European Journal of Echocardiography 2008 9(2):207-221; doi:10.1016/j.euje.2007.03.034
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org
Ischemic mitral regurgitation: mechanisms and echocardiographic classification
Eustachio Agricola1,*,
Michele Oppizzi1,
Matteo Pisani1,
Alessandra Meris1,
Francesco Maisano2 and
Alberto Margonato1
1 Division of Non-Invasive Cardiology, San Raffaele Hospital, Milano, Italy
2 Division 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.
* 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{at}hsr.it (E. Agricola).
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Abstract
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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,
leaflet motion, origin and direction of the regurgitant jets,
allows one to identify different specific 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,
leaflets, 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.
Keywords: Ischemic mitral regurgitation; Tethering; Echocardiographic classification; Mitral valve surgery
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Introduction
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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 leaflets 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; significant
coronary disease in a territory supplying the wall motion abnormalities
1;
and structurally normal MV leaflets 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.
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Prevalence and impact on outcome
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The prevalence of chronic IMR is difficult 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.
3–13 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 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 post-infarction.
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
defined 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 anterior–inferior MI, not or
ineffectively revascularized and with more severe coronary disease.
If an exact prevalence of IMR is difficult 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 orifice 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 stratification and management planning in all post-MI patients.
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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.
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Mechanisms
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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
significant 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 leaflet motion, termed ‘incomplete
mitral leaflet closure’ (IMLC).
16–19 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.
20–22 Therefore, there are multiple factors that interact in causing
regurgitation (
Figure 2).
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Left ventricular local and global remodeling
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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 leaflet closure. Even though Kaul
et al.
firstly postulated that MR results from global LV dysfunction,
17 other studies in experimental and clinical models demonstrated
that LV contractile dysfunction without LV dilation and distortion
fails to produce significant MR.
16,18,23 These studies revealed
that the only independent predictor of MR was the tethering
length, but not LV ejection fraction or d
P/d
t and the degree
of regurgitation correlated with LV sphericity. Interestingly,
a local remodeling in the region supporting the posterior papillary
muscle – involved in infero–posterior 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 (inferior–posterior and anterior–lateral)
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 leaflet tenting.
2,27 Therefore, IMR begets IMR in a self-perpetuating manner.
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Tethering and closing forces
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The closure and position of mitral leaflets 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 leaflets
avoiding leaflet 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 leaflets 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 sufficient to generate
significant IMR, whereas the LV dysfunction only generates traces
of MR.
16,18,23 Instead, when tethering is created, transmitral
pressure also significantly 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 direction and degree of the displacement (tethering)
are otherwise important. Lateral and posterior–lateral
papillary muscles displacement produces lesser degrees of leaflet
tenting and regurgitation than posterior–lateral with
apical displacement
16 and the degree of MR is directly related
to tethering distance.
16,22 The posterior–lateral with
apical displacement seems to be the direction that creates the
major leaflet tension
16 and this explains both why a local remodeling
in the posterior–lateral region post-inferior MI is sufficient
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 leaflet
motion and by creating a change in the geometry of the posterior
leaflets with a consequent interscallop malcoaptation.
28,29 This imbalance between the two forces generates a typical phasic
variation in the time course of regurgitant orifice area in
IMR, known as the ‘loitering pattern’
30: the orifice
area and regurgitation are greater in early and late systole
and lower in the mid systole, when peak LV pressure is higher.
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Annular factor
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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 significantly
the degree of MR in the presence of leaflet 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 flattened with loss of saddle configuration and the degree
of this geometric deformation is significantly 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 defined according to the segmental
classification 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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Mechanical dyssynchrony
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It has been demonstrated that one of the beneficial 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.
35–37 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 dysfunction,
mitral tenting and local LV remodeling are independent predictors
of degree of FMR but not regional dyssynchrony.
38 These findings
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 leaflets increasing tethering.
36 Second, a positive pressure gradient develops between left atrium
and LV due to improper timing of atrial–ventricular relaxation
and contraction cycles can create diastolic MR.
39 Finally, LV
dyssynchrony decreases the LV contraction efficiency 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.
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Dynamic component
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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 d
P/d
t 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 flash 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 significantly
affects the prognosis and provides a clinical practical consequence.
Post-MI patients with heart failure symptoms not justified 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.
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Quantification of regurgitation and characterization of mitral deformation indexes
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Approaching a patient with IMR, several kinds of echocardiographic
information have to be reported to well characterize and identify
specific 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
orifice 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 mm
2 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 cm
2 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 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 influenced by LV systolic function.
49 These findings
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.
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From mechanisms to echocardiographic patterns
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Assessing echocardiographic parameters such as leaflet motion
and origin and characteristics of regurgitant jets, it is possible
to distinguish in the spectrum of patients with chronic IMR
different specific subgroups of patients subjected to different
therapeutic approaches (
Table 1).
25
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Asymmetric tethering pattern
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This pattern is characterized by the predominant posterior tethering
of both leaflets. In this case, the asymmetrical displacement
of the posterior papillary muscle bends the posterior leaflet
posteriorly, whereas the anterior leaflet overrides superiorly
the posterior one.
25 Each papillary muscle supplies chordae
to both leaflets, consequentially a posterior displacement of
only one papillary muscle invariably exerts traction on both
leaflets.
19 Therefore, the different shapes of tethering depend
on the relationship of three tethering vectors (posterior, apical
and lateral). In the asymmetric group, the posterior leaflet
is simply drawn more posteriorly than apically (more parallel
to the posterior wall). This posterior restriction of the leaflet
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 leaflet
however is tethered, too. Its restriction is visible in the
‘hockey stick configuration’ of the anterior mitral
leaflet, which is due to tethered strut chordae, which exert
forces at the body of the anterior leaflet (
Figure 5A).
50 This pattern occurs frequently in patients with isolated inferior–lateral
MI in both single and multiple vessel disease and the ventricle
is more locally remodeled in the inferior– posterior–lateral
regions that support the posterior papillary muscle, than globally
remodeled. The mitral annulus was dilated and flattened, 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 leaflet
area and volume are less significantly 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 leaflet.
In the first subgroup, the tethering effect involves a large
part of the posterior leaflet (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 leaflet.
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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Figure 5 (A) Asymmetric tethering. The posterior leaflet (double arrows) is posteriorly restricted and parallel to the posterior wall. The basal anterior leaflet is restricted too (dotted arrow), but the distal portion is less restricted and overrides the posterior one determining the ‘hockey stick configuration’. This geometrical alteration of the leaflets determines eccentric regurgitant jet. (B) Symmetric tethering. Predominant apical displacement of both leaflets, also the motion of the distal portion of the anterior leaflet is restricted generating a central regurgitant jet.
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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 A2–P2 (c) and A3–P3 (d) and less at level of A1–P1 (b) with central origin of the regurgitant jet (B).
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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 A2–P2 (c) and A1–P1 (b) with origin of the regurgitant jet at level of posteromedial commissure (B).
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Symmetric tethering pattern
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The symmetric pattern is characterized by a predominant apical
tethering of both leaflets. In this case, a restricted motion
of the distal portion of the anterior mitral leaflet 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 flattened than in patients with asymmetric
pattern, the leaflets are widely tethered toward LV and the
tethered leaflet 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 leaflets
is equally affected (
Figure 8).
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Figure 8 (A) (a) Three-dimensional analysis of MV in patient with symmetric tethering pattern showing prevalent tethering at level A2–P2 (c), whereas the tethering is present but less pronounced at level A3–P3 (d) and A1–P1 (b) with central origin of the regurgitant jet (B).
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Prevalence of annular dilation/dysfunction
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In a small percentage of patients the MV leaflets 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 leaflets, dilated annulus with origin
and direction of regurgitant jet usually central or multiple
along the overall coaptation surface (
Figure 9). This pattern
may occur in patients with very limited MI localized in the
basal inferior–posterior segments of LV without remodeling
of LV in this region. Indeed, an ischemic injury in these zones
can provoke structural and functional modifications in the posterior
portion of the annulus.
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Figure 9 Three-dimensional analysis of MV in patient with akinesia of the only basal segments of infero–posterior wall. (A) The leaflets appear no tethered in all levels A2–P2 (c), A3–P3 (d) and A1–P1 (b) with central origin of the regurgitant jet (B).
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Ischemic prolapse
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In rare cases, a papillary muscle necrosis and fibrosis 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 fibrosis (
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 flail leaflet.
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Therapeutic options
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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 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
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Medical therapy
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The current medical therapy for heart failure includes vasodilators
(ACE-inhibitors), diuretics, spironolactone and β-blockers,
and its beneficial 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 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 flow through
the effect of systolic unloading on the regurgitant orifice
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 β-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 β-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 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
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Resynchronization therapy
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Recently, it has been demonstrated that the immediate reduction
of functional MR is one of the beneficial 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 d
P/d
t, and
by promoting the LV reverse remodeling.
35–37 This effect
seems evident also during exercise, preventing the increase
of functional MR during effort.
47 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 beneficial effects on MR from resynchronization
therapy can be obtained also after long-term stimulation.
64
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Surgical therapy
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Therapeutic options include coronary artery revascularization
alone, mitral valve replacement, and mitral valve repair with
or without revascularization.
Several studies had demonstrated that revascularization alone does not result in a significant 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 significant percentage of patients with mild-to moderate IMR has an increase in degree or recurrence of IMR during follow-up.65–68 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 3–5%).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 significant 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 stratified 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 Calafiore 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, leaflets, 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 firstly introduced this procedure to treat functional MR in dilated cardiomyopathy with good intermediate-term results.55 The aim of this procedure is to increase leaflet 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 specifically addresses the asymmetric tethering observed at the level of P2–P3 regions.77 Compared with conventional symmetric annuloplasty, this ring is designed with reduced middle to medial (P2–P3) curvature and a slight dip at the P2–P3 segments increasing coaptation of tethered P2–P3 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 leaflet 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 findings 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 Alfieri procedure represents a technique that has the leaflets as the target of repair. This technique consists in using a suture to join a portion of the anterior leaflet 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 leaflets.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 tethering effect. The cutting of the central basal chordae to anterior leaflets at the level of their valvular insertions results in correcting the stretch on the anterior leaflet, 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 David's 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 inflated, as proposed by Hung et al.85 The inflation 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 significant 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 efficacious results in the treatment of IMR.88 This device consists of two epicardial pads connected by a flexible suture-like cord. With the use of specific instruments and epicardial echocardiographic monitoring, the cord is passed through the LV and then tightened to improve leaflet 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 significant 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 first 6 months after operation
and stabilization thereafter.
76 The main goal of reducing the
likelihood of IMR recurrence is to achieve an optimal repair
in the operating room with no residual or trivial IMR. Indeed,
analysing the data of Leiden's group they obtained a very low
incidence of recurrence of 2.3%.
75 They obtained these results
for which main goal was the absence of residual IMR after repair
in the operating room and this was achieved: by using a real
undersized ring (
24–
26) and by obtaining a coaptation
length of at least 8 mm.
75 The absence of residual IMR is crucial
in preventing its deterioration during follow-up because the
presence of mild IMR can contribute to continued LV remodeling
resulting in a vicious cycle in which IMR begets more IMR.
90 However, there are some preoperative echocardiographic predictors
of recurrence despite optimal postoperative results (
Table 2).
First, a central jet can indicate restriction of both leaflets
causing more severe leaflet tenting. Second, complex jets probably
originating centrally and posteromedially can now be treated
with appropriately shaped rings. If we exclude these two preoperative
echocardigraphic predictors and surgical factors such as the
use of pericardial rings, other predictors, such as the indices
of MV apparatus remodeling – a mirror of LV remodeling
– and the shape and dimension of LV, allow us to conclude
that the LV preoperative status and its continuous remodeling
may be the main cause of the recurrence of IMR. Hung et al.
clearly demonstrated that recurrence of IMR after ring annuloplasty
is associated to LV remodeling progression, as shown by increases
in LV volumes and sphericity, which parallel increases in MR
and tethering.
90 Preoperative restrictive diastolic filling
pattern is associated to further negative remodeling of LV and
progression of IMR after repair, indicating an advanced stage
of myocardial dysfunction.
91 Patients with mitral annular diameter
3.7 cm with a tenting area of
1.6 cm
2 in long axis view and
an IMR grade >3.5 have a 50% of probability of failing during
follow-up.
92
|
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Abstract
Introduction
