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\begin{document}

\title{The role of three-dimensional transesophageal echocardiography in
predicting the effect of cardiac resynchronization therapy on mitral
regurgitation in patients with low ejection fraction heart failure}



\author[1]{Ayse  Demirtola}%
\author[2]{Turkan Tan}%
\author[3]{Anar Mammadli}%
\author[4]{irem Muge Akbulut}%
\author[5]{Demet Gerede}%
\author[6]{Irem Dincer}%
\affil[1]{Basaksehir Cam ve Sakura City Hospital}%
\affil[2]{Ankara University Department of Cardiology}%
\affil[3]{Bayindir Hastanesi Sogutozu}%
\affil[4]{Ankara University Faculty of Medicine}%
\affil[5]{Ankara University}%
\affil[6]{Ankara University School of Medicine}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Purpose: Cardiac resynchronization therapy (CRT) has a positive effect
on the improvement of functional mitral regurgitation in patients with
heart failure with reduced ejection fraction. However geometric changes
in the mitral valve apparatus, subvalvular structures and their
contribution to the improvement of mitral regurgitation after CRT have
not been clearly defined. The aim of our study was to evaluate the
geometric parameters of mitral valve apparatus measured with
3Dimensional (3D) transesophageal echocardiography (TEE) before CRT
implantation and to determine the parameters predicting the improvement
of mitral regurgitation after CRT. Methods: In this prospective study
thirty patients with moderate or severe mitral regurgitation with low EF
heart failure planned for CRT implantation and had an indication for TEE
were included. Effective regurgitant orifice (ERO) and regurgitant
volume (RV) measurements were performed before CRT implantation.
Detailed quantitative measurements of mitral valve were done from
recorded images by 3D TEE. ERO, RV measurements were repeated to
evaluate mitral regurgitation at the end of 3rd month. Results: There
were no significant changes in left ventricular EF and left ventricular
diameters at third month follow-up, whereas ERO and RV values were
decreased. posterior leaflet angle was found higher in non-responder
group compared to responder group. (28,93 \selectlanguage{ngerman}± 8,41 vs 41,25 ± 10,90, p =
0,006). Conclusion: Heart failure patients with moderate or severe
functional mitral regurgitation who underwent CRT implantation were
found lower posterior leaflet angle which was measured by 3D TEE in the
patient group whose mitral regurgitation improved after CRT.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Mitral regurgitation accompanies the heart failure with low ejection
fraction at the rate of 30-50\% (1). The coexistence of functional
mitral regurgitation in patients with HfrEF is asscoiated with two fold
increase in the mortality rates.(2) Progressive remodelling occurring in
heart failure leads to left ventricular dilatation, increase in cavity
sphericity, annulus expansion and displacement of papillary muscles
result in improper coaptation of the leaflets and functional mitral
regurgition. (3)-(4)

Although improvement in the mitral regurgitaion is expected after CRT
implantation this is not the case in all of the patients. Several
parameters were evaluated for the prediction of improvement of mitral
regurgitation after CRT implantation by 2D echocardiography. Tenting
hight and interpapillary muscle distance were found to be related to
improvement (5).

3D TEE is an integral part of the imaging in mitral valve disesases and
has proven to be the most convincing method for understanding the
complicated anatomy of the mitral valve and its dynamism.In addition to
high quality real time imaging of the mitral valve it allows us to make
quantitaive measurements by post process analysis.

Impact of CRT on geometric changes in mital valve apparatus and
subvalvular structures and the parameters that would predict the
improvement of mitral regurgitation still remain to be elucidated.

The aim of the this study was to evaluate the geometric parameters of
mitral valve measured by three dimensional transosephageal
echocardiography prior to CRT which would predict the improvement of
mitral regurgitation after CRT implantation.

\textbf{Methods}

\textbf{Study population}

Among 72 patients who had CRT implantation were reviewed. 30 of them who
had another indication for transeosephageal echocardiography ( E.g.
grading mitral regurgitation, trombus search etc.) and moderate to
severe mitral regurgitaion were included to the study.

Patients with rheumatic mitral valve disease, severe annular
calcifications, mitral valve prolapse and a history of mitral valve
repair or replacement and those with inadequate acoustic windows were
excluded from the study. Informed consent was obtained from the patients
and approval from Clinical Investigation Ethics Committee in accordance
with principles of Helsinki Declaration.

\textbf{Echocardiographic analysis}

Transthoracic and transosephageal echocardiograpy were performed with
Vivid E9 Ultrasound system (GE Healtcare, Waukesha, WI, USA), which had
both multiplane 2 dimensional and real time 3 dimensional imaging
capacity. In accordance with the guides of American Echocardiography
Association, left ventricle end systolic diameters (LVESD) and
end-diastolic diamaters(LVEDD) were measured in the parasternal
long-axis view in resting state , using transthoracic echocardiography
(TTE) . Left ventricle ejection fraction (LVEF) was calculated with
three dimensional echocardiographic method. In order to determine the
severity of MR, proximal isovelocity surface area (PISA) method was
utilized. ERO (Effective regurgitant orifice area) and RV ( Regurgitant
Volume ) measurements were carried out at both before CRT implantation
and at the end of 3. month follow up control.

Responder / Non-responder Definiton: As recommended by the guides, over
0.1 cm\textsuperscript{2} decrease in ERO and 15ml and higher decrease
in RV at the third month control TTE examination was regarded as
improvement in MR and patients were divided into responder and
non-responders according to this cutoff value.

\textbf{Assesment with three dimensional TEE}

In order to obtain values of mitral valve parameters before CRT
implantation, real time 3 dimensional transesophageal echocardiography
(TEE) Vivid 9 Ultrasound system was used. Using TEE probe in
mid-esophageal position at full volume and in real time zoom mode with
long axis view from left atrial perspective, images including mitral
valve, aorta and LAA (left atrial appendix) and equivalent to surgical
view were obtained. In order to increase temporal resolution multibeat
images (at least 4 beat) (Frame rate: 8-12 Hz) in the region of
interest, distance between sectors was decreased and gain was optimized
to evaluate valve anatomy clearly and prevent artifacts. (Figure1)

Figure 1: .Evaluation of mitral valve apparatus with 3 dimensional
transosephageal echocardiography

Data obtained in 3D zoom mode were recorded with EchoPac PC Software,
Version 6.3 (GE Vingmed US, Horten, Norway), performing semi automated
analysis. Detailed measurments of mitral valve was accessed with 4D MVQ
(Mitral Valve Quantification, GE Healthcare) program automatically and
data were anlysed in offline mode. (Figure 2)

Figure 2: Three dimensional evaluation of mitral valve with EchoPac PC
Software 4D MVQ program automatically

\textbf{Statistical analysis}

For statistical analysis, IBM SPSS Statistics v25 program was used. The
evaluation of continuous variables was made with histogram diagrams and
Kolmogorov-Smirnov test. .As continuous variables were not distributed
normally and group frequencies and sample size was small, non-parametric
methods were employed. Categorical (qualitative) variables were expreed
with frequency (n) and percentage (\%), and numerical variables with
mean , standard deviation (sd) Changes in ERO, RV, LVEF, LVEDD, LVESD
parameters before and three months after CRT were examined with Wilcoxon
rank test. Improvement in MR was taken as dependent variable.

The difference in mean values of TEE between the group responders and
non-responders was evaluated with Mann Whitney test. Logistic regression
analysis was carried out so as to determine the variables predicting
improvement in MR. \emph{P value of} \textless{} 0,05 was considered
statistically significant. .

\textbf{Results}

\textbf{Baseline characteristics}

Overall 30 patients ( \%70 male) were included to the study. Their mean
age was 63,7, \%36 had dilated cardiomyopathy while others had ishemic
cardiomyopathy. Baseline demographic charecteristics were shown at Table
1.

In ECG examination, 17 (\%56,7) patients had left bundle branch block, ,
9 had right bundle branch block (\%30) and 4 (\%13.3) had
interventriculer conduction delay with left bundle branch block variety
.

All patients were using optimal medical heart failure treatment
recommended by guidelines at baseline and at the end of 3rd month. At
3rd month control evaluation, there was no change in the use and the
dosage of the drugs.

Pacemaker controls done at the baseline and 3rd month follow up
evaluation, the rate of biventricular pace was at desired values i.e.
(mean \%95,6)

\textbf{Baseline TTE Findings}

At the baseline measurements mean EF value, mean LVEDD, mean LVESD, EROA
value and mean RV value were found to be 22,83 \selectlanguage{ngerman}± 5,88\%, 6,51 ± 0,68 cm,
5,38 ± 0,78 cm, 0,34 ± 0,15 cm2, 46,1 ± 15,73 mL respectively.

\textbf{3D TEE Findings}

In 3D TEE examination, mitral valve was accessed with 4D MVQ program
automatically ; mean mitral annulus area was found to be 9,62 ± 2,73
cm2, mean postero-medial to antero-lateral diameter (PM-AL) was found to
be 3,41 ± 0,47 cm, mean antero-posterior diameter was found to be 3,15 ±
0,53 cm, mean anterior leaflet angle was found to be 24,67° ± 8,06° and
mean posterior leaflet angle was found to be 35,5° ± 11,5°. 3D
Transosephageal echocardiographic findings of patients are illustrated
in Table 2

\textbf{Change in TTE parameters after CRT}

There was no significant difference between baseline and 3rd month
control measurments in terms of left ventricular size and EF
values.However, significant difference was found in effective
regurgitant orifice (ERO) and regurgitant volume (RV) measurements . (p
\textless{} 0,05). Baseline and 3rd month control transthoracic
echocardiography findings of patients are illustrated in Table 3.

\textbf{Echocardiographic improvement in MR and TEE findings}

In the present study, in accordance with the guides, at least 0,1
cm\textsuperscript{2} reduction in ERO or at least 15ml decrease in RV
was considered as echographic improvement of MR (Responder /
Non-responder). There were 19 patients with at least 0,1
cm\textsuperscript{2} reduction in ERO, 9 patients with at least 15ml
decrease in RV and 8 patients who fulfilled both parameters.

No statistically significant difference was found between patients with
and without at least 0.1 cm\textsuperscript{2} decrease in ERO and
between those with and without 15ml decrease in RV with regard to
demographic characteristics. Table 4

No significant difference was found between patients in whom regarded as
responder or non-responder according to status of change ERO, (Table 5)
with respect to mitral annulus area, posteromedial and anterolateral
diameter , antero-posterior diameter and anterior leaflet angle (p
\textgreater{} 0,05). Yet, it was established that posterior leaflet
angle was significantly lower in responder patients than that in
non-responder patients. (p = 0,029) (40,73 vs. 32,47, p = 0,029).

No significant difference was found between three dimensional TEE
paramers of patients in whom regarded as responder or non-responder
according to status of change RV in terms of 3D TEE parameters. (Table6)
However,, similar to the result obtained in ERO changes, in the
responder group there was a trend towards lower posterior leaflet angle
compared to non-responder group. . ( respectively 29,22 vs. 38,19 p =
0,063)

In the group with whom regarded as responder or non-responder according
to status of change ERO and RV both, When 3D TEE parameters were
compared, statisicallly significant difference was found in posterior
leaflet angle (p \textless{} 0,05). It was established that in
non-responder group, posterior leaflet angle was higher. (38,05 vs. 28,5
p = 0,049). (Table 7)

Although posterior leaflet angle was found to be significantly different
between responder and non-responder patients, in logistic regression
analysis performed to determine the independent predictor parameters of
MR improvement, it was not found to be significant.

\textbf{Discussion}

Aim of our study was to determine the parameters that will predict the
improvement of mitral regurgitation after implatation of CRT in patinets
with HFrRF with moderate or severe functional mitral regurgitation by
measuring the geometric parameters of mitral valve with 3D TEE by 4D MVQ
program automatically. Our results have shown that in patients with
lower posterior leaflet angle, CRT resulted in the marked improvement of
mitral regurgitation.

As it is known, functional mitral regurgitation arises as a consequance
of the imbalance between closing and tethering forces responsible for
valve competence. (4) Systolic dysfunction,ventricular remodelling,
mitral annulus dysfunction, alteration in LV geometry and size and
dyssnchrony are supposed to be the main causes of MR. (6)

Several echocardiogrphic parameters were found to be related to the
significance of functional mitral regurgitation in patients with low EF
heart failure. Posterior leaflet angle has been investigated many times
as in our study. In a study echocardiography and cardiac MR were used in
order to evaluate anterior and posterior leaflet angles, in the groups
with severe MR; along with asymmetrical tethering, mean posterior
leaflet angle was found to be a 38.37° and significant relation was
demonstrated between RV and posterior leaflet angle. (r = 0,90 p =
0,037) (7)

Likewise, in the study of Kwan et al, in the evaluation of geomteric
parameter measurements in ischemic cardiomyopathy, it was demonstrated
that posteior leaflet angle of 47 degree was major predictor of severe
MR with sensitivity of 96\% and specifity of 84\%. (positive predictive
value 92\%, negative predictive value 100\%) (8)

CRT is a treatment option which can interrupt the vicious circle that
deteriorates heart failure caused by MR.In acute period,
resynchronization of papillary muscle enables the MR duration to be
shortened and MR onset to be delayed , resulting in increase in
transmitral pressure gradient and modification of mitral annulus
contraction via increased con tractility. (6) Moreover, in chronic
period, resynchronization associated with remodelling brings about
increase in closing forces within weeks to months and restores more
coordinated movements of mitral valve components. (9) Beside this, there
is an improvement in ejection fraction in the long term after CRT and it
provides improvement in MR. However in our study we have evaluated the
short term improvent at the end of three month and there was no change
in LVEF and LV sizes and the improvement is only related to the CRT
treatment. Although long term studies would be more valuable, results of
our study shows solely effect of CRT on mitral regurgitaion is related
to posterior mitral valve angle.

In the study of Kanzaki et al investigating the impact of CRT on early
MR, it was revelaed through longitudinal strain measurements that after
CRT implantation, mechnical activation of papillary muscles retension
zone, became more coordinated and temporal delay between papillary
muscles was decreased and improvement in dysynchrony was linked to
improvement in MR.(10)

Three dimensional TEE, which has recently become popular in clinical
practice, yields quite objective data in the evaluation of mitral valve.
In a study including 112 patients with mitral valve prolapsus and severe
MR, 2D and 3D TEE were compared and it was stated that measurements made
with 3D TEE were superior in the determination of pathology. (11)

In addition to 3D TEE, full automated mitral analysis softwares enabling
detailed evaluation of mitral valve has become more common in clinical
practice. In the study of Nobuyuki et al comparing manual screening
software with fully automated software in the three dimensional
evaluation of mitral valve, it was stated that automated software had
comparable accuracy to manual software as well as being time saving.
(12)

Many measurements of the mitral valve can be made with these full
automated mitral analysis softwares. And these reveal the effects of CRT
on the mitral valve. Previous studies have demonstrated that the tenting
hight and tenting area are related to both severity of mitral
regurgitaiton and the response, by reason of tenting hight and the
tenting area are the final results of the all the geometrical changes
seen in dilated ventricle and accused for the development of mitral
regurgitaiton annulus also has an adjuctive role by seperating the
mitral leafleats.(13) However we had few number of the patients we could
not included all the parameters that we would be measured with 3D TEE,
we have included the parameters that are related to functional mitral
regurgitaiton such as annulus size and diameters, anterior leaflet angle
and as our results clinically important posterior leaflet angles.

Posterior leaflet angle is an indicator of posterior tethering. In
dilated ventricle, the displacement of posterior papilary muscle will
lead to increase in posterior tethering forces and in posterior leaflet
angle and the resulting imbalance between tethering and closing forces
will give rise to mitral regurgitation. Hence, in mitral valve complex
with higher posterior leaflet angle, the response to treatment with CRT
will be at a lower degree.

In conclusion, in heart failure patients with low ejection fraction, the
accompanying moderate or severe mitral regurgitation portends poor
prognosis and it is reduced after after CRT implantataion in about two
thirds of the patients, which yields clinical benefit with decrease in
mortality. Mitral valve measurments that will be made with 3D TEE prior
to implantation may help to predict the response of MR to CRT. Hence, in
the present study, we have tried to find out the parameters that will
predict reponse to treatment of MR by evaluating mitral valve anatomy
with 3D TEE and concluded that posterior leaflet angle may be an
important parameter influencing the improvement in mitral regurgitation
following CRT. (28,93 ± 8,41 vs. 41,25 ± 10,90, p = 0,006). Three
dimensional TEE and is a highly valuable method for the both visual
evaluation and quantitative analysis of mitral valve and further studies
would be done with larger number of the patients to predict the mitral
regurgitaiton responce to CRT implantation.

\textbf{Study limitations}

One of the limitatations, which may have influenced study results, is
that patient number was low and the etiology of low ejection fraction
was both ischemic and dialted cardiomyopathy, furthermore were dont have
only patients with LBBB but we also have patients with RBBB and LBBB
type interventricular conduction delay. All of these may have an
influence on the improvement of mitral regurgitaiton after CRT
implantation. Another limitation was follow up period restricted to
three months, as this period is not adequate to predict improvement
either in LVEF or in mitral regurgitation. In three months follow up, no
marked change was found in LVEF and volumes but in the long term,
improvement in these parameters associated with left ventricle reverse
remodelling, may decrease the degree of MR. For its evaluation, long
term follow up will be more appropriate.

In addition, although the severity of mitral regurgitation was evaluated
with transthoracic echocardiography at the third month follow up , as
the patients did not undergo control TEE examination, the parameters of
mitral valve, which are evaluated with TEE, improving and influencing
the response to treatment of mitral regurgitataion, could not be
determined.

\textbf{Conclusion}

In the present study, in patients with moderate and severe mitral
regurgitataion, 3D TEE parameters, which could predict the improvement
in MR after CRT, were investigated and it was established that patients
with lower posterior leaflet angle can derive more benefit from CRT.

\textbf{Conflicting interest:} The authors declare that there is no
conflict of interest.

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