European Journal of Echocardiography (2008) 9, 207221

doi:10.1016/j.euje.2007.03.034

REVIEW PAPERS

Ischemic mitral regurgitation: mechanisms

and echocardiographic classication
Eustachio Agricola1*, Michele Oppizzi1, Matteo Pisani1, Alessandra Meris1, Francesco Maisano2
and Alberto Margonato1
1

Division of Non-Invasive Cardiology, San Raffaele Hospital, Milano, Italy; and 2Division of Cardiac Surgery, San Raffaele
Hospital, Milano, Italy

Received 24 December 2006; accepted after revision 25 March 2007; online publish-ahead-of-print 30 June 2007

KEYWORDS

Chronic ischemic mitral regurgitation (IMR) is a common complication of myocardial infarction and
severely affects cardiovascular mortality and morbidity. Multiple pathophysiologic mechanisms, such
as left ventricular (LV) remodeling and dysfunction, annular dilation/dysfunction, and mechanical dyssynchrony, are involved in generating IMR, each of them having different weight. However, the prerequisite to initially creating regurgitation is the presence of local or global LV remodeling that alters
the geometrical relationship between the ventricle and valve apparatus. In the wide spectrum of
patients with chronic IMR, the assessment of some echocardiographic parameters, such as tethering
pattern, leaet motion, origin and direction of the regurgitant jets, allows one to identify different
specic subgroups of patients subjected to different therapeutic approaches. The aim of medical
and/or surgical therapy is to ameliorate heart failure symptoms, and improve LV remodeling and
function and the intermediate/long-term outcome. The targets of surgical MV repair involve annulus,
leaets, chordae and ventricles. The restricted annuloplasty is the most commonly adopted surgical
procedure that improves heart failure symptoms but not survival when compared to medical therapy
and is also subject to a high incidence of late failure (30%). There are some preoperative echocardiographic predictors of failure that include valve (degree of valve remodeling, jet characteristics),
ventricular (degree of remodeling, diastolic dysfunction) and surgical factors.

Introduction
Ischemic mitral regurgitation (IMR) is a common complication of coronary artery disease (CAD) and may develop
in the acute or chronic phase. The acute IMR is secondary
to papillary muscle infarction and rupture, and patients
usually present in cardiogenic shock due to acute volume
overload. In chronic IMR, mitral valve (MV) leaks but the
leaets and subvalvular apparatus appear normal. Chronic
MR is therefore not a disease of the valve per se, but
rather a disease of the left ventricle (LV). The diagnostic criteria of chronic IMR can be summarized as follows: MR occurring more than 16 days after myocardial infarction (MI) with
one or more LV segmental wall motion abnormalities; signicant coronary disease in a territory supplying the wall
motion abnormalities1; and structurally normal MV leaets

* Corresponding author: Cardiologia Diagnostica Non-Invasiva, Ospedale

San Raffaele, IRCCS, Via Olgettina 60, 20132 Milano, Italy. Tel: 39 02 2643
7313; fax: 39 02 2643 7358.
E-mail address: agricola.eustachio@hsr.it (E. Agricola).

and chordae tendinae.1,2 The third criterion is important

to exclude patients with organic MR and associated CAD.
This review article will focus on chronic IMR only examining the prevalence, outcome, pathogenesis, echocardiographic characteristics and therapeutic options.

Prevalence and impact on outcome

The prevalence of chronic IMR is difcult to estimate
because several factors are involved, such as the diagnostic
techniques used, the time of the diagnosis following the MI,
and the heterogeneity of MR patients included in the study.
The frequency of IMR varies largely according to the techniques used from 1.6% to 19.4% in the angiographic studies
to 8%74% in the echocardiographic ones.313 In addition,
the frequency of IMR depends on the timing of evaluation.
Indeed, the range of IMR incidence varies widely in the published studies depending on whether it is evaluated a few
hours or several days after MI. This depends on its dynamic
nature and particular sensitivity to the medical therapy.
Most of the reported data come from post-hoc analysis of

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2007.
For permissions please email: journals.permissions@oxfordjournals.org.

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Ischemic mitral regurgitation;

Tethering;
Echocardiographic
classication;
Mitral valve surgery

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If an exact prevalence of IMR is difcult to obtain, it is

certain that chronic IMR is associated with a risk of heart
failure and death.4,12,13 Importantly, this association is independent of LV systolic function and there is a graded positive
association between the severity of MR and risk of death and
heart failure. Indeed, the presence of even moderate MR
(effective regurgitant orice area  20 mm2) is associated
with a .3-fold risk of heart failure and .2-fold risk of
death at 5 years (Figure 1).4,12 The presence of MR, even
mild, carries an adverse prognosis due to the severe hemodynamic load on the post-infarcted ventricle. Therefore, it
can be postulated that the presence of MR is a marker of
the geometric abnormalities of the ventricle.1 Thus, the
investigation of MR must be part of routine risk stratication
and management planning in all post-MI patients.

Mechanisms
Historically, the mechanism of chronic IMR was attributed to
papillary muscle dysfunction.14 However, further studies
demonstrated that ischemia of papillary muscles themselves
fails to produce signicant MR without damage of the
underlying myocardial wall.15 From this starting point, the
pathophysiologic theory of IMR has evolved through many
hypotheses before reaching the conclusion that IMR is generated by an integration of several mechanisms each of them
having a different weight in generating MR.16 The prerequisite for the initial development of regurgitation is the presence of local or global LV remodeling that causes alteration
in the geometrical relationship between the ventricle and
valve apparatus generating a restricted leaet motion,
termed incomplete mitral leaet closure (IMLC).1619 The
mitral annular dilation and/or dysfunction, LV dysfunction,
and more recently the mechanical dyssynchrony of LV seem
to have additional roles as modulating factors of the degree
of MR.2022 Therefore, there are multiple factors that interact
in causing regurgitation (Figure 2).

Left ventricular local and global remodeling

In patients with post-MI, LV dysfunction and geometric distortion by LV dilation frequently coexist and both could be
involved in the genesis of MR. On one hand, the LV dysfunction decreases ventricular closing forces; on the other hand,
the geometrical changes due to displacement of papillary
muscles from the annular plane restrict the leaet
closure. Even though Kaul et al. rstly postulated that MR
results from global LV dysfunction,17 other studies in

Figure 1 (a) Survival free of heart failure according to degree of

MR. Reprinted from Bursi et al.4 Copyright 2005, American Heart
Association, Inc. (b) Survival according to degree of MR. Reprinted
from Grigioni et al.12 Copyright 2001, American Heart Association,
Inc.

Figure 2 Pathophysiologic factors and their interactions in determining IMR.

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clinical trials, case series or studies restricted to selected

subsets of patients with low ejection fraction or Q-wave
MI.1,12 Moreover, the heterogeneity of the data is accentuated by the fact that the patients included in the studies
are not selected according to the treatment performed for
the MI (conservative or revascularization), and in case of
revascularization the different effects of thrombolytic or
mechanical revascularization therapy on the appearance of
IMR are unknown. For example, a post-hoc analysis of the
SAVE trial reported a frequency of IMR of 19.4% among
patients who underwent catheterization 16 days postinfarction.1 In this study, patients with IMR were less likely
to have received thrombolytic therapy and more frequently
had a persistently occluded infarct related artery.1 Recently,
Bursi et al. reported data from a population-based geographically dened MI incidence cohort of 773 patients
who underwent echocardiographic study within 30 days
after MI.4 Interestingly, the strengths of this study are less
susceptibility to referral and selection biases, the echocardiographic evaluation, and a reported frequency according
to severity of IMR, therefore more applicability to real-life
populations of patients with MI. The authors report a frequency of IMR of 50% in the overall population, mild in 38%
and moderate to severe IMR in 12% of the patients.4
Finally, on average, a patient susceptible to developing
IMR is elderly, with history of multiple infarctions, more
likely to have experienced an inferior or a combined
anteriorinferior MI, not or ineffectively revascularized
and with more severe coronary disease.

E. Agricola et al.

Ischemic mitral regurgitation

experimental and clinical models demonstrated that LV contractile dysfunction without LV dilation and distortion fails
to produce signicant MR.16,18,23 These studies revealed
that the only independent predictor of MR was the tethering
length, but not LV ejection fraction or dP/dt and the degree
of regurgitation correlated with LV sphericity. Interestingly,
a local remodeling in the region supporting the posterior
papillary muscle involved in inferoposterior infarctions
causes severe MR. On the contrary, large anterior myocardial
infarctions with involvement of myocardial wall supporting
the anterior papillary muscle are not able to provoke MR,
but a global remodeling is required.22,24,25 The degree of
regional and global myocardial scarring is correlated with
the severity of MR due to the resultant geometric and functional changes, and each region of scar (inferiorposterior
and anteriorlateral) has an independent impact on MR.26
Finally, once IMR starts, end-diastolic LV volume and wall
stress increase side by side with preload causing more LV
dysfunction, which in turn results in further papillary
muscle displacement and leaet tenting.2,27 Therefore,
IMR begets IMR in a self-perpetuating manner.

209

direction and degree of the displacement (tethering) are

otherwise important. Lateral and posteriorlateral papillary
muscles displacement produces lesser degrees of leaet
tenting and regurgitation than posteriorlateral with
apical displacement16 and the degree of MR is directly
related to tethering distance.16,22 The posteriorlateral
with apical displacement seems to be the direction that
creates the major leaet tension16 and this explains both
why a local remodeling in the posteriorlateral region postinferior MI is sufcient to create IMR and why the incidence
of IMR is higher in inferior than in anterior MI. The tethering
produces a leak in the MV both by causing a lack of coaptation due to the restricted leaet motion and by creating a
change in the geometry of the posterior leaets with a consequent interscallop malcoaptation.28,29 This imbalance
between the two forces generates a typical phasic variation
in the time course of regurgitant orice area in IMR, known
as the loitering pattern30: the orice area and regurgitation are greater in early and late systole and lower in the
mid systole, when peak LV pressure is higher.

Annular factor
Tethering and closing forces

Mechanical dyssynchrony

Figure 3 Forces acting on mitral valve. LV: left ventricle, MR:

mitral regurgitation.

It has been demonstrated that one of the benecial effects

of the cardiac resynchronization therapy is the immediate
reduction of functional MR due to an improved coordinated
timing of mechanical activation of papillary muscle insertion
sites and the remote decrease secondary to LV reverse remodeling.3537 Thus, it is conceivable that the mechanical dyssynchrony of LV can play a potential role as an adjunctive
mechanism in determining the degree of functional MR. In
a prospective quantitative study of patients with LV dysfunction (ischemic and non-ischemic), we evaluated the contribution of the regional intraventricular dyssynchrony in
determining MR with respect to the degree of deformation
of mitral valve apparatus, and global and local LV remodeling. We found that in patients with ischemic LV

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The closure and position of mitral leaets are determined by

the balance between two forces acting on them: the closing
forces generated by the LV systolic contraction which effectively closes the valve and the tethering forces which
restrain the leaets avoiding leaet prolapse (Figure 3).
When tethering is increased by displacement the papillary
muscles and the closure forces are reduced by the LV dysfunction, the equilibrium between these two forces is
broken in favour of tethering forces with displacement of
the coaptation point of leaets in the ventricle with a
typical pattern of IMLC. Therefore, in the genesis of IMR
both forces are involved but with a different relative contribution. It is know that a local remodeling is sufcient to generate signicant IMR, whereas the LV dysfunction only
generates traces of MR.16,18,23 Instead, when tethering is
created, transmitral pressure also signicantly affects
regurgitation.16 Thus, tethering forces can be thought of
as a determinant and closing forces as not a dominant
factor (a modulator of regurgitation). Even though displacement of papillary muscles is the determinant factor, the

The annulus is another etiologic component in determining

chronic IMR. Annular dilation, in the context of ischemic
MR, generally acts as modulating factor because it is able
to increase signicantly the degree of MR in the presence
of leaet tethering.16,21 In the IMR the annulus is affected
in its geometry (shape and dimension) and motion (sphincteric function). The normal annulus presents a saddle
shape that is accentuated during systole to reduce the
stress on valve components.31 Compared with normal controls, in patients with chronic IMR the annulus is dilated
and attened with loss of saddle conguration and the
degree of this geometric deformation is signicantly
greater in the anterior MI than in the inferior one.32 The
annulus dilates uniformly and symmetrically. The anterior
and posterior portions and intertrigonal distance dilate proportionally, as well as each of the different six sectors
dened according to the segmental classication of Carpentier.33 Therefore, it is necessary to revisit the concepts that
in patients with IMR there is an annular distortion localized
at level of P3 region and that the anterior annulus does not
dilate. Finally, the annular area change, an index of sphincteric function, and the annular motion are decreased in
these patients indicating a loss of annular contraction.33,34

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dysfunction, mitral tenting and local LV remodeling are independent predictors of degree of FMR but not regional dyssynchrony.38 These ndings suggest that the local
remodeling of the region of the LV supporting the papillary
muscles is a necessary condition for the development of
FMR, whereas regional dyssynchrony could have only an
additional role.38 These results could be explained by the
fact that in ischemic ventricles the regional dyssynchrony
is the result of the regional ischemic and/or scar lesions
and not an index of evolution of LV global remodeling,
such as in patients with dilated cardiomyopathy. LV dyssynchrony can potentially contribute to MR by several mechanisms. First, an uncoordinated regional LV mechanical
activation in segments supporting papillary muscles provokes geometric changes in mitral leaets increasing
tethering.36 Second, a positive pressure gradient develops
between left atrium and LV due to improper timing of
atrialventricular relaxation and contraction cycles can
create diastolic MR.39 Finally, LV dyssynchrony decreases
the LV contraction efciency and the closing forces,
thereby generating an impairment of MV tenting (35). This
last mechanism seems to be the most important one by
which the LV dyssynchrony causes an increase of MR in
patients with LV dysfunction.

Chronic IMR is a dynamic lesion and its severity may vary over
time. This characteristic depends on the dynamic interplay
between tethering and closing forces, and on the physiologic
and pharmacologic factors able to modify this equilibrium.
Typical examples of this phenomenon are the dramatic
effects of inotropic agents and anesthetic induction on
intraoperative evaluation of the severity of MR. The inotropic
agents (i.e. dobutamine infusion) increase dP/dt and therefore the closing forces reducing MR.40 The general anesthesia
decreases the loading condition and consequently a preload
reduction decreases ventricular size with a reduction in
tethering forces and consequently in the MR.41 The same
effect is obtained with diuretic therapy. Chronic IMR is also
very sensitive to exercise. The increase in MR during exercise
depends directly on exercise-induced changes in mitral deformation indexes and local remodeling of LV supporting posterior papillary muscle, whereas it is inversely related to
the presence of contractile reserve and independent of the
degree of MR at rest.42 Therefore, the exercise is utilized
as stressor to unmask the dynamic component of chronic
IMR during stress echocardiography in patients with heart
failure. Using exercise echocardiography, Lancellotti et al.
have demonstrated the strong prognostic importance of the
dynamic component of IMR over the degree of MR at
rest.43,44 Large increase in the degree of MR during exercise
is associated with increased mortality risk and hospital admission for worsening heart failure.43 The link between
exercise-induced increase in MR and prognosis involves
several mechanisms: intermittent increase of MR during life
activities can provoke ash pulmonary edema,45 acute
increase in pulmonary systolic artery pressure is an independent predictor of cardiac death,46 and intermittent increase
of MR produces an LV volume overload and consequently LV
remodeling and subsequently electromechanical dyssynchronization.47 Thus, this clinical evidence may explain why
even mild IMR signicantly affects the prognosis and provides

a clinical practical consequence. Post-MI patients with heart

failure symptoms not justied by resting echocardiographic
picture need to undergo exercise echocardiography to
unmask the real symptoms and the underlying echocardiographic scenario during exercise and to better stratify their
prognosis.

Quantication of regurgitation and

characterization of mitral deformation indexes
Approaching a patient with IMR, several kinds of echocardiographic information have to be reported to well characterize and identify specic patterns of IMR. Among these, and
the severity of MR and the LV dysfunction and remodeling,
the degree of MV apparatus deformation, and the origin
and direction of regurgitant jets are the most useful and
essential. To graduate the severity of IMR, quantitative
parameters such as the effective regurgitant orice area
(EROA) calculated by PISA or Doppler methods provides a
measure of severity of valve lesion independent of hemodynamic conditions and it is an independent predictor of prognosis.48 An EROA  20 mm2 is considered a threshold of
severity affecting an adverse prognosis.12 Sometimes, a
semiquantitative approach using the vena contracta width
is useful particularly in the presence of an extremely
eccentric jet.48 To evaluate the characteristics of the LV, it
is necessary to evaluate the ventricular volumes, the sphericity index, the ejection fraction, the diastolic function, and
the distribution of wall motion abnormalities. Annular
dimension, coaptation depth, and tenting area assessed in
long-axis view in the mesosystolic phase of the cardiac
cycle are the most important parameters to describe the
degree of MV apparatus deformation (Figure 4). In a group
of normal individuals, we found that 1 cm2 for tenting area
and 0.6 cm for coaptation depth are the normal reference
values in long-axis view.25 The coaptation depth and
tenting area are positively related to the severity of MR
and the severity of LV dysfunction and remodeling.22

Figure 4 H: coaptation depth dened as the distance between

leaet coaptation and mitral annular plane. T: tenting area
dened as the area enclosed between the annular plane and
mitral leaets.

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Dynamic component

E. Agricola et al.

Ischemic mitral regurgitation

211

Recently, tenting volume derived from real-time

3-dimensional echocardiography has been demonstrated to
be a better novel index of MV remodeling than tenting
area.49 Tenting volume takes into account all geometric
components of tethering and tenting and may be a geometric parameter of IMR severity more helpful than other
2-dimenisional parameters.49 Moreover, tenting volume presents sequential change during systolic phase very similar to
a biphasic change of EROA and the extent of these dynamic
changes is inuenced by LV systolic function.49 These ndings suggest that the dynamic systolic change of EROA
might be mainly determined by that of tenting volume.49
Thus, these parameters can be considered a mirror of the
status of LV and of the degree of MR. A big question arises
regarding the dynamic nature of the regurgitation, i.e.
whether the potential status of severity of MR is better
described by MV remodeling indices like glycosylated
haemoglobin in diabetes or by the MR degree at the
moment of observation.

From mechanisms to echocardiographic

patterns

Asymmetric tethering pattern

This pattern is characterized by the predominant posterior
tethering of both leaets. In this case, the asymmetrical displacement of the posterior papillary muscle bends the posterior leaet posteriorly, whereas the anterior leaet
overrides superiorly the posterior one.25 Each papillary
muscle supplies chordae to both leaets, consequentially
a posterior displacement of only one papillary muscle invariably exerts traction on both leaets.19 Therefore, the
different shapes of tethering depend on the relationship

Symmetric tethering pattern

The symmetric pattern is characterized by a predominant
apical tethering of both leaets. In this case, a restricted

Table 1 Echocardiographic and clinical characteristics of different subgroups of IMR

Posterior leaet tethering

Apical leaet tethering
Eccentric jet
Central jet
Coaptation depth
Tenting area
Annular dilation
Annular attening
Local remodeling
Global remodeling
Anterior myocardial infarction
Inferiorlateral myocardial
infarction
Multiple myocardial infarction
Single vessel disease
Multiple vessel disease

Asymmetric
tethering

Symmetric
tethering

Prevalence of annular dilation/

dysfunction

Ischemic
prolapse

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Assessing echocardiographic parameters such as leaet

motion and origin and characteristics of regurgitant jets, it
is possible to distinguish in the spectrum of patients with
chronic IMR different specic subgroups of patients subjected to different therapeutic approaches (Table 1).25

of three tethering vectors (posterior, apical and lateral).

In the asymmetric group, the posterior leaet is simply
drawn more posteriorly than apically (more parallel to the
posterior wall). This posterior restriction of the leaet
prevents it from reaching its normal, more anteriorly
located coaptation point, so that the coaptation point
moves posteriorly, creating the asymmetric tethering
shape. The anterior leaet however is tethered, too. Its
restriction is visible in the hockey stick conguration of
the anterior mitral leaet, which is due to tethered strut
chordae, which exert forces at the body of the anterior
leaet (Figure 5A).50 This pattern occurs frequently in
patients with isolated inferiorlateral MI in both single and
multiple vessel disease and the ventricle is more locally
remodeled in the inferior posteriorlateral regions that
support the posterior papillary muscle, than globally
remodeled. The mitral annulus was dilated and attened,
but these geometrical deformations of the annulus are
smaller in this pattern than in patients with anterior MI,
the tenting is localized in the posterior region and the
tethered leaet area and volume are less signicantly pronounced than in patients with anterior MI with IMR.32,51
Finally, in this pattern we can identify two different subgroups of patients depending on the extent of the tethering
process of the posterior leaet. In the rst subgroup, the
tethering effect involves a large part of the posterior
leaet (central and medial commissural regions) and the
origin of the jet is usually central and posteriorly directed
(Figure 6), but sometimes the jet can be centrally directed
when a shift toward the symmetric pattern is happening
with initial apical displacement of the tethered posterior
leaet. In the second subgroup, the tethering effect
involves prevalently the medial commissure and the
regurgitant jet originates only from this localized region
(Figure 7).

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E. Agricola et al.

motion of the distal portion of the anterior mitral leaet is

also seen (Figure 5B). There is an apical and mediolateral
tethering in addition to the posterior component. The net
result of these forces is a more apical tenting, with the
coaptation point being displaced more apically. This
pattern occurs in patients with anterior or multiple MI
usually with multiple vessel disease. The LV appears to be
much more globally remodeled than in the asymmetric
one, being more spherical, enlarged and dysfunctioning
with a higher wall motion score index. The mitral annulus
is more dilated and attened than in patients with
asymmetric pattern, the leaets are widely tethered
toward LV and the tethered leaet area and volume are
larger with respect to the asymmetric one.32,51 The regurgitant jet has usually a central origin and direction, because
the systolic motion of both leaets is equally affected
(Figure 8).

(Figure 9). This pattern may occur in patients with very

limited MI localized in the basal inferiorposterior segments
of LV without remodeling of LV in this region. Indeed, an
ischemic injury in these zones can provoke structural and
functional modications in the posterior portion of the
annulus.

Ischemic prolapse
In rare cases, a papillary muscle necrosis and brosis secondary to localized infarction of a papillary muscle, frequently
the posterior, creates an ischemic prolapse with leakage of
MV.14,52,53 The prolapse is the consequence of an elongation
of a papillary muscle due to a post-MI brosis (Figure 10).
Moreover, a remarkable tethering, due to local posterior
remodeling, can determine an elongation and an excessive
tension of chordae that can eventually provoke chordal
rupture with ail leaet.

Prevalence of annular dilation/dysfunction

In a small percentage of patients the MV leaets are not particularly tethered whereas the annulus appears dilated and/
or loses its contractile function. This pattern is characterised by a limited apical displacement of leaets, dilated
annulus with origin and direction of regurgitant jet usually
central or multiple along the overall coaptation surface

Therapeutic options
Early coronary revascularization, also in small inferior MI, is
the best option to prevent LV remodeling and therefore the
development of IMR.54 After the appearance of IMR, the aim
of medical and/or surgical therapy is to ameliorate heart
failure symptoms, and improve LV remodeling, ejection

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Figure 5 (A) Asymmetric tethering. The posterior leaet (double arrows) is posteriorly restricted and parallel to the posterior wall. The
basal anterior leaet is restricted too (dotted arrow), but the distal portion is less restricted and overrides the posterior one determining
the hockey stick conguration. This geometrical alteration of the leaets determines eccentric regurgitant jet. (B) Symmetric tethering.
Predominant apical displacement of both leaets, also the motion of the distal portion of the anterior leaet is restricted generating a central
regurgitant jet.

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213

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Figure 6 (A) (a) Three-dimensional analysis of MV in patient with asymmetric tethering pattern showing prevalent tethering at level of
A2P2 (c) and A3P3 (d) and less at level of A1P1 (b) with central origin of the regurgitant jet (B).

fraction and the intermediate/long-term outcome. Even

though there are no randomized trials that compare
surgical versus medical therapy, the restricted annuloplasty,
which is the most standardized surgical procedure, is
associated to low surgical mortality and leads to improvement of heart failure symptoms,55,56 but it seems does not
confer long-term survival advantage compared to medical
therapy.57

Medical therapy
The current medical therapy for heart failure includes
vasodilators (ACE-inhibitors), diuretics, spironolactone and
b-blockers, and its benecial effects on symptoms of heart
failure in patients with IMR and LV dysfunction may be dramatic. Various combinations of these drugs are commonly
used in these patients for two reasons: to reduce the

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Figure 7 (A) (a) Three-dimensional analysis of MV in patient with asymmetric tethering pattern showing prevalent tethering at level of A3
P3 (d) and less at level of A2P2 (c) and A1P1 (b) with origin of the regurgitant jet at level of posteromedial commissure (B).

severity of MR and to revese or delay the LV remodeling

process. The use of afterload-reducing agents, including
ACE-inhibitors, might reduce the regurgitant volume and
improve forward output by decreasing the pressure gradient
between LV and left atrium. Vasodilators may effectively
decrease regurgitant ow through the effect of systolic
unloading on the regurgitant orice area.58,59 A similar
effect of reduction in MR is obtained with preload reduction
through the use of diuretics that decrease ventricular size

and further reduce tethering with a consequent decrease in

the regurgitant volume.58 The use of ACE-inhibitors and
b-blockers is an independent predictor of better long-term
survival in patients with IMR and LV dysfunction, as reported
by Wu and colleagues.57 This could be due to the effects of
ACE-inhibitors and b-blockers on progression of LV remodeling
and prevention of sudden death. However, ACE-inhibitors are
able to attenuate but not completely prevent or reverse the
post-MI LV remodeling and their effects on the post-MI

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215

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Figure 8 (A) (a) Three-dimensional analysis of MV in patient with symmetric tethering pattern showing prevalent tethering at level A2P2
(c), whereas the tethering is present but less pronounced at level A3P3 (d) and A1P1 (b) with central origin of the regurgitant jet (B).

incidence of IMR and prognosis are lacking and contrary.

Indeed, in the SAVE study (Survival And Ventricular Enlargement),1 patients with MR treated with captopril had the
same mortality as the placebo group. Beta-blocker therapy
for heart failure reduces all cause mortality, cardiovascular
mortality and mortality due to pump failure and sudden
death by roughly 31%39%.60 Accordingly, it has been demonstrated that a combined therapy of carvedilol plus
ACE-inhibitors decreases functional MR by reducing LV
dilation.61,62

Resynchronization therapy
Recently, it has been demonstrated that the immediate
reduction of functional MR is one of the benecial effects
of the cardiac resynchronization therapy by improving coordinated timing of mechanical activation of papillary muscle
insertion sites, by increasing closing forces with an improvement in dP/dt, and by promoting the LV reverse remodeling.3537 This effect seems evident also during exercise,
preventing the increase of functional MR during effort.47

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Figure 9 Three-dimensional analysis of MV in patient with akinesia of the only basal segments of inferoposterior wall. (A) The leaets
appear no tethered in all levels A2P2 (c), A3P3 (d) and A1P1 (b) with central origin of the regurgitant jet (B).

However, some considerations arise: resynchronization

reduces but does not abolish MR with the result that a critical level of regurgitation remains which is able to perpetuate the LV remodeling process; presence of severe MR per
se is a predictor of lack of response to resynchronization
therapy.63 As demonstrated by the Multicenter InSync Randomized Clinical Evaluation study (MIRACLE), the magnitude
of the changes in MR is greater in non-ischemic than
ischemic heart failure patients.37 At present, the effects
of biventricular pacing have been evaluated at 12 months
follow-up period,37 therefore we do not know whether
these effects are sustained in the long-term. However,

Brandt et al. demonstrated that the withdrawal of biventricular stimulation after long-term (median 427 days) has detrimental effects on patients, hemodynamics including an
increase in MR severity,64 suggesting that benecial effects
on MR from resynchronization therapy can be obtained
also after long-term stimulation.64

Surgical therapy
Therapeutic options include coronary artery revascularization alone, mitral valve replacement, and mitral valve
repair with or without revascularization.

Ischemic mitral regurgitation

Several studies had demonstrated that revascularization

alone does not result in a signicant change in IMR grade
both in patients with mild-to-moderate IMR (1 or 2)
and with moderate-to severe IMR (3 or 4) and a signicant percentage of patients with mild-to moderate IMR has
an increase in degree or recurrence of IMR during
follow-up.6568 However, revascularization alone appears
to produce long-term survival similar to that for revascularization plus annuloplasty both in patients with moderate and

severe IMR, whereas the risk of operative mortality is higher

after combined revascularization and MV repair than after
revascularization alone (9.5%15% vs 35%).65,69 Kim et al.
reported a 5-year actuarial survival in patients with 3 or
4 IMR of 44% + 5% after combined procedure and 41% +
7% after revascularization alone,67 Wong et al. reported no
signicant difference in mortality for concomitant annuloplasty compared with revascularization alone in patients
with 3 IMR with a 5-year survival of 67.5% in the whole
group of patients.68 Analyzing the impact of patients
characteristics on survival, we can note the detriment of
poor LV function and comorbidities on survival with or
without annuloplasty. In general, the LV function, age and
comorbidities appear to lessen or eliminate the effect of
IMR on survival.70,71 However, the patients with untreated
IMR at the time of isolated revascularization have a higher
incidence of hospitalization for congestive heart failure
during follow-up.66 Thus, the goal of surgical therapy is
not only to improve survival but also to improve late functional status and late quality of life. Therefore, high risk
perioperative patients with multiple comorbidities with
mild-to-moderate IMR and/or life expectancy smaller than
5 years should be treated conservatively with revascularization alone,2 whereas low risk perioperative patients with
few or no comorbidities and mild-to-moderate IMR can
undergo a combined procedure.2 Moreover, these last
patients can be further stratied with exercise echocardiography to study the behaviour of IMR during stress, which
has been demonstrated predictive of late events.43,44,72
Patients with moderate-to-severe IMR should be considered
for combined procedure.
MV replacement with or without revascularization for IMR
was associated with high early and late mortality and low
long-term survival in early studies.73 Actually, MV replacement with preservation of the entire subvalvular apparatus
can represent a valid alternative to MV repair in some subgroups of patients. In particular, patients with comorbidities, complex regurgitant jets and/or severe remodeling
of MV apparatus can be treated with a biological prosthesis.70 Calaore et al. recommend MV replacement in cases
of severe tethering of MV with a coaptation length
.10 mm.74 However, there are no randomized trials comparing MV replacement to MV repair.
The targets of repair include annulus, leaets, chordae
and ventricle.
The most commonly used annular procedure is undersized
mitral annuloplasty using very small symmetric annuloplasty
rings (size 26 or less). Bolling and colleagues rstly
introduced this procedure to treat functional MR in dilated
cardiomyopathy with good intermediate-term results.55
The aim of this procedure is to increase leaet coaptation
by correcting annular dilation. Even though this procedure
is initially effective in correcting IMR and obtaining LV
reverse remodeling in a large proportion of patients,55,75 a
high percentage of persistence or recurrence of IMR at
mid-long-term is observed. McGee et al. reported a recurrence of IMR in 35% of patients 6 months after surgery.76
Recently, new asymmetric prosthetic rings have been developed to approach IMR more pathophysiologically. The
Carpentier-McCarthy-Adams IMR Etlogix ring (CMA IMR
ETlogix ring; Edwards Lifesciences, Irvine, CA) is a new prosthetic ring that incorporates the principles of undersizing
and specically addresses the asymmetric tethering

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Figure 10 (A) Ischemic prolapse of the posterior leaet (a) due to

infarction of the posterior papillary muscle (long axis transgastric
view) (b, arrow) causing severe MR (B).

217

218

tethering effect. The cutting of the central basal chordae

to anterior leaets at the level of their valvular insertions
results in correcting the stretch on the anterior leaet,
improving the coaptation, and reducing IMR, whereas the
marginal chordae continue to prevent the prolapse.83 The
main criticism to this technique is whether the second-order
chordal cutting negatively affects the LV function. In a case
report and in a consistent series of more than 30 patients of
Davids group in which this technique was adopted with
annuloplasty correction of IMR, no decrease of LV function
was observed.2
The LV is the last and the most pathophysiologic target of
surgical therapy with the goal to reshape the LV and realign
papillary muscles resulting in reducing IMR. Several
approaches were proposed. The plication of infarcted area
was proposed by Liel-Cohen and coworkers with the intention to reduce myocardial bulging of the remodeled area
supporting the papillary muscles and to pull these towards
the anterior annulus reducing the tethering.84 A similar
effect can be obtained by the use of an external device
containing a patch and an epicardial balloon that is
positioned over the infarcted region and can be inated,
as proposed by Hung et al.85 The ination of this system
repositions the displaced papillary muscle and is adjustable
under echocardiographic monitoring in the beating heart
until tethering and IMR are relieved. The relocation of posterior papillary muscle can be obtained by re-suspension of
a papillary muscle connecting its tip to the mitral annulus
by sutures, as described by Kron and associates.86 Menicanti
and coworkers proposed an LV restoration by the Dor procedure to reduce LV size associated with papillary muscles
embrication without a prosthetic ring to realign the papillary muscles and obtained a signicant reduction of IMR in
the majority of the treated patients.87 Finally, the Coapsys
device (Myocor, Inc, Maple Grove, MN) is a system that not
only addresses the annular distortion but also corrects the
ventricular change by reshaping the LV in the anterior
posterior dimension and seems to have initial efcacious
results in the treatment of IMR.88 This device consists of
two epicardial pads connected by a exible suture-like
cord. With the use of specic instruments and epicardial
echocardiographic monitoring, the cord is passed through
the LV and then tightened to improve leaet coaptation
and stabilize LV wall.88 In this way the device seems to
have several effects: it places the tension in the anterosuperior dimension, restores the papillary muscles to a more
subvalvular position reducing the annular dimension and
tenting area, and positively reshapes the LV.88

Mechanisms and predictors of recurrence

of IMR
Recurrence of IMR is a more appropriate indicator of procedural success than freedom from reoperation, because
many patients with suboptimal results do not undergo reoperation for several reasons such as advanced age, severe
LV dysfunction, comorbidities etc. However, patients with
postoperative IMR greater than 2 have a worse survival
than those without signicant IMR recurrence.89 As previously
mentioned, there is a high rate of recurrence (30%) of IMR
after undersized annuloplasty and good early postoperative
results with high incidence in the rst 6 months after operation and stabilization thereafter.76 The main goal of

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observed at the level of P2P3 regions.77 Compared with

conventional symmetric annuloplasty, this ring is designed
with reduced middle to medial (P2P3) curvature and a
slight dip at the P2P3 segments increasing coaptation of
tethered P2P3 segments.77 Surgical repair of IMR with
this novel asymmetric CMA IMR ETLogix annuloplasty ring
seems to provide excellent early results with effective
reduction of IMR degree, mitral annular dilation and
leaet the tethering.77 This ring could be particularly
useful in those patients in whom the tethering effect
involves the medial commissure and the regurgitant jet
origins from this localized region. Another geometrically
designed ring is the GeoForm ring (Edwards Lifesciences).
This ring presents a reduction of anteroposterior diameter
of 41% at the level of P2 to bring the annulus inward to
counteract the outward pull of enlarged LV and is elevated
6 mm at level P2 to raise the MV apparatus to counteract
the downward pull of the enlarged LV. The goal of using
this ring is that the remodeling of the annulus reforms the
shape and the function of LV. The early results seem promising: 3 months follow-up shows decrease of LV volume,
sphericity, the degree of MR and the tethering length and
an increase of ejection fraction.78 Percutaneous mitral
annuloplasty with transvenous implantation of a device in
the coronary sinus has been recently proposed. The initial
human experience suggests that the remodeling of the
annulus with this approach is feasible with a possible favorable effect on IMR.79 The ultimate goal of the annular procedure is to obtain LV reverse remodeling as a
consequence of the disappearance of MR and LV volume
overload. The preoperative LV dimensions predict the likelihood of reverse remodeling. The chance of reverse remodeling occurs is low if preoperative end-diastolic diameter
exceeds 65 mm and/or end-systolic diameter is more than
51 mm.75 These ndings suggest that baseline LV remodeling
plays a key role in the likelihood of reverse remodeling
and subsequent favorable long-term outcome. Therefore,
beyond these cut-off values an additional surgical approach
to restore LV dimension or delay the progressive remodeling
can be useful. For this purpose, as observed in the Acorn
Clinical Trial,80 the application of a CorCap cardiac support
device (Acorn Cardiovascular, Inc., St Paul, MN) in addition
to MV procedures seems to lead to greater decrease of LV
volume and improvement in quality of life compared to MV
procedures alone with low operative mortality.
The edge-to-edge Aleri procedure represents a technique that has the leaets as the target of repair. This technique consists in using a suture to join a portion of the
anterior leaet to the posterior one.81 According to the
site of origin of the jet, the edge-to-edge repair is performed centrally (in case of central jet) or posteromedially
(in case of origin from posterior commissure). The association of edge-to-edge to undersized annuloplasty in patients
with excessive tethering (coaptation length  1 cm) seems
to reduce the incidence of repair failure when compared
to undersized annuloplasty alone.81 The percutaneous
approach of this technique has been also proposed but the
lack of annuloplasty may increase the tension of tethered
leaets.82
The chordal cutting technique proposed by Messas and
coworkers has the second-order chordae tendinae as the
target of repair.83 They propose to cut a limited number of
secondary chordae which are mainly responsible for the

E. Agricola et al.

Ischemic mitral regurgitation

Table 2 Predictors of recurrence of IMR after repair

Valvular
Tethering area91
Annular diameter91
Degree of preoperative IMR91
Central regurgitant jet75
Complex regurgitant jet75
Ventricular
End-systolic sphericity index89
LV volumes89
Lateral wall abnormalities75
Restrictive diastolic lling pattern90
Surgical
Pericardial annuloplasty75

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