Journal of the American College of Cardiology
© 2003 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Ischemic Mitral
Regurgitation, the Dynamic
Lesion: Clues to the Cure*
Robert A. Levine, MD, FACC,
Judy Hung, MD, FACC
Boston, Massachusetts
Functional ischemic mitral regurgitation (MR) is now
receiving increased attention as one of the last frontiers in
mitral valve repair as well as a therapeutic opportunity in
heart failure (1–5). Valve repair has proved more challenging for ischemic MR than for degenerative mitral valve
prolapse, in which surgery is tailored to the detailed anatomy displayed by echocardiography and inspection. Successful valve repair must target the mechanism of dysfunction in the individual patient; to date, however, both
understanding of mechanism and targeting of therapy have
been elusive for ischemic MR (6 –9).
See page 1921
Changes with exercise. Until now, ischemic MR has been
evaluated almost exclusively at rest. In this issue of the
Journal, Lancellotti et al. (10) for the first time quantitatively measured changes in ischemic MR with semi-supine
exercise. The dynamic changes they observed provide mechanistic insights that can sharpen the therapeutic approach in
general and clarify the course of action in the individual
patient.
Balance of forces. These dynamic changes in MR can best
be understood by considering the basic forces acting on the
mitral leaflets. Ischemic MR occurs in the setting of normal
mitral leaflets but abnormal left ventricular (LV) function
and geometry. Ischemic LV distortion leads to papillary
muscle displacement and annular dilatation, tethering the
mitral leaflets and restricting their ability to close effectively
(Fig. 1) (11–21). Annuloplasty addresses only one end of
this “tug of war” (22–25). Tethering is compounded by LV
dysfunction, which decreases the force needed to close the
leaflets in opposition to the tethering (26). This interplay of
competing forces creates a dynamic lesion that varies during
the cardiac cycle. Noninvasively emulating the approach of
Yoran et al. (27,28) and Keren et al. (29), Schwammenthal
(30) showed that effective regurgitant orifice area in ischemic MR typically peaks in early and late systole and
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Cardiac Ultrasound Laboratory, Department of Medicine, Massachusetts
General Hospital, Harvard Medical School, Boston, Massachusetts. Supported in
part by grants R01 HL38176, K24 HL67434, and K23 HL04504 of the National
Institutes of Health, Bethesda, Maryland.
Vol. 42, No. 11, 2003
ISSN 0735-1097/03/$30.00
doi:10.1016/j.jacc.2003.09.004
decreases in midsystole as LV pressure rises and the transmitral closing force increases. This behavior was reproduced
in vitro by He et al. (14) and shown by Hung et al. (31) to
be determined in patients primarily by the midsystolic rise
in LV pressure, closing the mitral leaflets more completely,
with a lesser contribution from midsystolic annular contraction. Thus, MR variation within the cardiac cycle (32)
provides clues to the basic forces influencing leaflet closure
(33).
Changes with loading. Ischemic MR also varies dynamically with loading conditions that modulate LV volume.
This variation is expressed most dramatically in the operating room, where anesthetic induction and inotropic agents
can reduce moderate MR to trace amounts, confounding
decisions regarding need for repair (34 –36). Dynamic
changes with unloading have also been described by Kizilbash et al. (37). In patients with heart failure, effective
orifice area is similarly reduced by medical decompression of
the LV (38). The dominant factor in these dynamic changes
is variation in ventricular geometry as the proximate cause of
tethering.
Exercise-induced variation. The current article provides
further insight into the pathophysiology of postinfarction
MR as a characteristically dynamic lesion. The authors
prospectively examined 70 patients with at least mild MR
and LV ejection fraction ⬍45%, excluding patients with
evidence of exercise-induced ischemia. During semi-supine
exercise, the effective regurgitant orifice area was quantified
by two complementary Doppler methods. The observed
changes were important and largely adverse, with orifice
area increasing by ⬎20 mm2 (enough to change grade of
severity) in nearly 30% of patients. The exception was
patients with inferior myocardial infarctions and recruitable
systolic function, in whom regurgitant orifice area tended to
decrease. Exercise-induced changes in MR did not correlate
with degree of MR or LV dysfunction at rest. Instead, they
correlated best with changes in mitral valve configuration
and mitral apparatus geometry at both ends of the tethered
leaflets, including annular dilatation and posterior displacement of the papillary muscles (10).
Clinical implications. Patients with milder degrees of MR
at rest who undergo coronary revascularization are not
generally considered to require additional efforts to address
the mitral valve. Yet, as this study demonstrates, patients
with milder MR may actually have more severe regurgitation when provoked by exercise. These same authors have
shown that such exercise-induced increases in MR are
accompanied by increases in pulmonary artery pressure (39).
These adverse exercise hemodynamics could potentially
explain the clinical puzzle of patients who have exertional
dyspnea out of proportion to their degree of dysfunction or
MR at rest if exercise increases their MR and pulmonary
pressures (assuming this scenario is not due to intermittent
ischemia with “flash pulmonary edema”). Thus, assessing
the true impact of ischemic MR often becomes a “moving
1930
Levine and Hung
Editorial Comment
JACC Vol. 42, No. 11, 2003
December 3, 2003:1929–32
Figure 1. Mechanism of functional mitral regurgitation (MR). AO ⫽ aorta; LA ⫽ left atrium; LV ⫽ left ventricle.
target,” engendering discussions among echocardiographers,
surgeons, and anesthesiologists. The dynamic nature of
ischemic MR can support the contention of some surgeons
that decisions should not be based on MR assessment alone,
given its dependence on load and volume, but rather on the
appearance of restricted leaflet closure, which sets the stage
for important MR. This study naturally leads to the question of whether exercise testing should be performed on all
patients with ischemic MR. That will require further
investigation, but we can anticipate that provocative testing
could be most useful when the quantitative and clinical
importance of MR are unclear, particularly when MR is
mild to moderate at rest.
Is bypass alone sufficient to reduce ischemic MR?
Although several studies demonstrate frequent persistence
of ischemic MR after revascularization alone (34), others
maintain that coronary bypass is sufficient therapy in most
patients (40). Moreover, no approach currently predicts in
which patients MR will resolve with revascularization alone.
Exercise testing may be informative in this controversial
decision. This study suggests that exercise-induced reduction in MR caused by improved motion of the inferior LV
base would predict that revascularization alone is likely to
reduce the MR. If MR persists or increases with exercise,
however, the implications are not obvious. Evidence of
myocardial viability with low-dose dobutamine could provide comparable information, but the decrease in LV
volume with higher dobutamine doses may decrease tethering and MR without predicting lasting benefit off inotropic support (41).
Caveats. Patient position during exercise testing may also
influence the degree of MR. This study evaluated MR
during semi-supine exercise. As Kelbaek et al. (42) have
shown, exercise ventricular volumes are smaller in the sitting
than in the supine position, causing functional MR to
decrease in the more upright position. However, Osbakken
et al. (43) showed that LV end-systolic volume increased
with supine exercise in patients with coronary artery disease;
the decrease in volume seen in the patients of Lancellotti et
al. (10) suggests that they resemble patients exercising in the
sitting position (44,45). The increases in MR, therefore,
cannot be simply ascribed to positional variation. The
authors acknowledge the technical challenges of quantifying
MR during exercise, with substantial limits of variation and
standard deviations between observers and methods (39),
and they recognize the limitations of applying the proximal
flow convergence method at only one time point and
velocity (30,46).
Clues to the cure. Returning to the principle that successful valve repair must address mechanism, this study provides
further evidence for the decisive role of adverse mitral and
ventricular geometry in the mechanism of ischemic MR.
Increased MR with exercise is associated with greater
tethering at both the annular and papillary muscle ends of
the leaflets. Unbalanced tethering can therefore be addressed by papillary muscle repositioning, achieved by infarct plication (18,47,48), by external constraint applied to
reverse LV remodeling locally (49,50), or by direct traction
(51,52). Biventricular pacing can potentially reduce tethering (related to LV end-systolic volume) (53–55) as well as
increase mitral valve closing force (56). Additionally, specific chordal modification can minimize mitral leaflet deformity and MR, either alone or combined with annular ring
reduction (57). In summary, therefore, the dynamic changes
in ischemic MR with exercise provide clues to increasing the
effectiveness of therapy by addressing the geometric culprits.
Acknowledgment
The authors thank Shirley Sims for her excellent editorial
assistance.
Reprint requests and correspondence: Dr. Robert A. Levine,
Massachusetts General Hospital, Cardiac Ultrasound Laboratory,
55 Fruit Street, VBK 508, Boston, Massachusetts 02114. E-mail:
[email protected].
JACC Vol. 42, No. 11, 2003
December 3, 2003:1929–32
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