2015;
170: 1050–59, e3.
67 Obadia JF, Armoiry X, Iung B, et al. The MITRA-FR study: design
and rationale of a randomised study of percutaneous mitral valve
repair compared with optimal medical management alone for severe
secondary mitral regurgitation. EuroIntervention 2015; 10: 1354–60.
68 Korn D, Desanctis RW, Sell S. Massive calcification of the mitral
annulus. A clinicopathological study of fourteen cases. N Engl J Med
1962; 267: 900–09.
69 Akram MR, Chan T, McAuliffe S, Chenzbraun A.
Non-rheumatic annular mitral stenosis: prevalence and
characteristics. Eur J Echocardiogr 2009; 10: 103–05.
70 Kanjanauthai S, Nasir K, Katz R, et al. Relationships of mitral
annular calcification to cardiovascular risk factors: the Multi-Ethnic
Study of Atherosclerosis (MESA). Atherosclerosis 2010; 213: 558–62.
71 Silbiger JJ. Anatomy, mechanics, and pathophysiology of the mitral
annulus. Am Heart J 2012; 164: 163–76.
72 Nestico PF, Depace NL, Morganroth J, Kotler MN, Ross J.
Mitral annular calcification: clinical, pathophysiology, and
echocardiographic review. Am Heart J 1984; 107: 989–96.
73 Adler Y, Fink N, Spector D, Wiser I, Sagie A. Mitral annulus
calcification--a window to diffuse atherosclerosis of the vascular
system. Atherosclerosis 2001; 155: 1–8.
1333
 Series
74 Barasch E, Gottdiener JS, Larsen EK, Chaves PH, Newman AB,
Manolio TA. Clinical significance of calcification of the fibrous
skeleton of the heart and aortosclerosis in community dwelling elderly.
The Cardiovascular Health Study (CHS). Am Heart J 2006; 151: 39–47.
75 Muddassir SM, Pressman GS. Mitral annular calcification as a
cause of mitral valve gradients. Int J Cardiol 2007; 123: 58–62.
76 Roberts WC. The senile cardiac calcification syndrome.
Am J Cardiol 1986; 58: 572–74.
77 Fox CS, Vasan RS, Parise H, et al. Mitral annular calcification
predicts cardiovascular morbidity and mortality: the Framingham
Heart Study. Circulation 2003; 107: 1492–96.
78 Hamirani YS, Nasir K, Blumenthal RS, et al. Relation of mitral
annular calcium and coronary calcium (from the Multi-Ethnic Study
of Atherosclerosis [MESA]). Am J Cardiol 2011; 107: 1291–94.
79 Allison MA, Cheung P, Criqui MH, Langer RD, Wright CM.
Mitral and aortic annular calcification are highly associated with
systemic calcified atherosclerosis. Circulation 2006; 113: 861–66.
80 Guerrero M. SAPIEN in native calcific mitral valve disease
feasibility and registry results. Transcatheter Valve Therapies;
Chicago, IL; June 4–6, 2015. http://www.tctmd.com/show.
aspx?id=398&ref_id=129168 (accessed March 11, 2016).
81 Carpentier AF, Pellerin M, Fuzellier JF, Relland JY.
Extensive calcification of the mitral valve anulus: pathology and
surgical management. J Thorac Cardiovasc Surg 1996; 111: 718–29.
82 Feindel CM, Tufail Z, David TE, Ivanov J, Armstrong S. Mitral valve
surgery in patients with extensive calcification of the mitral
annulus. J Thorac Cardiovasc Surg 2003; 126: 777–82.
83 Uchimuro T, Fukui T, Shimizu A, Takanashi S. Mitral valve surgery
in patients with severe mitral annular calcification. Ann Thorac Surg
2015; 101: 889–95.
1334
Downloaded for Renato Melendez (renatom@ufm.edu) at Francisco Marroquín University from ClinicalKey.com by Elsevier on
May 18, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
84 Machler H, Anelli-Monti M. Complete intra-atrial implantation of a
mitral-valve prosthesis in a severely calcified mitral annulus.
Eur J Cardiothorac Surg 2011; 40: 1547.
85 Lee R, Fukuhara S, George I, Borger MA. Mitral valve replacement
with a transcatheter valve in the setting of severe mitral annular
calcification. J Thorac Cardiovasc Surg 2015; 151: e47–49.
86 Guerrero M, Greenbaum A, O’Neill W. First in human
percutaneous implantation of a balloon expandable transcatheter
heart valve in a severely stenosed native mitral valve.
Catheter Cardiovasc Interv 2014; 83: e287–91.
87 Hasan R, Mahadevan VS, Schneider H, Clarke B. First in human
transapical implantation of an inverted transcatheter aortic valve
prosthesis to treat native mitral valve stenosis. Circulation 2013;
128: e74–76.
88 Ribeiro HB, Doyle D, Urena M, et al. Transapical mitral
implantation of a balloon-expandable valve in native mitral valve
stenosis in a patient with previous transcatheter aortic valve
replacement. JACC Cardiovasc Interv 2014; 7: e137–39.
89 Sinning JM, Mellert F, Schiller W, Welz A, Nickenig G,
Hammerstingl C. Transcatheter mitral valve replacement using a
balloon-expandable prosthesis in a patient with calcified native
mitral valve stenosis. Eur Heart J 2013; 34: 2609.
90 Himbert D, Bouleti C, Iung B, et al. Transcatheter valve
replacement in patients with severe mitral valve disease and
annular calcification. J Am Coll Cardiol 2014; 64: 2557–58.
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