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Chapter 19. Impact of cardiac resynchronization therapy on mitral regurgitation
240 CARDIAC RESYNCHRONIZATION THERAPY
consistently reported that CRT is associated with
a significant decrease in functional MR, both
acutely16–18 and in long-term follow-up.19–28 To
understand the mechanisms responsible for this
CRT-related improvement in the severity of
functional MR, it is necessary to take a closer
look at the complex pathophysiology of this
PATHOPHYSIOLOGY OF FUNCTIONAL MITRAL
REGURGITATION IN HEART FAILURE
The term ‘functional MR’ implies the presence of
MR in the absence of structural damage to the
mitral valve leaflets. In the presence of systolic
heart failure, the incomplete systolic closure
of the mitral leaflets is provoked by several
LV remodeling (i.e., spherical dilatation)
regional wall motion abnormalities
depressed LV systolic function
The most frequently cited (and probably
somewhat overemphasized) responsible condition for the occurrence of functional MR is
progressive dilatation of the mitral annulus in
the failing heart. It has been postulated that the
mitral leaflet area is insufficient to compensate
for the dilatation of the mitral annulus in heart
failure patients,29 but anatomic studies have
demonstrated that the actual available mitral
leaflet area is theoretically large enough to
compensate for an amount of annular dilatation
that is usually beyond the degree observed in
heart failure patients.30 Thus, mitral annular
dilatation alone cannot sufficiently explain the
occurrence of functional MR. Simultaneous with
the dilatation of the mitral annulus, the LV
undergoes spherical LV remodeling with a progressively increasing distance between the mitral
leaflets and the papillary muscles. Since the
chordal apparatus is inelastic, the increased distance will in turn lead to an increased tethering
force that drags on the leaflet edges during systole and delays or even completely prevents complete leaflet coaptation during systole (Figure
19.1).31,32 The amount of tethering can be quantified by measuring the outward displacement of
the mitral leaflets, the so-called ‘tenting’ area.31,33
These observations led to the experimental concept of selective chordal cutting to reduce the
tethering forces and thereby the severity of functional MR.34 Furthermore, it has been well documented not only that regional dysfunction in
the area of papillary muscle insertion after
myocardial infarction may cause or aggravate
functional MR,1 but also that an additional
isolated loss of papillary muscle contraction may
paradoxically reduce the amount of MR. While
any regional dysfunction of the myocardium
around the papillary muscle insertion may augment the tethering forces, the additional loss of
contractile function within the papillary muscle
itself will counterbalance the increased tethering
Figure 19.1 (a) Balance of forces acting on the mitral valve. (b) Left ventricular (LV) dilatation displaces the papillary muscle
(PM) and increases the mitral tethering forces. This restricts complete mitral valve closure and causes functional mitral regurgitation (MR). LA, left atrium. (Reproduced from Otsuji Y, Handschumacher MD, Schwammenthal E, et al. Insights from threedimensional echocardiography into the mechanism of functional mitral regurgitation: in vivo demonstration of altered leaflet
tethering geometry. Circulation. 1997; 96(6):1999–2008.31)
IMPACT OF CRT ON MITRAL REGURGITATION 241
forces and cause less apical tenting and a
decrease in the effective orifice area.35
The increased tethering force is counterbalanced by the LV ‘closing force’, which is determined by the effective transmitral pressure
gradient. LV dilatation will not cause significant
functional MR as long as myocardial contractility is still preserved and as long as the LV
is able to generate enough force to overcome
the increased tethering force. An example is the
patient with severe aortic regurgitation and preserved LV function who develops LV dilatation
(eccentric remodeling) but no significant functional MR. However, if LV myocardial contractility is also depressed – as it is by definition in
patients with systolic heart failure – then the
pressure rise in the LV will be delayed and
diminished. Thus, the closing force that is
required to overcome the increased tethering
forces cannot be generated, and functional MR
will be further aggravated.36 This concept is
supported by the observations that inotropic
stimulation (e.g., by dobutamine stress) in a
patient with heart failure will decrease the severity of functional MR, while dynamic physical
exercise, with an increase in afterload but only a
modest increase in inotropy, will aggravate
functional MR.37,38 The dependence of the effective
MR orifice area on the LV pressure rise also
explains the dynamic changes of the effective
regurgitant orifice area (EROA) during systole.39
Delayed, asynchronous electrical activation of
the LV as is typically seen in patients with left
bundle branch block (LBBB) is another independent cause of functional MR mediated
by the delayed LV pressure rise.40 A prolonged
atrioventricular interval further delays the onset
of LV contraction and pressure rise. In the
presence of an abnormally tethered mitral valve,
this situation predisposes to incomplete mitral
valve closure with the occurrence of pre-systolic
(diastolic) MR (Figure 19.2a).41 The end-diastolic
pressure reversal may not exert enough force to
close the restricted mitral leaflets (Figure 19.3).42
The critical value for the PR interval for the
appearance of diastolic MR has been determined
to be around 0.23 s.43
In summary, the progressive spherical remodeling of the LV during the evolutionary process
of systolic heart failure increases the mitral
annulus diameter and the distance between the
mitral leaflets and the papillary muscles. Both
effects will decrease the mitral leaflet coaptation
area and increase the tethering forces on the
leaflets, thereby increasing the EROA. Severe
regional wall motion abnormalities around the
Figure 19.2 (a) A patient with left bundle branch block, showing a prolonged PR interval of 280 ms and pre-systolic mitral regurgitation (MR) on continuous-wave (CW) Doppler (arrow). (b) Cardiac resynchronization therapy (CRT) with atrioventricular delay
optimization eliminates pre-systolic MR, and LV dP/dtmax increases from 530 mmHg/s to approximately 1000 mmHg/s, as
indicated by the steeper slope of the regurgitant signal during CRT (dashed lines in (a) and (b)). Note that CW Doppler tends
to overestimate the improvement in LV dP/dtmax. Reprinted from The American Journal of Cardiology: Vol 97: Nof E, Glikson M,
Bar-Lev D, et al. Mechanism of Diastolic Mitral Regurgitation in candidates for Cardiac Resynchronization therapy. Issue II, pages
1611–1614. (2006). With permission from Elsevier.
242 CARDIAC RESYNCHRONIZATION THERAPY
Figure 19.3 The effect of the left ventricular end-diastolic pressure (LVEDP) gradient on a normally (a) and abnormally
(b) tethered mitral valve. If diastolic leaflet motion is restricted due to increased tethering forces, the end-diastolic reversal of
the left ventricular (LV) – left atrial (LA) pressure gradient may not exert enough force to close the leaflets sufficiently.
(Reproduced from Am J Cardiol. Vol 97. Nof E, et al. Mechanism of diastolic mitral regurgitation in candidates for cardiac resynchronization therapy. Pages 1611–14 (2006). With permission from Elsevier. 42)
papillary muscles will further aggravate the
severity of MR, but papillary dysfunction in
itself will not further contribute to functional MR.
Electrical conduction delays as in first-degree
atrioventricular (AV) block and bundle branch
block contribute independently to the problem.
The volume overload of the LV contributes
further to LV dilatation and the progressive
deterioration in LV function, which in turn again
increases MR severity. Thus, it is often quoted
that ‘MR begets MR’.44
EFFECTS OF CRT ON FUNCTIONAL
On the basis of the pathophysiology described
above, it becomes evident that any therapy that
improves global LV systolic function and that
simultaneously reduces wall motion abnormalities will also help to decrease the severity
of functional MR. CRT is such a therapy, and
has been shown to improve LV systolic function
as measured by an acute increase in LV dP/dtmax
and pulse pressure45,46 mediated by an improved
synchrony of myocardial contraction.22,47–49
The diastolic (pre-systolic) component of
functional MR is mainly dependent on delayed
AV coupling, which can be identified by a prolonged PR interval. It is eliminated by pacing
with a short (optimized) AV delay, independent
of the ventricular pacing site (Figure 19.2b).
Thus, diastolic MR can theoretically also be
effectively treated by conventional right ventricular (RV) pacing; however, this approach might
aggravate mechanical LV dyssynchrony and
thereby the systolic MR component.
As explained above, the systolic MR component is mainly determined by the imbalance
between the tethering and closing forces on
the leaflets. This led to the assumption that the
CRT-related acute improvement in LV systolic
function will augment the closing force on the
IMPACT OF CRT ON MITRAL REGURGITATION 243
mitral leaflet and thereby immediately produce
a more rapid and more effective closure of the
valves. This was tested in an acute experiment
with reprogramming of the CRT device at rest
to on-and-off pacing in 24 patients with an
implanted CRT device.17 The severity of MR
was quantified with echocardiography by the
proximal isovelocity surface area (PISA) method
and compared with the non-invasively determined changes in LV systolic function (LV
dP/dtmax by continuous-wave Doppler). As
postulated, a linear correlation between the
EROA and LV dP/dtmax was observed in this
small study, demonstrating the close relationship between the accelerated rise in the systolic
closing force and the severity of functional MR
(Figure 19.4 and 19.5). This is in good agreement
with the observations by Fukuda et al,28 who
showed in a detailed color flow Doppler analysis
of the dynamic behavior of functional MR that
CRT reduced only the amount of earlysystolic MR, but not the late-systolic MR fraction
Kanzaki et al26 were able to confirm the relationship between the increase in LV dP/dtmax
and severity of MR. In addition, they analyzed
the deformation sequence of the papillary
muscles by strain rate imaging and found a relationship between the interpapillary muscle activation time delay and the improvement in the
degree of MR by CRT (Figures 19.7 and 19.8).
Similar observations were made by Porciani
et al,50 who demonstrated that the improvement
in MR was mainly related to the improved ventricular synchrony in the midventricular level.
Thus, the immediate reduction in severity of MR
can be attributed to an improved coordination of
ventricular contraction, including resynchronized
Figure 19.4 Effect of CRT on functional mitral regurgitation. Color Doppler shows moderate mitral regurgitation during no pacing
(LBBB) (a), and the estimated LV dP/dtmax <400 mmHg/s (b). During CRT, the mitral regurgitant velocity is smaller, corresponding to mild mitral regurgitation (c). The simultaneously acquired LV dP/dtmax by continuous-wave Doppler has improved significantly, as indicated by the faster rise of the regurgitant velocity (d). (Reprinted from J Am Coll Cardiol. Vol 46. Bax JJ et al.
Part 2–Issues During And After Device implantation and Unresolved Questions. Pages 2168–82 (2005). With permission from
American College of Cardiology Foundation.)
244 CARDIAC RESYNCHRONIZATION THERAPY
LA and LV pressure
Figure 19.5 Schematic representation of the relationship between the increase in transmitral pressure (TMP, the instantaneous difference between left ventricular (LV) and left atrial (LA) pressure) and the decrease in effective regurgitant orifice area (EROA). During
no pacing (a), LV contractility is low and results in a slow rise in the LV pressure curve and TMP, with a relatively late systolic maximum. Due to the slow LV pressure rise with delayed development of an effective transmitral closing force (~TMP), EROA remains
large for a relatively long period until it finally reaches its minimum value. In contrast, during CRT (b) LV contractility improves, TMP
rises faster and to a higher maximum value, which is also reached earlier. Consequently, the reduction in EROA occurs earlier, and
EROA reaches lower values and for a prolonged period of time. The shaded area represents the time in systole during which EROA
is <50% of its initial value. Note that in the example chosen here, the reduction in the height of the V-wave following a decrease in
the initial mitral regurgitation will contribute to a preserved TMP during the latter half of systole. (Reprinted from J Am Coll
Cardiol. Vol 41. Breithart OA, et al. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced
systolic heart failure. Pages 765–70 (2003). With permission from American College of Cardiology Foundation.17)
Figure 19.6 Dynamic behavior of the mitral regurgitant (MR) jet throughout systole. (a) Before CRT, the mitral jet area and the
proximal flow convergence zone are much larger during early systole compared with late systole. (b) CRT reduces the total
amount of MR and reverses this pattern, with a late systolic peak of the MR jet. (Reproduced from Fukuda S et al. J Am Coll
IMPACT OF CRT ON MITRAL REGURGITATION 245
Figure 19.7 (a, b) Parametric strain images from the apical four-chamber and two-chamber views. (c, d) Time–strain plots from
the LV myocardial segments adjacent to the papillary muscles, showing the extent of segmental shortening before and during
CRT. At baseline (c), clear dyssynchrony is observed, with delayed peak shortening of the mid-inferior segment. After CRT (d),
both segments shorten simultaneously. (Reprinted from American College of Cardiology Foundation. Vol 44. Kanzaki H, et al. A
mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation.Pages 1619–25 (2004). With permission from American College of Cardiology Foundation.26)
papillary muscle activation, which results in
improved systolic function and reduced mitral
leaflet tethering forces.
The effect of CRT on MR is largely independent of the underlying disease, and is found both
in ischemic and non-ischemic cardiomyopathy
patients.25 The immediate reduction of the MR
volume approaches about 30–40% on average
at rest.17,22,26 A further 10–20% improvement can
be observed in the long term after some months
of CRT, and is probably partly related to LV
reverse remodeling,22 although a direct relationship between reverse remodeling and MR reduction has not yet been demonstrated.51 However,
even a modest decrease in the MR volume
will improve the volume load to the LV and
contribute to long-term LV reverse remodeling.
Recent studies have also demonstrated that
the improvement in functional MR is not limited
to resting conditions, but can also be observed
during exercise. Lafitte et al52 found that about
30–40% of heart failure patients with a normal
QRS width (<120 ms) and 60–70% of patients
with a prolonged QRS width (>120 ms) demonstrate significant echocardiographic dyssynchrony at rest. Of those patients, about 30–40%
show a deterioration of the degree of dyssynchrony during exercise, which is accompanied
by a worsening of the severity of their MR. The
exercise-related increase in MR can be reduced
by appropriate biventricular pacing, as demonstrated by Lancellotti et al18 (Figure 19.9). It was
concluded that the inadequate rise in the mitral
closing force (i.e., LV dP/dtmax) during bicycle
exercise was the main determinant for the
increase in MR in non-synchronized patients
(CRT off at rest and during exercise). In alreadyresynchronized patients (CRT on at rest and
during exercise), the residual increase in MR
was mainly determined by geometrical factors
(namely the residual tenting area) and independent
of the increase in LV dP/dtmax.
The acute beneficial effects of CRT on MR are
sustained during mid- and long-term follow-up
and contribute significantly to the observed longterm benefit of CRT. Yu et al22 demonstrated that
246 CARDIAC RESYNCHRONIZATION THERAPY
Baseline: RV PACED
Figure 19.8 Bull’s-eye plots of myocardial shortening from representative heart failure patients before and during CRT:
(a) a patient with LBBB; (b) a patient with RV pacing. The time to peak systolic strain is color-coded with lines representing
isochrones of mechanical shortening (activation) times at 50 ms intervals. The ‘X’ indicates the site of lead placement and
the arrow indicates the direction of the propagating mechanical shortening. The time to peak strain is shown for sites adjacent
to the anterolateral (AL P) and posteromedial (PM P) papillary muscles. (Reprinted from J Am Coll Cardiol. Vol 44. Kanzaki H,
et al. A mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation strain mapping. Pages 1619–25 (2004). With permission from American College of Cardiology Foundation.26)
brief cessation of CRT after 3 months of active
pacing led to a return of MR to baseline levels
(Figure 19.10). Even after more than 1 year,
abrupt cessation of active CRT will worsen the
severity of MR, indicating that the clinical and
hemodynamic benefit of CRT persists over time.27
In general, the reduction in MR seems to be independent of the etiology of heart failure (ischemic
vs non-ischemic).25 However, in another series of
169 patients, the magnitude of the CRT response,
defined as an increase in LVEF, was larger in
non-ischemic patients with a lesser extent of scar
IMPACT OF CRT ON MITRAL REGURGITATION 247
Difference −15 mm2
Difference +23 mm2
Difference +9 mm2
Difference −29 mm2
Figure 19.9 Proximal flow convergence zone in a representative patient with pacing during rest (upper row) and exercise (lower
row) without CRT (left) and with active CRT (right). CRT reduced MR at rest (calculated effective regurgitant orifice area (ERO)
from 39–24 mm2) and diminished the relative increase during exercise. (Reprinted from Am J Cardiol. Vol 94. Lancellotti P,
et al. Effect of cardiac resynchronization therapy on functional mitral regurgitation in heart failure. Pages 1462–5 (2004). With
permission from Elsevier. 18)
Mitral regurgitation (%)
3mo off–immed off–1wk off–4wk
Figure 19.10 Changes in LV dP/dtmax (a) and MR (expressed as the percentage of the MR jet in relation to LA size) (b) over time
during CRT. Both parameters improve with CRT and return towards baseline levels after cessation of CRT after 3 months of active
pacing. *Significant difference versus baseline. †Significant difference versus 3 months. (Reproduced from Yu CM et al. Tissue
Doppler echocardiographic evidence of reverse remodeling and improved synchrony by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;40:111–18.22)
248 CARDIAC RESYNCHRONIZATION THERAPY
segments and a lower wall motion score
index.53 Patients with a marked response (LVEF
increase >10%) showed a greater improvement
in severity of MR than moderate responders
(LVEF increase 4–10%), while LVEF nonresponders (LVEF increase ഛ4%) experienced
no change in MR.
It has become evident that the clinical long-term
benefit of CRT is closely related to its acute and
long-term effects on mitral valve competence.
The most impressive improvement is observed
in patients with non-ischemic cardiomyopathies
and with mild to moderate functional MR.
Preliminary evidence suggests that the response
to CRT might be more dubious in patients
with very severe MR. These patients usually
respond less to pacing, and should probably
also be evaluated for reconstructive mitral valve
surgery. Among the multiple clinical and
procedural factors that determine the success of
CRT, the effects on the mitral valve are of utmost
clinical and prognostic importance. A patient
with a CRT-related improvement in functional
MR is also likely to experience a significant
clinical and prognostic long-term benefit.
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250 CARDIAC RESYNCHRONIZATION THERAPY
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