JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 65, NO. 12, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2015.02.009
THE PRESENT AND FUTURE
STATE-OF-THE-ART REVIEW
Secondary Mitral Regurgitation
in Heart Failure
Pathophysiology, Prognosis, and Therapeutic Considerations
Anita W. Asgar, MD,* Michael J. Mack, MD,y Gregg W. Stone, MDz
ABSTRACT
The development of secondary mitral regurgitation (MR) due to left ventricular dysfunction, also known as functional
MR, is strongly associated with a poor prognosis in patients with heart failure. The mechanisms underlying secondary MR
are multifactorial; accurate imaging assessment of secondary MR may be challenging and nuanced; and the appropriate
roles of medical, surgical, and interventional therapies for management of secondary MR are controversial and evolving.
In this review, the pathophysiology, evaluation, and prognosis of secondary MR in patients with heart failure are discussed, and we evaluate in detail the evidence for the various therapeutic approaches for secondary MR, including
guideline-directed medication for left ventricular dysfunction, cardiac resynchronization therapy and revascularization
when appropriate, and mitral valve surgery and transcatheter interventions. The role of a multidisciplinary heart team in
determining the optimal management strategy for secondary MR is also discussed. (J Am Coll Cardiol 2015;65:1231–48)
© 2015 by the American College of Cardiology Foundation.
M
itral regurgitation (MR) is among the most
diagnosis of secondary MR, as well as potential
common valvular heart disorders, with an
therapeutic approaches.
estimated prevalence in the United States
of w1.7%, increasing with age to w9.3% in those >75
PATHOPHYSIOLOGY OF SECONDARY MR
years of age (1). MR is classiﬁed as primary (also
known as organic) when principally due to a struc-
The MV consists of 2 leaﬂets (anterior and posterior)
tural or degenerative abnormality of the mitral valve
sitting within the annulus (Figure 1). The posterior
(MV), whether of the leaﬂets, chordae tendineae,
mitral leaﬂet originates from the left atrial (LA)
papillary muscles, or mitral annulus. Secondary
endocardium. A subvalvular apparatus, comprising 2
(also known as functional) MR occurs in the absence
papillary muscles (anteromedial and posterolateral)
of organic MV disease, usually from left ventricular
arising from the LV myocardium and the chordae
(LV) dysfunction. It is more common than primary
tendineae, supports the leaﬂets. LV dilation due to
MR (2), is associated with a worse prognosis (com-
ischemic or nonischemic cardiomyopathy secondarily
pounded by the underlying cardiomyopathy), and
impairs leaﬂet coaptation of a structurally normal
(in contrast to primary MR) the beneﬁts of MV surgery
MV, resulting in secondary MR. Speciﬁcally, LV
are uncertain. The present report reviews the etiol-
dysfunction and remodeling lead to apical and lateral
ogy, pathophysiology, prognostic implications, and
papillary muscle displacement, resulting in leaﬂet
From the *Montreal Heart Institute, Montreal, Quebec, Canada; yHeart Hospital Baylor Plano, Baylor HealthCare System, Dallas,
Texas; and the zColumbia University Medical Center and Cardiovascular Research Foundation, New York, New York. Dr. Asgar has
served as a consultant for Abbott Vascular. Dr. Mack was a member of the executive committee of the Partner Trial (Edwards
Lifesciences, uncompensated); and is co-principal investigator of the Coapt Trial (Abbott Vascular, uncompensated). Dr. Stone has
equity in Guided Delivery Systems and Micardia; and is co-principal investigator of the Coapt Trial (Abbott Vascular,
uncompensated).
Manuscript received December 8, 2014; revised manuscript received January 16, 2015, accepted February 3, 2015.
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Asgar et al.
JACC VOL. 65, NO. 12, 2015
MARCH 31, 2015:1231–48
Secondary Mitral Regurgitation
ABBREVIATIONS
tethering (3), dilation and ﬂattening of the
posteriorly directed asymmetric regurgitant jet (Car-
AND ACRONYMS
mitral annulus, and reduced valve closing
pentier Type IIIB) (10). Mitral annular dilation typically
forces. Because these changes are dependent
occurs late in the pathophysiology of secondary MR,
on loading conditions and the phase of the
and is often asymmetric, with greater involvement
cardiac cycle, secondary MR is dynamic in
of the posterior annulus (11). Papillary muscle in-
nature.
farction is rarely the cause of secondary MR (12).
ACEI = angiotensin-converting
enzyme inhibitor(s)
CRT = cardiac
resynchronization therapy
Papillary muscle displacement occurs as a
Nonischemic MR, most commonly due to long-
oriﬁce area
result of global LV enlargement or focal
standing hypertension or idiopathic dilated car-
EROA = effective regurgitant
GDMT = guideline-directed
myocardial scarring, and can affect 1 or
diomyopathy, is characterized by global LV dilation
medical therapy
both papillary muscles, causing posteriorly
with increased sphericity and (typically) a centrally
HF = heart failure
directed or central MR (Figure 2) (4). With
located regurgitant jet. Symmetric mitral annular
LBBB = left bundle branch
chronic MR, the mitral leaﬂet area may in-
dilation is greatest in the septal-lateral direction, and
block
crease up to 35% over time, an adaptive
correlates with the severity of LV dysfunction (13).
LVEF = left ventricular
response
of
MR DUE TO ATRIAL FIBRILLATION. An additional,
regurgitation; insufﬁcient leaﬂet remodeling
although relatively infrequent, cause of severe sec-
may contribute to severe MR (5,6). However,
ondary MR is isolated LA enlargement, with or with-
even in patients with increased mitral leaﬂet
out atrial ﬁbrillation, resulting in a dilated mitral
area, papillary muscle displacement with
annulus and reduced leaﬂet coaptation (without
subsequent decreased coaptation length may
tenting or prolapse), with normal LV function and
still result in signiﬁcant MR (6).
mitral leaﬂets (Carpentier Type I) (14). In patients
ejection fraction
MDCT = multidetector
computed tomography
MR = mitral regurgitation
MV = mitral valve
NYHA = New York Heart
Association
that
minimizes
the
degree
The normal saddle-shape of the annulus is
with atrial ﬁbrillation, improvement in MR severity
important for maintaining normal leaﬂet stress (7).
may occur with restoration of sinus rhythm, sug-
Loss of this shape and annular ﬂattening with LV
gesting a causal relationship (14).
remodeling result in increased leaﬂet stress with
secondary MR. In addition, LV systolic dysfunction
PROGNOSTIC IMPLICATIONS OF SECONDARY MR
reduces the strength of MV closing, which opposes
the leaﬂet tethering forces created by papillary
A strong association between secondary MR severity
muscle displacement. These pathological changes
and both all-cause mortality and heart failure (HF)
culminate in failure of leaﬂet coaptation and de-
hospitalizations has been reported. Among 303 pa-
creased valvular closing forces due to LV dysfunc-
tients with a completed Q-wave MI, any ischemic MR
tion, resulting in MR. The Carpentier classiﬁcation,
was detected by echocardiography in 194 patients
commonly used by surgeons to describe MV pathol-
(64.0%) and was a powerful, independent correlate
ogy, categorizes MR using a mechanistic and func-
of long-term all-cause mortality (relative risk: 1.88
tional approach to the mitral leaﬂets (8). Secondary
[95% conﬁdence interval (CI): 1.23 to 2.86], p ¼ 0.003)
MR is most commonly Carpentier type IIIB, and
(15). In a study from the Duke Cardiovascular Data-
occasionally type I.
bank, qualitatively assessed 3þ to 4þ MR on left
ISCHEMIC VERSUS NONISCHEMIC MR. MR can be
ventriculography was present in 29.8% of 2,057 HF
further classiﬁed as either ischemic or nonischemic.
patients with an LVEF <40% and was an independent
In ischemic MR (the more frequent etiology), LV
predictor of 5-year mortality (adjusted hazard ratio
remodeling after myocardial infarction (MI) results
[HR]: 1.23 [95% CI: 1.13 to 1.34]) (16). Among 1,256
in papillary muscle displacement, causing systolic
patients with dilated cardiomyopathy at the Mayo
tenting of the MV. Global left ventricular ejection
Clinic, quantitatively assessed severe secondary MR
fraction (LVEF) does not have to be reduced; regional
(deﬁned as an effective regurgitant oriﬁce area
wall motion abnormalities with remodeling may
[EROA] >0.2 cm 2, a regurgitant volume >30 ml, or a
result in sufﬁcient MV tethering to cause severe MR,
vena contracta width >0.4 cm) was present in 24% of
despite preserved LVEF (9). Symmetric or asymmetric
patients, and was an independent predictor of death
leaﬂet tethering may occur. Symmetric tethering
or HF hospitalization at median 2.5-year follow-up
is associated with substantial systolic dysfunction,
(adjusted HR: 1.5 [95% CI: 1.2 to 1.9]), independent
global remodeling, and increased LV sphericity
of LVEF (17). This relationship was present separately
with a central regurgitant jet. Asymmetric tethering
for death and HF hospitalizations, and in patients
most frequently results from localized remodeling
with ischemic and nonischemic MR (Figure 3). Sec-
affecting the posterior papillary muscle, with posterior
ondary MR is a powerful predictor of death or trans-
tenting of both leaﬂets (most pronounced at the medial
plant, even with less severe HF (18). However,
or P3 portion of the posterior leaﬂet) causing a
although secondary MR is widely accepted to predict
Asgar et al.
JACC VOL. 65, NO. 12, 2015
MARCH 31, 2015:1231–48
Secondary Mitral Regurgitation
distance and length, and tenting area are useful
F I G U R E 1 Mitral Valve Anatomy
in evaluating the suitability of secondary MR for
various interventional options. Conversely, because
LV unloading may lessen regurgitation, quantiﬁcation of MR severity is most accurately assessed in
the awake patient by transthoracic echocardiography,
thereby avoiding the vasodilatory effects of sedation, hypovolemia, and/or anesthesia with transesophageal echocardiography. Echocardiography is
also indispensable for determining LV volumes,
function, and sphericity; for assessing pulmonary
artery pressures and right ventricular function and
quantifying tricuspid regurgitation; for assessing the
anatomic likelihood for successful MV repair or
transcatheter approaches; for guiding surgical and
transcatheter repair procedures; and for appraising
the durability and functional effect of MV therapies
through serial assessments over time.
The diagram illustrates the valve and supporting structures.
The echocardiographic degree of MR, evaluated by
integrating qualitative and quantitative assessments,
is classiﬁed as mild, moderate, or severe (20). Qualia poor prognosis in patients with primary LV dys-
tative ﬁndings include MV morphology and color ﬂow
function and HF, whether this relationship is causal
and continuous wave signals of the MR jet. Semi-
and whether reducing MR improves patient prognosis
quantitative insights into MR severity are provided
remain unknown.
by pulmonary vein ﬂow and mitral inﬂow patterns.
Quantitative measures include EROA, regurgitant
EVALUATION OF SECONDARY MR
volume, and regurgitant fraction. Enlarged LA and LV
chamber size and increased pulmonary artery pres-
Comprehensive evaluation of the patient with HF
sures provide supportive data for severe MR.
and secondary MR requires a detailed medical history
Conventional 2-dimensional (2D) assessment for
and physical examination, with laboratory, electro-
MR quantiﬁcation relies on measurement of the MR
cardiographic, and echocardiographic assessment.
jet core at its vena contracta or proximal convergence
Most important is an accurate appraisal of the func-
zone using methods that assume circular oriﬁce ge-
tional limitations attributable to HF, the MV anatomy
ometry. MR severity may, therefore, be signiﬁcantly
and severity of MR, and evaluation of the left and
underestimated when the oriﬁce is elliptical (as
right heart circulation, including measurement of
is typical in secondary MR) (4), a situation that is
chamber size and cardiac pressures. By integrating
compounded if multiple jets are present. Three-
these ﬁndings, secondary MR can be categorized into
dimensional (3D) echocardiography overcomes this
4 stages that deﬁne prognosis and guide therapy:
limitation by permitting direct planimetry of the
1) at risk of secondary MR; 2) progressive secondary
vena contracta, regardless of oriﬁce shape or number
MR; 3) asymptomatic severe secondary MR; and 4)
of jets (21). Conversely, both 2D and 3D color ﬂow
symptomatic severe secondary MR (Table 1) (19).
Doppler tend to overestimate the oriﬁce area because
ECHOCARDIOGRAPHY. The
diag-
of their inability to resolve the high velocity jet core
nostic evaluation of MR is echocardiography, with
due to aliasing and blooming artifacts. Secondary
transesophageal and transthoracic echocardiogra-
MR severity also varies during the cardiac cycle, and
phy playing complementary roles. Transesophageal
can peak in early or late systole, further complicating
echocardiography most often accurately identiﬁes
evaluation, which is traditionally done in midsystole.
cornerstone
of
the underlying cause and mechanism of MR, whether
No single parameter is sufﬁcient to quantify the
primary or secondary. A mixed etiology is not un-
degree of MR, and multimodality assessment using
common (e.g., secondary MR with leaﬂet thickening
both 2D and 3D echocardiography is optimal (22).
or mitral annular calciﬁcation). Transesophageal
Although
somewhat
controversial,
outcomes
echocardiographic measurements of leaﬂet length
studies suggest that lesser absolute quantitative
and angles (particularly the posterolateral angle,
degrees of regurgitation in secondary MR may have
signifying posterior leaﬂet tethering), coaptation
the same or greater effect on mortality than in
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Asgar et al.
JACC VOL. 65, NO. 12, 2015
Secondary Mitral Regurgitation
MARCH 31, 2015:1231–48
F I G U R E 2 Secondary MR Due to Left Ventricular Dilation
(A) A representative echocardiogram and diagram of ischemic MR, with a posteriorly directed jet. (B) A representative echocardiogram and
diagram of MR due to idiopathic dilated cardiomyopathy, with a central jet. Note the lateral displacement of the papillary muscles (arrows).
Apical displacement is also typically present, although less well demonstrated in these views. LVOT ¼ left ventricular outﬂow tract;
MR ¼ mitral regurgitation; TEE ¼ transesophageal echocardiography.
primary MR (15,20). Whereas severe primary MR is
mitral annulus. Such changes can occur in the
usually deﬁned as an EROA of $40 mm 2 and a
absence of ischemia (26) and may result in acute
regurgitant volume of $60 ml, Sarano et al. (15) pro-
pulmonary edema (27). Exercise-induced severe MR
posed and the most recent U.S. and European valve
may identify patients at heightened risk for death or
guidelines have accepted EROA $20 mm 2 and regur-
HF hospitalization (28). Quantitatively, an exercise-
gitant volume $30 ml as consistent with severe sec-
induced EROA increase of $13 mm 2 has been as-
ondary MR (19,23) (Table 2). However, the amount of
sociated with increased morbidity and mortality,
MR (assessed by either EROA or regurgitant volume)
although measuring EROA during or immediately
resulting in loss of >50% of total stroke volume (i.e.,
after exercise is technically challenging due to
the regurgitant volume) depends on the LV end-
tachycardia and tachypnea (29). Exercise echocardi-
diastolic volume and LVEF (24). This likely explains
ography may also demonstrate increasing pulmonary
why some studies show an adverse prognostic effect
artery pressures and lack of LV contractile reserve,
of lesser EROA values, whereas others do not.
ﬁndings associated with LV dysfunction and poor
Exercise echocardiography may be useful when
prognosis after MV surgery (30,31). Exercise may also
symptoms appear disproportionate to resting MR
induce greater LV dyssynchrony with increased
severity (25). Exercise results in greater pre-load
MR, which might improve with cardiac resynchroni-
and afterload, a more spherical ventricle, increased
zation therapy (CRT) (see later discussion). However,
coaptation distance, and systolic expansion of the
the predictive value of exercise echocardiography is
Asgar et al.
JACC VOL. 65, NO. 12, 2015
MARCH 31, 2015:1231–48
Secondary Mitral Regurgitation
F I G U R E 3 Prognosis of Quantitatively Determined Secondary Mitral Regurgitation in Patients With
Ischemic and Nonischemic Cardiomyopathy
Survival Free From
HF Hospitalization (%)
100
Adj HR for sev FMR = 1.5 (1.2 to 1.9; p=0.001)
Adj HR for mild/mod FMR = 1.2 (0.96 to 1.6), p=0.09)
80
60
No FMR (n=335)
40
20
Mild/moderate FMR (n=611)
P<0.0001
Severe FMR (n=304)
0
0
1
2
3
4
Years
5
Ischemic cardiomyopathy
(n=645)
100
7
Non-Ischemic cardiomyopathy
(n=424)
100
80
80
60
No FMR
Mild/moderate FMR
40
Severe FMR
20
Survival (%)
Survival (%)
6
No FMR
60
Mild/moderate FMR
40
Severe FMR
20
P<0.0001
0
P<0.0001
0
0
1
2
3
4
5
6
0
Years
1
2
3
4
5
6
Years
(Top) Freedom from death or heart failure (HF) hospitalization in 1,256 patients according to the degree of functional mitral regurgitation
(FMR). (Bottom) Freedom from death according to the degree of FMR in patients with ischemic (lower left) and nonischemic (lower right)
cardiomyopathy. Adapted with permission from Rossi et al. (17). HR ¼ hazard ratio.
imperfect, given the technical issues of measuring
(LV end-diastolic dimension >65 mm, end-systolic
key parameters at or just after peak exercise;
dimension >51 mm, or systolic sphericity index
confounding interpretations due to concomitant
>0.7); and 3) local LV remodeling (interpapillary
ischemia and/or patient deconditioning (with limited
muscle distance >20 mm, posterior papillary-ﬁbrosa
exercise capacity); and the potential for LV remodel-
distance >40 mm, or lateral wall motion abnormal-
ing with changing loading conditions after MV repair
ity) (32). In a series of 300 patients with severe MR
in some patients. Larger studies are required to
undergoing MitraClip (68% of whom had secondary
determine the role of exercise echocardiography in
MR), failure to achieve #2þ MR occurred in 31 pa-
evaluation of the patient with secondary MR.
tients (10.3%). By multivariable analysis, predictors
Echocardiography is also useful in determining the
of failed MitraClip included greater EROA (odds
likelihood of successful MV repair by either surgery or
ratio [OR]: 1.21 per 10 mm2 increase, p ¼ 0.005) and
transcatheter procedures (e.g., the MitraClip, Abbott
baseline transmitral pressure gradient $4 mm 2 (OR:
Vascular, Menlo Park, California) in patients with
1.26, p ¼ 0.03). Success rates were similar with pri-
secondary MR. In patients with secondary MR
mary and secondary MR (33). Of note, due to the
undergoing surgery, successful repair is less likely
double MV oriﬁce and artifacts from the clip(s),
in the presence of: 1) MV deformation (coaptation
quantifying MR severity after the MitraClip with
distance $1 cm, tenting area >2.5 to 3 cm2 , and/or
echocardiography can be challenging.
complex jets originating centrally and posteromedially, posterolateral angle >45 [high poste-
NONECHOCARDIOGRAPHIC IMAGING TECHNIQUES.
rior leaﬂet tethering]); 2) global LV remodeling
Cardiac magnetic resonance (CMR) imaging and
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JACC VOL. 65, NO. 12, 2015
MARCH 31, 2015:1231–48
Secondary Mitral Regurgitation
T A B L E 1 Stages of Secondary (Functional) MR
Valve Anatomy
Valve Hemodynamics*
Cardiac Structure and Function
Symptoms
A: At risk of MR
Grade
Normal valve leaﬂets,
chords, and annulus in a
patient with coronary
disease or cardiomyopathy
No MR jet or small central
jet area <20% LA on
Doppler
Small vena contracta
<0.30 cm
Normal or mildly dilated
LV size with ﬁxed
(infarction) or inducible
(ischemia) regional wall
motion abnormalities
Primary myocardial disease
with LV dilation and systolic dysfunction
Symptoms due to coronary ischemia or HF may
be present that respond
to revascularization and
appropriate medical
therapy
B: Progressive MR
Regional wall motion
abnormalities with mild
tethering of mitral leaﬂet
Annular dilation with mild
loss of central coaptation
of the mitral leaﬂets
EROA <0.20 cm2
Regurgitant volume
<30 ml
Regurgitant fraction <50%
Regional wall motion
abnormalities with reduced
LV systolic function
LV dilation and systolic
dysfunction due to primary
myocardial disease
Symptoms due to coronary ischemia or HF may
be present that respond
to revascularization and
appropriate medical
therapy
C: Asymptomatic
severe MR
Regional wall motion
abnormalities and/or LV
dilation with severe tethering of mitral leaﬂet
Annular dilation with
severe loss of central
coaptation of the mitral
leaﬂets
EROA $0.20 cm2
Regurgitant volume
$30 ml
Regurgitant fraction $50%
Regional wall motion
abnormalities with reduced
LV systolic function
LV dilation and systolic
dysfunction due to primary
myocardial disease
Symptoms due to coronary ischemia or HF may
be present that respond
to revascularization and
appropriate medical
therapy
D: Symptomatic
severe MR
Regional wall motion
abnormalities and/or LV
dilation with severe tethering of mitral leaﬂet
Annular dilation with
severe loss of central
coaptation of the mitral
leaﬂets
EROA $0.20 cm2
Regurgitant volume
$30 ml
Regurgitant fraction $50%
Regional wall motion
abnormalities with reduced
LV systolic function
LV dilation and systolic
dysfunction due to primary
myocardial disease
HF symptoms due to MR
persist even after revascularization and optimization of medical therapy
Decreased exercise
tolerance
Exertional dyspnea
*Several valve hemodynamic criteria are provided for assessment of MR severity; not all criteria for each category will be present in each patient. Categorization of MR severity as mild, moderate, or severe
depends on data quality and integration of these parameters in conjunction with other clinical evidence. Adapted with permission from Nishimura et al. (19).
EROA ¼ effective regurgitant oriﬁce area; HF ¼ heart failure; LA ¼ left atrium; LV ¼ left ventricular; MR ¼ mitral regurgitation.
multidetector row computed tomography (MDCT)
(CRT) when appropriate. Coronary revascularization
can provide complementary information to echocar-
may also be considered in patients with extensive
diography in patients with MR. CMR, in particular,
ischemia and preserved myocardial viability, al-
is highly accurate for quantifying the degree of MR
though it rarely markedly reduces or eliminates sec-
(34). Given its high spatial resolution, MDCT can
ondary MR. The role of surgical and transcatheter
accurately depict MV structure and morphology
MV repair or replacement to interrupt the progres-
(35), and is useful in demonstrating the relationship
sive cycle of LV volume overload / LV dilation /
of the MV complex to other cardiac structures
secondary MR / increasing LV volume overload and
(e.g., the relationship of the coronary sinus to the
dilation / increasing MR is less well established,
mitral annulus and circumﬂex coronary artery) (36).
although some patients may symptomatically beneﬁt.
Both techniques provide true volumetric measures of
Finally, in patients with severe HF and secondary
chamber dimensions and function and also assess
MR refractory to standard therapies, consideration
myocardial ﬁbrosis (scar). In the future, CMR and
should be given to mechanical LV assist devices and
MDCT will likely be increasingly used in the evalua-
heart transplantation.
tion of patients with HF and MR.
THERAPEUTIC CONSIDERATIONS FOR
SECONDARY MR
MEDICAL THERAPY FOR SECONDARY MR
GDMT for HF is ﬁrst-line treatment for patients with
secondary MR (19), although the morbidity and mor-
The goals of therapy in patients with secondary MR
tality of patients with LV dysfunction and secondary
are to improve symptoms and quality of life, reduce
MR remain high. Among 404 secondary MR patients
HF hospitalizations, and potentially improve sur-
treated with GDMT, 4-year cardiac mortality occurred
vival. To date, the most effective therapies for
in 43% and 45% with moderate and severe MR,
secondary MR are aimed at the underlying LV
respectively, compared with only 6% with mild MR
dysfunction, including guideline-directed medical
(p ¼ 0.003) (37). Moderate or severe MR was also an
therapy (GDMT) for HF and biventricular pacing
independent predictor of new onset HF in patients
Asgar et al.
JACC VOL. 65, NO. 12, 2015
MARCH 31, 2015:1231–48
with ischemic LV dysfunction (relative risk: 3.2
[95% CI: 1.9 to 5.2], p ¼ 0.0001).
Secondary Mitral Regurgitation
T A B L E 2 Quantitative Echocardiographic Criteria for Severe MR in
Primary and Secondary Disease of the Mitral Valve
Beta-blockers and angiotensin-converting enzyme
inhibitors (ACEIs) are recommended for all patients
Primary
(Organic) MR
Secondary
(Functional) MR
with LV dysfunction and secondary MR. By reversing
EROA
$0.4 cm2
$0.2 cm2*
LV remodeling, maximal GDMT may secondarily
Regurgitant volume
$60 ml
$30 ml
reduce severe MR. Surprisingly, however, few studies
Regurgitant fraction
$50%
$50%
have examined the effect of medical therapies on
Vena contracta
$0.7 cm
—
secondary MR. In several small, nonrandomized
Jet area
Central jet >40% LA
or holosystolic eccentric jet
—
studies, carvedilol in patients with HF and secondary
MR was associated with improved LV systolic function with reduced MR severity lasting 6 to 12 months
(38,39). In a randomized trial of 59 patients with
*Measurement of the proximal isovelocity surface area by 2-dimensional transthoracic echocardiography in secondary MR underestimates the true EROA due to the crescent shape of the
proximal convergence. Adapted with permission from Nishimura et al. (19).
Abbreviations as in Table 1.
HF and severe dilated cardiomyopathy, treatment
with carvedilol versus placebo resulted in reduced
LV mass and sphericity, with improved systolic
$150 ms. CRT may also be useful in patients with
function. The severity of MR, assessed by the ratio of
LVEF #35%, with sinus rhythm and non-LBBB pattern
MR jet area/LA area, increased during follow-up in
with QRS duration $150 ms, and in those with LBBB
the placebo group, but decreased in the carvedilol
and QRS duration 120 to 149 ms (Class IIa indications)
group (p ¼ 0.04) (40). In the largest randomized trial,
(43). Randomized trials demonstrated improvements
among 138 patients with dilated cardiomyopathy on
in both survival and HF rehospitalization rates in
stable doses of digoxin, diuretic agents, and ACEI
patients treated with CRT with or without a deﬁbril-
assigned to metoprolol (titrated to 50 mg, 3 times
lator (44), along with reductions in LV end-diastolic
a day) or placebo, the metoprolol group had greater
and end-systolic dimensions and improved LVEF.
6-month reductions in LV end-diastolic and end-
The effect of CRT on secondary MR is inconsistent,
systolic volumes, which correlated with improved
although most studies show a reduction in overall
secondary MR (41). However, MR improved in only
MR severity with restoration of synchronous ven-
w42% of metoprolol-treated patients (vs. 20% of
tricular contraction and LV remodeling. In the
control-group patients), and there were no signiﬁcant
sham-controlled MIRACLE (Multicenter InSync Ran-
differences in symptoms or rates of cardiac read-
domized Clinical Evaluation) trial of 450 NYHA
mission or death during follow-up.
functional class III/IV HF patients with LVEF #35%
Less has been reported on the ability of ACEI and
and QRS duration $130 ms, CRT resulted in marked
other agents to reduce secondary MR. In a small study
reductions in LV end-diastolic and end-systolic vol-
of 19 patients with severe dilated cardiomyopathy
umes, improved LVEF, and sustained reductions in
(mean LVEF w20%) and 3þ/4þ MR on stable doses
MR (assessed by the relative size of the mitral jet area
of digoxin, diuretic agents, lisinopril, and isosorbide
in the LA) (45). Similarly, in a sham-controlled trial of
dinitrate, lisinopril was up-titrated from a mean 16
610 NYHA functional class I/II HF patients with
to 55 mg/day, and isosorbide from 30 to 286 mg/day.
LVEF #40% and QRS duration $120 ms, CRT resulted
At 12-month follow-up, MR had decreased to grade
in sustained reductions in MR severity at 3 and
0/1þ in 8 patients (42%; the MR responders), and
6 months, with parallel improvements in LV di-
remained 3þ/4þ in the remainder. LVEF improved
mensions (46). In addition to reducing LV dimen-
in both groups, but to a greater degree in the MR
sions and restoring papillary muscle geometry, CRT
responders, and the LV end-diastolic dimension
can acutely reduce secondary MR by increasing the
decreased in the responders, but increased in the
rise in the transmitral pressure gradient and altering
nonresponders (42).
the balance between the closing and tethering forces
CRT FOR SECONDARY MR
moderate/severe MR, 43% experienced immediate
on the MV (47). In a study of 63 patients with HF and
improvement in MR by $1 grade, as assessed by vena
CRT is a well-established treatment for HF in selected
contracta width after CRT, and an additional 20%
patients with LV dyssynchrony. CRT is a Class I
demonstrated late improvement at 6 months (48).
recommendation for patients in sinus rhythm with
Unfortunately, severe secondary MR improves in
New York Heart Association (NYHA) functional class
no more than one-half of patients after CRT, although
II to IV symptoms on GDMT with LVEF #35%,
such improvement identiﬁes a cohort with an
left bundle branch block (LBBB), and QRS duration
improved prognosis. In a study of 85 HF patients with
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Secondary Mitral Regurgitation
3þ/4þ secondary MR, MR grade at 6 months was
long-term follow-up failed to demonstrate a survival
reduced after CRT in 42 (49%). Two-year survival was
beneﬁt. Isolated MV annuloplasty was performed in
92% in MR responders versus 67% in nonresponders
126 of 419 patients with severe secondary MR and
(p < 0.001) (49). In a recent study of 240 HF patients
LVEF #30% at the University of Michigan (52). At a
(114 with $2þ secondary MR), MR severity at 6
mean 5.5-year follow-up, the propensity-adjusted
months decreased in 48 (42%), remained stable in 42
freedom from death, LV assist device, or United
(37%), and worsened in 24 (21%). The 4-year adverse
Network
event rates were strongly predicted by the presence
occurred in 41% of patients treated with medical
of at least moderate MR after (but not before) CRT
therapy alone versus 49% with annuloplasty. Mor-
(50). It is not clear whether CRT improves the prog-
tality occurred in 38% versus 48% of patients in
nosis of secondary MR independent of its effects
the medical versus surgical groups, respectively.
on LV dysfunction or whether MR responders after
Unfortunately, quality of life and functional outcome
CRT represent a cohort with a more favorable prog-
measures were not assessed.
for
Organ
Sharing-1
transplant
listing
nosis. In this regard, CRT-treated HF patients with
Recurrent MR is frequent after MV annuloplasty for
versus without secondary MR have a worse prog-
secondary MR. Despite its initial abolition in nearly
nosis; EROA $0.20 cm2 predicts poor response to
all patients, moderate or greater MR recurs in 15% to
CRT, increased mortality, and HF rehospitalizations
25% of patients at 6 to 12 months, increasing to w70%
(51). Nonetheless, if otherwise indicated, CRT is a
at 5 years (55). Risk factors for MR recurrence include
reasonable front-line therapy for secondary MR in HF
more severe pre-operative MR, centrally directed or
patients (along with GDMT), and should be performed
multiple jets, greater degree of LV dilation, symmet-
prior to MV surgery or transcatheter intervention.
ric anterior leaﬂet tethering, presence of a basal
SURGERY FOR SECONDARY MR
aneurysm/dyskinesis, $11 mm coaptation height, and
a posterior leaﬂet angle of >45 (56). Recurrent MR
is also more frequent with use of partial bands or
Surgical options for secondary MR include surgical
ﬂexible complete rings (57–59), although recurrence
MV repair and replacement, mechanical LV assist
rates remain high even with complete rigid rings (60).
devices, and orthotopic heart transplantation. Al-
The current standard repair uses a complete rigid
though secondary MR can be acutely corrected by
ring, most commonly 28 mm in men and 26 mm in
MV surgery, the surgery has never clearly been
women. Various ring designs have been developed,
demonstrated to alter the natural history of the pri-
including 1 speciﬁcally for ischemic MR, which
mary disease (dilated cardiomyopathy) or improve
overcorrects for the increased tethering of the P3
survival (52–55). Moreover, whether the response to
segment (61). In patients with severe tethering,
surgery is different in secondary MR due to ischemic
chordal-sparing replacement may be preferable to
versus nonischemic cardiomyopathy has not been
annuloplasty due to less frequent MR recurrence,
established.
as discussed in the following text.
MV ANNULOPLASTY. MV reconstruction with pres-
STUDIES IN NONISCHEMIC MR. In 54 patients with
ervation of annular-chordal-papillary muscle conti-
dilated cardiomyopathy at a single center, secondary
nuity results in maintenance of LV systolic function
MR was treated primarily with undersized annulo-
with reduced LV volumes and end-systolic wall
plasty rings with or without concomitant edge-
stress. The most commonly performed surgical tech-
to-edge repair (57). At 5-year follow-up, 30% of
nique is MV annuloplasty, which addresses only 1
patients had died, and moderate/severe MR had
component of secondary MR: mitral annular dilation.
recurred in 19%. In the ACORN trial, 193 patients with
“Undersizing” the annuloplasty ring by matching
predominately nonischemic MR underwent MV sur-
the ring size to the anterior leaﬂet overcorrects the
gery (84% with an annuloplasty ring) with or without
annular dilation, minimizing the effects of leaﬂet
placement of the CorCap LV restraint device (Acorn
tethering (56). Annular dilation is most pronounced
Cardiovascular, St. Paul, Minnesota). ACORN patients
in the septal lateral dimension, and various ring
were younger and more often female than in most
designs have been used to overcorrect in this
surgical series of secondary MR, and 30-day mortality
dimension, thus restoring leaﬂet coaptation.
was only 1.6% (62). However, during 5-year follow-
The risk-beneﬁt ratio for MV annuloplasty in pa-
up, 30% of patients died, 15% had recurrent MR,
tients with secondary MR not requiring coronary
and 5% underwent repeat MV surgery (63). Additional
artery bypass grafting (CABG) compared with med-
studies are required before surgery can routinely
ical therapy alone is uncertain. Although initial re-
be recommended for secondary MR in nonischemic
sults of undersized annuloplasty were encouraging,
cardiomyopathy.
Asgar et al.
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Secondary Mitral Regurgitation
MV ANNULOPLASTY VERSUS REPLACEMENT. MV
replacement (with either mechanical or bioprosthetic
replacement was used initially for secondary MR, but
valves) at 13 Italian centers between 1996 and 2011,
was quickly abandoned due to frequent ventricular
although the 8-year mortality rate was similar be-
decompensation. LV dysfunction in this setting was
tween the 2 groups, recurrent MR and MV reoperation
due to early techniques including excision of the
was 2.8-fold more common with repair (70).
mitral leaﬂets and subvalvular apparatus, resulting
The issue of repair versus replacement was
in annular-ventricular discontinuity. Current valve-
addressed in a recently reported National Institutes
sparing MV replacement techniques, which leave
of Health–sponsored trial from the Cardiothoracic
the leaﬂets and subvalvular apparatus intact, pre-
Surgical Trials Network (CTSN), in which 251 patients
serve LV function. In general, valve-sparing MV
with severe ischemic MR were randomized to un-
replacement is preferred in patients with the most
dergo either MV repair with an undersized rigid or
severe degrees of tethering, as determined by a
semirigid complete annuloplasty ring or chordal-
tenting height >11 mm, a posterior leaﬂet angle >45 ,
sparing MV replacement (60). As seen in Table 3,
or a basal aneurysm or dyskinesis (64–69). Other sit-
there were no signiﬁcant differences in the 1-year
uations in which replacement is preferred include:
primary endpoint of LV end-systolic volume index
ruptured papillary muscle (acute ischemic MR); pa-
or mortality. However, recurrence of at least moder-
tients in cardiogenic shock; complex MR leaks with
ate MR at 1 year was substantially greater with MV
multiple jets; failure of an initial repair; and for
repair compared with replacement (32.6% vs. 2.3%,
surgeons who do not do many repairs.
p < 0.001). The strongest predictor of MR recurrence
Clinical studies suggested that repair is associated
after repair was a basal aneurysm/dyskinesis at
with lower perioperative mortality, whereas replace-
baseline (present in 62.1% of patients with vs. 20.5%
ment provides better long-term correction with a
without recurrence, p < 0.001) (71). Hence, MV
lower risk of recurrence (an important consideration,
replacement should be strongly considered when an
because MR recurrence predisposes to HF, atrial
inferobasal aneurysm is present.
ﬁbrillation, and readmission). This perceived tradeoff
between reduced operative morbidity and mortality
OTHER SURGICAL PROCEDURES FOR SECONDARY MR.
with repair versus better long-term correction of
Although MV annuloplasty and replacement are the
ischemic MR with replacement has generated sub-
most common surgical procedures, a number of
stantial variation in surgical practice for this high-
other techniques have been employed with varying
prevalence condition.
degrees of success. In at least 2 series, cutting of the
A meta-analysis of 9 retrospective, nonrandomized
2 critical secondary chords to the anterior leaﬂet
studies from 2004 to 2009, comprising 1,730 total
corrected secondary MR without signiﬁcant ven-
patients, compared MV repair with replacement for
tricular decompensation (72,73). This technique is
ischemic MR, with the majority of patients also un-
most commonly employed in patients with severe
dergoing CABG (69). The OR for short-term mortality
with MV replacement versus repair was 2.67 (95% CI:
1.86 to 3.82), with a long-term mortality HR of 1.35
(95% CI: 1.13 to 1.62). A more recent single-center
T A B L E 3 Selected 1-Year Outcomes of MV Repair Versus Replacement for
Severe Ischemic MR (From the Cardiothoracic Surgical Trials Network)
nonrandomized series conﬁrmed this observation:
2.3% in-hospital mortality with MV repair versus
12.5% with replacement (p ¼ 0.03), a difference
LVESVI (ml/m2; primary endpoint)
maintained at a median 2.3-year follow-up (70). In
Recurrent moderate/severe MR
addition, those treated with MV repair (but not
Moderate
replacement) experienced improved LV function with
Severe
reverse LV remodeling.
Some studies have suggested that MV replacement
with preservation of the subvalvular apparatus may
be associated with similar or even lower mortality
than repair in HF, especially in patients with severe
bileaﬂet tethering (posterior lateral angle >45 ),
complex jets, and/or severe LV dysfunction or
multiple comorbidities (67). Among 244 propensitymatched patient pairs with ischemic MR undergoing CABG with either MV ring annuloplasty or
Death
MV Repair
(n ¼ 126)
MV Replacement
(n ¼ 125)
54.6 25.0
60.7 31.5
0.18*
32.6%
2.3%
<0.001
28.4%
2.3%
—
4.2%
0%
—
14.3%
17.6%
0.45
0.25
p Value
MV reoperation
2.4%
0%
Major adverse cardiac events†
32.5%
33.6%
0.86
New York Heart Association
functional class III/IV
9.0%
14.0%
0.28
24.5 23.1
19.6 19.4
0.12
Minnesota Living With
Heart Failure score
Values are mean SD or %. *Adjusted for death. †Death, stroke, New York Heart Association
functional class increase by $1 grade, heart failure rehospitalization, or mitral valve reoperation.
Adapted with permission from Acker et al. (60).
LVESVI ¼ left ventricular end-systolic volume index; MV ¼ mitral valve.
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Secondary Mitral Regurgitation
tethering of the anterior leaﬂet by the secondary
be addressed at the time of CABG, because coronary
chords (seagull deformity). The restriction of the
revascularization alone will only occasionally ame-
anterior leaﬂet can be relieved and coaptation
liorate MR (77,78). In the RIME (Randomised Ischae-
restored with the free margin of the leaﬂet left intact.
mic
Kron et al. (74) described subvalvular repositioning
moderate secondary MR were randomized to CABG
of the displaced posterior papillary muscle toward
plus MV annuloplasty versus CABG alone (79).
the right, ﬁbrous trigone as an adjunct to annulo-
MV repair prolonged the duration of aortic cross-
plasty when severe degrees of tethering are present.
clamping, cardiopulmonary bypass, intubation, and
Another technique employed restoration of both
hospitalization, and led to more blood transfusions,
papillary muscles from their apical and lateral
although operative mortality was 3% in both groups.
distracted position into a more physiological parallel
At 1 year, MV annuloplasty resulted in improved
alignment, resulting in less leaﬂet tethering.
peak oxygen consumption during exercise (the pri-
In patients with severe mitral annular calciﬁcation
in which the annulus has been rendered immobile,
Mitral
Evaluation)
trial,
73
patients
with
mary endpoint), LV remodeling, and reduced MR
severity (80).
annuloplasty will not be effective, and replacement
Several retrospective nonrandomized studies have
is often not feasible. In these patients, a free edge-
failed to demonstrate a survival beneﬁt of MV repair
to-edge approximation with suture (Alﬁeri tech-
in patients undergoing CABG for ischemic heart
nique) can improve the degree of MR (75). Likewise,
disease with coexisting secondary MR (81,82). Con-
in patients undergoing surgical aortic valve replace-
versely, in the prospective STICH (Surgical Treatment
ment with concomitant moderate secondary MR, an
of Ischemic Heart Failure) trial, 220 patients had site-
Alﬁeri suture can be placed through the LV outﬂow
reported moderate/severe MR. Of 104 such patients
track after the aortic valve has been excised.
assigned to CABG, MV repair was performed at oper-
VENTRICULAR APPROACHES TO SECONDARY MR.
Two investigational extracardiac devices, the CorCap
(Acorn Cardiovascular) and Coapsys (Myocor, Maple
Grove, Minnesota), have been used to reshape the LV,
which may secondarily reduce the degree of secondary MR (Figure 4). The CorCap is a passive external
LV mesh restraint intended to reduce wall stress (62).
In the 300-patient randomized ACORN trial, the CorCap reduced LV dimensions, but not MR severity
or mortality compared with control patients (63). The
Coapsys cardiac support device also reshapes the
ventricle by placing a tether between anteriorly
and posteriorly placed extracardiac pads, with some
correction of the mitral annulus in the septal lateral
dimension, thereby reducing secondary MR (76). The
randomized RESTOR-MV (Randomized Evaluation
of a Surgical Treatment for Off-Pump Repair of the
Mitral Valve) trial in patients undergoing CABG with
at least moderate secondary MR was terminated
prematurely. Analysis of available data in 165 patients
at mean 28-month follow-up showed a survival
advantage for those treated with CABG plus Coapsys
without MV repair compared with CABG plus selective MV repair (HR: 0.42 [95% CI: 0.20 to 0.87],
p ¼ 0.04). Although LV dimensions were reduced to
a greater degree with Coapsys, MR reduction was
greater with conventional MV repair (p < 0.0001).
ator discretion in 49, whereas 116 were assigned to
medical therapy only (83). The 5-year adjusted HR
for mortality in patients with MR treated with CABG
plus MV repair versus medical therapy alone (without
CABG) was 0.41 (95% CI: 0.22 to 0.77, p ¼ 0.006),
whereas no survival advantage was evident with
CABG alone versus medical therapy. Thus, although
surgical correction of severe MR in patients undergoing CABG is generally recommended to improve
quality of life, in the absence of a large-scale randomized trial, it is uncertain whether survival is
improved by mitral repair or replacement in this
setting. The recent American College of Cardiology
(ACC)/American Heart Association (AHA) guidelines
for the management of valvular heart disease give
MV surgery for secondary MR in the setting of CABG
a Class IIa indication (Level of Evidence [LOE]: C),
noting that addressing the MV at the time of surgery
is reasonable to avoid leaving the patient with severe MR, despite the absence of conclusive evidence
that this approach prolongs life or ameliorates
symptoms (19).
The management of moderate MR in patients undergoing cardiac surgery has been controversial. In
a recently reported National Institutes of Health–
sponsored randomized trial from the CTSN, 301
patients with moderate ischemic MR undergoing
CABG were randomized to coronary revascularization
MANAGEMENT OF SECONDARY MR DURING CABG.
alone versus coronary revascularization plus MV
Optimal management of concomitant secondary MR
annuloplasty with an undersized rigid annuloplasty
in patients undergoing CABG is still uncertain.
ring (84). The addition of annuloplasty resulted
There is general agreement that severe MR should
in a longer duration of aortic cross clamping and
Asgar et al.
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1241
Secondary Mitral Regurgitation
cardiopulmonary bypass, and a longer hospital stay.
Annuloplasty did result in a reduction in the prev-
F I G U R E 4 Extracardiac Devices Used to Remodel the Left Ventricle, Which May
Reduce Secondary Mitral Regurgitation
alence of moderate or severe MR at 1 year (11.2% vs.
31.0%, p < 0.001), but no signiﬁcant improvement in
CorCap device
Coapsys implant
LV systolic volume index, the primary endpoint
of the trial (p ¼ 0.61). There were also no signi-
Right
ventricle
ﬁcant between-group differences in deaths, read-
Mitral valve
Posterior
pad
missions, functional status, or quality of life at
1 year, although the annuloplasty group had a higher
1-year rate of neurological events (9.6% vs. 3.1%, p ¼
0.03).
Thus,
although
longer-term
follow-up
is
required to determine whether there is late beneﬁt
Sub–valvular
chord
Anterior
pad
from the observed difference in MR at 1 year, ring
annuloplasty of moderate ischemic MR cannot be
routinely
recommended
in
patients
Left
ventricle
undergoing
CABG at this time.
CURRENT
GUIDELINES
FOR
MV
SURGERY
IN
SECONDARY MR. The 2014 ACC/AHA valvular heart
(Left) The CorCap cardiac support device is a passive external mesh restraint that directly
disease guidelines contain 3 recommendations for
reduces the left ventricular end-diastolic dimension and wall stress. (Right) The Coapsys
surgery in secondary MR (19). The ﬁrst states that MV
device consists of a single-headed anterior pad and a dual-headed posterior pad connected
surgery is reasonable for patients with chronic, severe secondary MR (stages C and D) undergoing CABG
by a ﬂexible cord that reduces the left ventricular end-diastolic and end-systolic
dimension.
or aortic valve replacement (Class IIa, LOE: C). The
second states that MV repair may be considered for
patients with chronic moderate secondary MR (stage
B) undergoing other cardiac surgery (Class IIb, LOE:
C). This latter recommendation was reached prior
to the negative results of the randomized moderate
ischemic MR trial being known (84). The third recommendation states that isolated MV surgery may
be considered for severely symptomatic patients
perform direct or indirect annuloplasty, edge-to-edge
repair, chordal plication or replacement, complete
MV replacement, or other approaches (86). The present review is restricted to the MitraClip, the only
device in widespread use (>15,000 implants to date)
and
with
sufﬁcient
outcomes
data
to
provide
comment.
(NYHA functional class III to IV) with chronic severe
THE
secondary MR (stage D) who have persistent symp-
polyester-covered cobalt-chromium clip inserted via
MITRACLIP
toms despite optimal GDMT for HF (Class IIb, LOE: B).
the
Similarly, the most recent European guidelines (2012)
esophageal echocardiographic guidance into the LA
give a Class IIb (LOE: C) recommendation for MV
following trans-septal puncture (Figure 5). The clip is
repair for isolated severe secondary MR, but only for
opened, positioned above the regurgitant jet, and
patients at low surgical risk with LVEF $30% (23).
advanced into the LV. It is then retracted to grasp the
femoral
vein
DEVICE. The
and
MitraClip
advanced
under
is
a
trans-
free edges of the mitral leaﬂets, the grippers are
TRANSCATHETER DEVICES FOR SECONDARY MR
dropped, and the clip is closed and released,
emulating a surgical edge-to-edge repair (Figure 6)
Despite the poor prognosis with GDMT, most HF pa-
(87). Multiple clips may be safely placed, if necessary.
tients with secondary MR do not undergo MV surgery.
The MitraClip has CE mark approval for general use,
Between 2000 and 2008 at the Cleveland Clinic, only
and Food and Drug Administration approval in the
36% of 814 patients with 3þ/4þ secondary MR un-
United States for treatment of symptomatic patients
derwent MV surgery, and secondary MR comprised
with severe primary MR at prohibitive risk for MV
90% of all nonoperated patients with severe MR (85).
surgery, although not for secondary MR.
Given the uncertain risk–beneﬁt ratio, MV surgery
In the EVEREST II (Endovascular Valve Edge-
is uncommon in patients not requiring CABG. As a
to-Edge REpair Study), 278 relatively low-risk pa-
result,
technologies
tients with 3þ/4þ MR were randomized to the
have been developed to treat secondary MR. These
lesser-invasive
transcatheter
MitraClip or surgical MV repair. Compared with MV
devices are designed to imitate surgical approaches
surgery, the MitraClip was substantially safer, but
that have proven to be successful in acutely reducing
not as effective in reducing MR and LV remodeling
MR, and may be classiﬁed according to whether they
(88). Moreover, reﬂecting the early learning curve
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Secondary Mitral Regurgitation
F I G U R E 5 The MitraClip Device
contraindicated for MV surgery, most commonly for
secondary MR. Numerous registries have demonstrated high rates of procedural success and favorable
short-term outcomes (Table 4) (90–103). The TRAMI
(Transcatheter Mitral Valve Interventions) study is
the largest published registry to date (90). Among
1,064 patients treated with the MitraClip at 20
German centers, the median age was 75 years; 87%
had NYHA functional class III/IV HF symptoms; 69%
had LVEF <50%; secondary MR was present in 71%
of patients; and the median Society of Thoracic
Surgeons mortality score was 10. Procedural success
was achieved in 95% of patients, with no procedural
deaths. At w3-month follow-up, 12% of patients had
Close-up views of the MitraClip device’s fabric-covered clip (left) and guiding catheter
died and 12% had been hospitalized for HF, although
with clip delivery system (right). Images courtesy of Abbott Vascular, Menlo Park,
66% remained in NYHA functional class I/II. In the
California.
ACCESS-EU (MitraClip Therapy Economic and Clinical
Outcomes Study Europe) registry, the MitraClip was
with this device, acute procedural success (MR #2þ at
discharge) was achieved in only 77% of patients, and
21% required MV surgery. Nonetheless, with followup to 4 years, NYHA functional class and overall
survival were similar in the 2 groups (89). Of note,
73% of the patients had primary MR, and only 27%
had secondary MR. A signiﬁcant interaction was
present between the randomized therapy and the
primary composite endpoint of death, MV surgery, or
3þ/4þ MR at both 1 and 4 years according to MR etiology; patients with primary MR had signiﬁcantly
improved results with surgical MV repair, whereas
outcomes were at least as good with the MitraClip
in patients with secondary MR (Central Illustration)
(88,89).
Since device approval in Europe, the MitraClip
has been used extensively in patients at high risk or
implanted in 567 patients at 14 sites between April
2009 and April 2011 (91). The mean logistic EuroSCORE was 23, and 77% of patients had secondary
MR. The clip implant rate was 99.6%, with multiple
clips used in 40% of patients. MR was reduced
to #2þ in 91% of patients, and there were 0 procedural deaths. NYHA functional class and 6-min walk
distance substantially improved at 1-year follow-up.
Similarly,
in
the
25-center,
8-country,
2011
to
2012 European Sentinel Pilot Registry, 72% of 628
MitraClip-treated patients had secondary MR, 86%
had NYHA functional class III/IV symptoms, and the
mean EuroSCORE was 20.4 (92). Acute procedural
success was high (95.4%), with multiple clips used
in 39% of patients. In-hospital (2.9%) and 1-year
(15.3%) mortality were similar in patients with secondary and primary MR, although rehospitalization
for HF was more common in the secondary MR group
(25.8% vs. 12.0%, p ¼ 0.009). At 1 year, severe MR
F I G U R E 6 Pathological Changes After Edge-to-Edge Repairs
was present in only 6% of patients. Pooled data
from the EVEREST II High-Risk Registry and U.S.
REALISM (Real World Expanded Multi-center Study
of the MitraClip System) registry were recently published in which the MitraClip was used in 351 patients
with a Society of Thoracic Surgeons score or surgeonpredicted operative mortality of $12% (70% of whom
had secondary MR) (93). By paired echocardiographic
core laboratory analysis, MR was #2þ in 89.7% of
patients at discharge and in 83.4% of patients at
1 year. Mortality was 4.8% at 30 days and 22.8% at
(Left) Double oriﬁce appearance 4 years after a surgical Alﬁeri repair for a patient with
1 year. LV end-diastolic and end-systolic dimensions
severe secondary MR due to ischemic cardiomyopathy. A indicates the anterior leaﬂet. The
decreased through 1-year follow-up, the physical and
arrow denotes tissue growth over the suture site. Reproduced with permission from
Privitera et al. (87). (Right) Pathological appearance 6 months after creation of a double
mental components of the Short Form-36 quality-
oriﬁce mitral valve with the MitraClip. MR ¼ mitral regurgitation. Image courtesy of
of-life score improved, and the proportion of patients
Frederick St. Goar.
with NYHA functional class III/IV symptoms was
reduced from 82.1% at baseline to 17.1% at 1 year.
Asgar et al.
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Secondary Mitral Regurgitation
CENTRAL I LLU ST RAT ION Secondary MR in Heart Failure: Interaction Between the Etiology of MR and the
Relative Success Rates of MV Surgery and MitraClip in the Randomized EVEREST II Trial
Success was deﬁned as freedom from the combined outcome of death, MV surgery, or reoperation, or MR >2þ (echocardiographic core laboratory
determination). Adapted with permission from Feldman et al. (88) and Mauri et al. (89). EVEREST II ¼ Endovascular Valve Edge-to-Edge REpair Study;
MR ¼ mitral regurgitation; MV ¼ mitral valve.
The rate of hospitalizations for HF was signiﬁcantly
The MitraClip cohort was signiﬁcantly older, and
reduced
insertion,
had more diabetes and chronic kidney disease,
compared with the year before (median per patient
higher logistic EuroSCOREs, lower LVEFs, and more
0.41 vs. 0.79, p < 0.0001). All outcomes were direc-
comorbidities. Conversely, 35% of the surgical MV
tionally consistent in patients with secondary and
repair patients also underwent CABG (and other
primary MR. The MitraClip has also been used suc-
cardiac procedures). MitraClip-treated patients had
cessfully in HF patients who are nonresponders to
signiﬁcantly lower rates of hospital mortality and
CRT (an especially high-risk group), with resultant
major infections, and a shorter length of stay
improvements in MR grade, functional capacity, and
compared with surgical patients, although MR was
LV remodeling (104).
reduced to a lesser degree. Survival in the 2 groups
in
the
year
after
MitraClip
In a retrospective study, investigators in Italy
was similar at 1 year (105). In contrast, comparable
compared the outcomes of 91 patients with 3þ/4þ
in-hospital and 6-month results were reported from
secondary MR undergoing surgical MV repair be-
a retrospective comparison of 171 patients with
tween 2001 and 2011 with those of 52 patients
secondary MR treated with either the MitraClip
treated with MitraClip between 2008 and 2011.
(n ¼ 95) or isolated MV repair (n ¼ 76) from the
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Secondary Mitral Regurgitation
T A B L E 4 Large-Scale Published Registries of the MitraClip: Baseline Characteristics and Acute Procedural Success
Registry (Ref. #)
N
Mean Age
(yrs)
Male
Mean or
Median Risk
NYHA
Functional
Class III/IV
Mean
LVEF
FMR
Etiology
#2þ MR
Post
Multiple
Clips
Procedural
Success*
1,064
75
62%
10%†
87%
‡
71%
96%
1.5 mean
95%
ACCESS-EU (91)
567
78
64%
23%§
85%
k
77%
91%
40%
99.6%
European Sentinel (92)
95%
TRAMI (90)
628
74
63%
20%§
86%
43%
72%
98%
37%
EVEREST II and REALISM (93)
351
76
61%
11%†
85%
48%
70%
86%
39%
—
GRASP (94)
171
71
62%
7%†
81%
37%
78%
93%
41%
99%
MARS (95)
142
71
64%
17%§
68%
47%
54%
77%
47%
94%
Taramasso et al. (96)
109
69
84%
22%§
82%
28%
100%
87%
65%
99%
MitraSwiss (97)
100
77
67%
17%§
82%
48%
62%
85%
40%
85%
62
73
72%
19%§
81%
40%
74%
88%
17%
95%
202
75
63%
44%§
98%
44%
65%
92%
35%
92%
121
77
69%
11%†
96%
42%
59%
99%
28%
97%
104
74
62%
36%§
100%
43%
66%
92%
38%
92%
French multicenter (98)
Treede et al. (99)
Bozdag-Turan et al. (100)
Rudolph et al. (101)
Braun et al. (102)
119
71
67%
28%§¶
86%
35%‡
35%¶
-
-
86%
Neuss et al. (103)
157
74
67%
22%§
100%
41%
73%
100%
16%
98%
*According to the registry protocol deﬁnition, which varied per study. †By Society for Thoracic Surgery score. ‡LVEF #50% in 69% of patients. §By the logistic EuroSCORE.
kLVEF #40% in 53% of patients. ¶In patients with FMR.
ACCESS-EU ¼ MitraClip Therapy Economic and Clinical Outcomes Study Europe; EVEREST II ¼ Endovascular Valve Edge-to-Edge REpair STudy; FMR ¼ functional mitral
regurgitation; GRASP ¼ Getting Reduction of Mitral Insufﬁciency by Percutaneous Clip Implantation; LVEF ¼ left ventricular ejection fraction; MARS ¼ MitraClip Asia-Paciﬁc
Registry; MR ¼ mitral regurgitation; NYHA ¼ New York Heart Association; REALISM ¼ Real World Expanded Multi-center Study of the MitraClip System; TRAMI ¼ Transcatheter
Mitral Valve Interventions.
University of Hamburg (106). Differences in baseline
CURRENT GUIDELINES FOR TRANSCATHETER DEVICE
characteristics
treated
USE IN SECONDARY MR. The 2012 European Society of
groups in these studies emphasize the challenges
Cardiology/European Association for Cardio-Thoracic
in
Surgery valve and HF guidelines provide a Class IIb
and
interpreting
procedures
the
results
of
between
nonrandomized
(LOE: C) recommendation to consider MitraClip use
comparisons.
T A B L E 5 Comparison of Ongoing Randomized Trials of the MitraClip in Patients With Heart Failure and Secondary Mitral Regurgitation
COAPT
RESHAPE-HF
MITRA-FR
Number of patients and sites
430 patients at 75 U.S. and Canadian sites
800 patients at 50 E.U. sites
288 patients at 18 French sites
Secondary MR grade (core
laboratory veriﬁed)
$3þ (EROA $30 mm2 and/or
Rvol >45 ml)
$3þ (EROA $30 mm2 and/or
Rvol >45 ml)
Severe (EROA >20 mm2 þ
Rvol >30 ml)
NYHA functional class
II, III, or ambulatory IV
III or ambulatory IV
II–IV
LVEF
$20% to #50%
$15% to #40%
$15% to #40%
Surgical criteria
Not appropriate for mitral valve
surgery (heart team)
None
None
Left ventricular volume
entry criterion
LV end-systolic dimension #70 mm
LV end-diastolic dimension
$55 mm
None
Control arm
Guideline-directed medical therapy
(þCRT, if indicated)
Guideline-directed medical
therapy (þCRT, if indicated)
Guideline-directed medical
therapy (þCRT, if indicated)
Primary efﬁcacy endpoint
(superiority)
Heart failure rehospitalizations at 1 yr
Death or heart failure
hospitalization at 1 yr
Death or recurrent heart failure
hospitalization at 1 yr
Primary safety endpoint
(noninferiority)
The composite of: SLDA; device
embolization; endocarditis requiring
surgery; echocardiography core
laboratory-conﬁrmed mitral stenosis
requiring surgery; LVAD implant; heart
transplant; or any device-related
complications requiring nonelective
cardiovascular surgery at 12 months
None
None
Health economics
Assessed
Assessed
Follow-up, yrs
5
None
2
2
COAPT ¼ Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation; EROA ¼ effective
regurgitant oriﬁce area; LV ¼ left ventricular; LVAD ¼ left ventricular assist device; MITRA-FR ¼ Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in
Patients With Severe Secondary Mitral Regurgitation; Rvol ¼ regurgitant volume; RESHAPE-HF ¼ Randomized Study of the MitraClip Device in Heart Failure Patients With
Clinically Signiﬁcant Functional Mitral Regurgitation; SLDA ¼ single leaﬂet device attachment; other abbreviations as in Table 4.
Asgar et al.
JACC VOL. 65, NO. 12, 2015
MARCH 31, 2015:1231–48
Secondary Mitral Regurgitation
in symptomatic patients with severe secondary
of MR severity in such patients can be challenging,
MR, despite GDMT and CRT, who are inoperable or at
but is essential to help deﬁne patient risk and guide
high risk (23). The 2013 ACCF/AHA HF guidelines
treatment decisions. GDMT for HF is foundation
provide a Class IIb (LOE: B) recommendation to
therapy for moderate and severe secondary MR,
consider MitraClip in symptomatic patients with
along with CRT and coronary revascularization if
severe secondary MR despite GDMT after “careful
indicated. When effectively applied, these measures
candidate selection” (43). Transcatheter MV repair
will often reduce secondary MR and improve pa-
for secondary MR did not receive an ofﬁcial recom-
tient prognosis. The appropriate role of surgical and
mendation in the 2014 ACCF/AHA valvular heart
transcatheter interventions for persistent severe
disease guidelines, although it is recommended with
secondary MR is less clear and is evolving; both
Class IIb (LOE: B) guidance for severe primary MR
options may be considered in carefully selected
in symptomatic patients at prohibitive risk for
patients after balancing the likely risks and bene-
MV surgery (19).
ﬁts. Adequately designed randomized trials are
are
essential to further guide optimal use of these
randomizing symptomatic HF patients with 3þ/4þ
invasive strategies, and several such trials with
secondary MR to the MitraClip plus GDMT versus
the MitraClip are ongoing. Collaboration among
GDMT alone (Table 5). The results of these trials will
HF
clarify the role of the MitraClip in secondary MR, as
diac surgeons, and imaging experts as a multi-
well as whether a therapy purely aimed at reducing
disciplinary heart team is imperative to reach
secondary MR improves prognosis in patients with
consensus on appropriate care for patients with
LV dysfunction as the primary pathophysiologic
secondary MR.
ONGOING
TRIALS. Three
large-scale
trials
specialists,
interventional
cardiologists,
car-
disturbance.
CONCLUSIONS
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Gregg W. Stone, Columbia University Medical Center,
The development of secondary MR is strongly asso-
The Cardiovascular Research Foundation, 111 East
ciated with a worsened prognosis in patients with
59th Street, 11th Floor, New York, New York 10022.
HF, regardless of its etiology. Accurate assessment
E-mail: [email protected].
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KEY WORDS cardiac resynchronization
therapy, echocardiography, heart failure,
mitral valve annuloplasty, prognosis, therapy