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\begin{document}

\title{Secondary Leaflet Tethering in Patients with degenerative mitral
regurgitation and its Association with the Severity of Mitral
Regurgitation}



\author[1]{Zhenyi Ge}%
\author[1]{Chunqiang Hu}%
\author[1]{Fangyan  Tian}%
\author[1]{Yingjie Zhao}%
\author[1]{Yongshi Wang}%
\author[1]{Dehong Kong}%
\author[1]{Wei Li}%
\author[2]{Yashu Xie}%
\author[1]{Zhengdan Ge}%
\author[1]{zibire fulati}%
\author[1]{Yufei Cheng}%
\author[1]{Yao Guo}%
\author[1]{Yingying Jiang}%
\author[1]{Cuizhen Pan}%
\author[1]{Xianhong Shu}%
\affil[1]{Zhongshan Hospital Fudan University}%
\affil[2]{ChengDu Healthcare Security Administration}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Background} The purpose of the study was to determine the
association between vena contracta area (VCA) and secondary leaflet
tethering among mitral valve prolapse (MVP) patients, and thus to
further identify and characterize an MVP with pathological leaflet
tethering (MVPt+) phenotype. \textbf{Methods} We prospectively evaluated
94 consecutive MVP patients with significant mitral regurgitation (MR)
and 20 healthy controls. MVPt+ group was defined as tenting volume index
(TVi) \textgreater{} 0.7 ml/m \textsuperscript{2}. The three-dimensional
(3D) geometry of mitral valve apparatus and VCA was measured with
dedicated quantification software. \textbf{Results} Of the 94 patients
with MVP and significant MR, 31 patients showed a TVi \textgreater{} 0.7
ml/m \textsuperscript{2} and entered the MVP with leaflet tethering
(MVPt+) group. In stepwise multivariate analysis, only prolapse volume
index and TVi was independently associated with 3D VCA. Apart from
marked left ventricular and annular enlargement, MVPt+ group presented
significantly higher frequency of leaflet flail, greater VCA, elevated
plasma levels of NT-proBNP and sPAP. ROC curve revealed that occurrence
of leaflet tethering is associated with a VCA [?]0.55 cm
\textsuperscript{2} in MVP patients. \textbf{Conclusions} Secondary
leaflet tethering is a significant mechanism behind severe degenerative
mitral regurgitation, resulting an MVPt+ phenotype featuring more
advanced morphological and hemodynamical characteristics \textbf{.}%
\end{abstract}%



\sloppy


\textbf{Secondary Leaflet Tethering in Patients with degenerative mitral
regurgitation and its Association with the Severity of Mitral
Regurgitation}

\textbf{Zhenyi Ge\textsuperscript{1,2}, MD, Chunqiang
Hu\textsuperscript{1,2}, MD, Fangyan Tian\textsuperscript{1,2}, MD,
Yingjie Zhao\textsuperscript{1,2}, MD, Yongshi Wang\textsuperscript{1},
MD, Dehong Kong\textsuperscript{1}, MD, Wei Li\textsuperscript{1}, MD,
Yashu Xie\textsuperscript{3}, MD, Zhengdan Ge\textsuperscript{1,2}, MD,
Zibire Fulati\textsuperscript{1}, MD, Yufei Cheng\textsuperscript{1},
MD, Yao Guo\textsuperscript{1}, MD, Yingying Jiang\textsuperscript{1},
MD, Cuizhen Pan\textsuperscript{1,2}, MD, Xianhong
Shu\textsuperscript{1,2}, MD, PhD}

\textsuperscript{1}Department of Echocardiography, Shanghai Institute of
Cardiovascular disease, Zhongshan Hospital, Fudan University, Shanghai,
China

\textsuperscript{2}Shanghai Institute of Medical Imaging, Fudan
University, Shanghai, China

\textsuperscript{3}ChengDu Healthcare Security Administration, Sichuan,
China

Drs. Zhenyi Ge, Chunqiang Hu and Fangyan Tian are co-first authors.

Drs. Cuizhen Pan and Xianhong Shu contributed equally to this work and
should be considered co-corresponding authors.

Corresponding to: Cuizhen Pan or Xianhong Shu

Address: Department of Echocardiography, Zhongshan Hospital, Fudan
University, No.1609 Xietu Road, Xuhui District, Shanghai, China.

E-mail: pan.cuizhen@zs-hospital.sh.cn or shu.xianhong@zs-hospital.sh.cn



\textbf{Abstract}

\textbf{Background} The purpose of the study was to determine the
association between vena contracta area (VCA) and secondary leaflet
tethering among mitral valve prolapse (MVP) patients, and thus to
further identify and characterize an MVP with pathological leaflet
tethering (MVPt+) phenotype.

\textbf{Methods} We prospectively evaluated 94 consecutive MVP patients
with significant mitral regurgitation (MR) and 20 healthy controls.
MVPt+ group was defined as tenting volume index (TVi) \textgreater{} 0.7
ml/m\textsuperscript{2}. The three-dimensional (3D) geometry of mitral
valve apparatus and VCA was measured with dedicated quantification
software.

\textbf{Results} Of the 94 patients with MVP and significant MR, 31
patients showed a TVi \textgreater{} 0.7 ml/m\textsuperscript{2} and
entered the MVP with leaflet tethering (MVPt+) group. In stepwise
multivariate analysis, only prolapse volume index and TVi was
independently associated with 3D VCA. Apart from marked left ventricular
and annular enlargement, MVPt+ group presented significantly higher
frequency of leaflet flail, greater VCA, elevated plasma levels of
NT-proBNP and sPAP. ROC curve revealed that occurrence of leaflet
tethering is associated with a VCA [?]0.55 cm\textsuperscript{2} in MVP
patients.

\textbf{Conclusions}

Secondary leaflet tethering is a significant mechanism behind severe
degenerative mitral regurgitation, resulting an MVPt+ phenotype
featuring more advanced morphological and hemodynamical
characteristics\textbf{.}

\textbf{Keywords:} 3D transesophageal echocardiography; mitral valve
prolapse; degenerative mitral regurgitation; mitral valve geometry



\textbf{Introduction}

Mitral valve (MV) prolapse (MVP), as the most common finding in
degenerative mitral regurgitation, is defined by superior displacement
during systole of the free edge of leaflet beyond the annular level,
resulting in coaptation failure and mitral regurgitation
(MR).\textsuperscript{{[}1, 2{]}} Conventional two-dimensional (2D)
echocardiographic studies showed it frequently accompanied with varied
degrees of annular dilation, leaflet redundancy, and chordal
dysfunction.\textsuperscript{{[}3, 4{]}}

MVP tends to progress over time with increase in volume overload.
Moreover, left ventricular remodelling can begin with even mild MR as a
continuous adaptive process to volume overload and progresses that
paralleled to MR severity. \textsuperscript{{[}5-7{]}}

Three-dimensional (3D) transesophageal echocardiography (TEE) could
provide excellent images of MV apparatus and accurate measurements of
the mitral complex and has increase our understanding of DMR disease.
Recent study using 3D TEE has revealed that left ventricular remodelling
in MVP patients can exacerbate mal-coaptation through apical tethering
of non-prolapsed leaflet segments, constituting a vicious MR-tethering
cycle.\textsuperscript{{[}8{]}} Subsequently, leaflet tethering in MVP
patients has been reported to be associated with residual MR after
surgical repair and transcatheter edge-to-edge
repair.\textsuperscript{{[}9-11{]}} However, it remains unclear about
how severe the MR is when the MR-tethering cycle is triggered. One of
the possible reasons may be lack of specific criteria for
differentiating normal from pathological leaflet tethering in MVP
patients. Indeed, limitations existed with the small population and
narrow spectrum of MR severity in the previous
study.\textsuperscript{{[}8{]}}

The goals of this study were using 3D TEE determine the association
between vena contracta area (VCA) and secondary leaflet tethering among
MVP patients, and thus to further identify and characterize an MVP with
pathological leaflet tethering (MVPt+) phenotype.

\textbf{Methods}

\textbf{Patient population}

From July 2018 to December 2020, a total of 117 consecutive patients
with degenerative mitral valve disease and significant MR (grade 2+) in
a prospective multicenter study underwent transthoracic and
transesophageal echocardiographic assessment and were included in the
study.

Twenty-three were excluded for the following reasons: (1) 10 were
excluded owning to inadequate echocardiographic image quality for MVN or
3D VCA analysis; (2) 7 were excluded because of with mixed atrial
functional mitral regurgitation or presence of mitral annular
disjunction; (3) 4 were excluded because of significant concomitant
aortic valve disease; (4) 2 was excluded due to having abnormal
segmental wall motion. Twenty subjects (ages 67\selectlanguage{ngerman}±8.5) undergoing
clinically indicated TTE and TEE who have no MR with normal left
ventricular (LV) function and mitral apparatus were also examined as
controls. The protocol of this study was approved by the institutional
review board of Zhongshan Hospital and was conducted in accordance with
the Declaration of Helsinki. Written informed consent was obtained at
the time of consent for the clinical TEE procedure in all of the
patients.

\textbf{MVN analysis}

The Mitral Valve Navigation (MVN) analysis was performed as previously
described.\textsuperscript{{[}11{]}} Imaging data sets were analyzed by
the core laboratory echocardiographer using Philips Mitral Valve
Navigation software (Qlab version 13; Philips Medical Systems). Images
with the highest volume rate (\selectlanguage{english}[?] 10 Hz) and best image quality were
selected for analysis. The MVN software provides semiautomated 3D
modeling and quantification of the mitral annulus and apparatus (Figure
1). Measurements were performed by two core laboratory
echocardiographers, which were blinded to the result of 3D VCA. The mean
of three measurements of each parameter was calculated and reported as
final value.

The end-systolic frame was identified as the last systolic frame just
before aortic valve closure and selected to perform MVN analysis. For
the definition of annulus geometry, we assessed anterior--posterior (AP)
diameters, lateral/medial (ALPM) diameters, annulus height, annulus area
and circumference, and the MV annular ellipticity (defined as ALPM/AP
diameter).The ratio of annular height to commissural width (AHCWR) was
computed as a surrogate of annular saddle-shaped
flattening.\textsuperscript{{[}7{]}} Severity of prolapse or leaflet
tethering was quantified using prolapse height/volume or tenting height
/volume, respectively. Two-dimensional and 3D echocardiographic
parameters were index to body surface area (BSA) as appropriate, such as
AP diameter index (APi).

Secondary leaflet tethering (MVPt+ group) was defined as tenting volume
index (TVi)\textgreater{} 0.7 ml/m\textsuperscript{2}, based on the
scatterplot of TVi of our MVP patients and normal value for healthy
subjects (Figure 2A). Note that there are no references regarding the
threshold of normal values of tenting volume index (TVi) in the
literature.\textsuperscript{{[}12, 13{]}}

\textbf{3D VCA analysis}

Three-dimensional color Doppler dataset was acquired to perform off-line
analysis of 3D vena contracta area (VCA). Care was taken to include the
entire proximal convergence region in the data set with the highest
volume rate. The Nyquist limit was controlled within 50--60 cm/s for
optimal visualization of the MR jet. Using the commercial software 3DQ
(Cardiac 3D Quantification; Philips Medical Systems), the two-orthogonal
long-axis planes were aligned parallel with the direction of the
proximal MR jet. The transverse plane was then scanned proximally to
distally in order to identify the narrowest portion of the jet
immediately distal to the regurgitant orifice. The resultant short-axis
image of the VC was traced to obtain the 3D
VCA\textbf{.\textsuperscript{{[}14{]}}}

\textbf{Statistical analysis}

Data are expressed as mean +- SD, median (interquartile range), or number
of patients (percentages) as appropriate. Normality of all continuous
data was confirmed with the Kolmogorov-Smirnov test. Group comparisons
for baseline characteristics, 2D and 3D echocardiographic parameters
used analysis of variance (ANOVA), Kruskal-Wallis test, chi-square test,
or Fisher exact test as appropriate. Univariate and multivariate linear
regression analyses were performed to identify MV 3D geometric variables
associated with 3D VCA. Degenerative variables of mitral valve
morphology previously shown to be associated with MR in MVP were tested.
Variables with P values \selectlanguage{english}[?] 0.07 on univariate analysis were tested in the
multivariate linear regression with stepwise method. The association
between the TVi and other morphological variables was investigated with
Pearson correlation analysis. A receiver operating characteristic (ROC)
curve was drawn to identify the cutoff value of 3D VCA for MVPt+.

\textbf{Results}

\textbf{Determinants of 3D Vena Contracta Area}

All MVP patients presented significant and holosystolic MR.
Morphological determinants of 3D VCA are summarized in Table 1. In
univariate analysis, factors significantly associated with 3D VCA
included annular area index (AAi), prolapse volume index (PVi), TVi and
PV + TV and AHCWR. In stepwise multivariate analysis, only PVi and TVi
was independently associated with 3D VCA.

\textbf{Clinical and 2-Dimensional Echocardiographic Characteristics}

Clinical and two-Dimensional Echocardiographic Characteristics are
listed in Table 2. Of the 94 patients with MVP and significant MR, 31
patients showed a TVi \textgreater{} 0.7 ml/m\textsuperscript{2} and
entered the MVP with tethering (MVPt+) group, while the rest MVP patents
entered the MVP without tethering (MVPt-) group.

There were no differences in age, gender, body surface area and Society
for Thoracic Surgeons (STS) risk score (P = NS for all). The frequency
of NYHA functional class III/IV was slightly higher in MVPt+ group, but
this difference did not reach statistical significance (P \textgreater{}
0.05). Levels of NT-proBNP and sPAP was markedly elevated in MVPt+
patients.

In addition, MVPt+ group also had larger 3D VCA, LV volume index, max
and mean MV gradient (P \textless{} 0.01 for all), but similar max VCW
compared with MVPt- group. The frequency of leaflet flail in the MVPt+
group was significantly higher than in the MVPt- group (94\% vs 73\%, P
= 0.034). Flail/coaptation gap was larger in MVPt+ group and prolapse
width was comparable between the two groups.

\textbf{Quantitative 3D analysis of MV Characteristics}

The geometry of mitral complex in healthy controls, MVPt- and MVPt+
patients are summarized in Table 3. Expectedly, MVPt+ group had a
significantly higher tenting volume index (TVi), while MVPt- group had a
similar TVi to normal controls.

AML TVi and AML angle was comparable in normal controls and MVPt- group,
but MVPt+ group had a significantly larger AML angle. Interestingly, PML
TVi and PML Angle was lowest in MVPt- group, intermediate in normal
controls, and highest in MVPt+ group. (Figure 2B). Annular dimensions,
including ALPM diameter, AP diameter and AAi and annular circumference
index, were significantly different among the groups, being lowest in
normal controls, intermediate in MVPt- group, and highest in MVPt+ group
(Figure 2C).

MVP patients (MVPt- and MVPt+ group) had a larger prolapse height index
(PHi) and PVi compared with normal group. Notably, MVPt- patients had
significantly larger PHi and PVi compared with MVPt+ patients (Figure
2D).

MVPt+ group was not associated with a lower AWCHR as AWCHR is comparable
among three groups (Figure 1E).

\textbf{Correlations between tenting volume index and other
morphological variables}

A mild relationship was observed between TVi and 3D VCA (r= 0.56,
P\textless{} 0.001) (Figure 3B). The correlations between TVi and PVi
were negative and significant (r = -0.319, p = 0.0017), while AAi (r =
0.459, p \textless{} 0.001) correlated positively and significantly with
TVi.

NT-proBNP also mildly correlated with TVi (r = 0.387, p \textless{}
0.001) (Figure 3A), whereas no significant association was found between
NT-proBNP and PVi (P = 0.648).

ROC analysis showed that a 3D VCA \selectlanguage{english}[?]0.55 cm\textsuperscript{2} was the
optimal cutoff point for predicting the occurrence of MVPt+ (area under
curve 0.82; 95\% CI, 0.74-0.91; P \textless{} 0.001) with a sensitivity
of 98\% and specificity of 57\% (Figure 3C).

\textbf{Discussion}

The present study conducted provides new information on the 3D MV
geometry focusing on leaflet tethering and its association with 3D VCA,
with a large population of MVP patients.

The principal finding of the present study is that, secondary leaflet
tethering is a significant mechanism behind severe degenerative mitral
regurgitation, resulting an MVPt+ phenotype featuring more advanced
morphological and hemodynamical characteristics.

In detail, (1) we corroborated that TVi and PVi, rather than annular
dimension, were the major independent determinants of 3D VCA in MVP
patients with significant MR (2) we carefully defined a cutoff value to
characterize the occurrence of pathological leaflet tethering in MVP
patients (MVPt+ group) (3) apart from marked LV and annular enlargement,
MVPt+ group presented significantly greater 3D VCA, elevated plasma
levels of NT-proBNP and sPAP (4) Occurrence of leaflet tethering is
associated with a 3D VCA \selectlanguage{english}[?] 0.55 cm\textsuperscript{2} in MVP patients
and it could be a specific marker for severe MR (Figure 4). Our findings
may bring new insights into risk stratification and surgical decision
making to MVP patients.

\textbf{Determinants of degenerative mitral regurgitation severity}

MR severity for MVP patients varies from trivial to severe according to
the failure of coaptation driven by leaflet prolapse or chordal
elongation and annular enlargement. \textsuperscript{{[}3, 15{]}} It
tends to progress over time with increase in volume overload
(regurgitant volume) due to increase in regurgitant orifice. Progression
of MVP is determined by progression of lesions, particular a new flail
leaflet, or mitral annulus size. \textsuperscript{{[}4, 16{]}} In
addition, left ventricular enlargement is a continuous adaptive process
that begins with even mild MR and progresses paralleled to MR
severity.\textsuperscript{{[}5, 17, 18{]}}

Otani et al. first reported AML tenting volume was proportional to
papillary muscle displacement attributed to both annular and LV
dilatation, suggesting that degenerative MV prolapse causes secondary LV
dilatation and mitral leaflet tethering, especially in non-prolapsed
leaflets. \textsuperscript{{[}8{]}} More recently,
Morningstar\textsuperscript{{[}19{]}} et al demonstrated that mechanical
changes induced by a prolapsing valve can engender fibrosis within the
inferobasal wall and attached PM that are physically and mechanically
linked to the prolapsing leaflets. These changes may also contribute to
leaflet tethering in MVP.\textsuperscript{{[}20{]}}

Previous studies have revealed that prolapse and tenting volume, annular
dimension and AHCWR correlated with MR severity in MVP
patients.\textsuperscript{{[}4, 7{]}} We tested these factors in the
multivariate model and found that only PVi and TVi was associated with
3D VCA, independent of annular dimension. Indeed, in functional MR
(FMR), isolated annular dilation does not usually cause important MR
without leaflet tethering caused by LV dilation and
dysfunction.\textsuperscript{{[}8, 21{]}} Although annular dilation is
not the most significant determinant of 3D VCA, it contributed to the
severity of leaflet tethering. \textsuperscript{{[}8{]}}

Despite further annular dilatation, our MVPt+ group showed similar AHCWR
with normal controls and MVPt- patients. Flattening of annular saddle
shape is commonly seen in MAD patients as an intrinsic annular
abnormality, which is our exclusion criteria for the current study.
Flattening of annular saddle shape also recently has been demonstrated
to be correlated with reduction of LV longitudinal contraction (GLS) in
atrial FMR. \textsuperscript{{[}22, 23{]}} Indeed, annular saddle shape
is more preserved in FED phenotype\textsuperscript{{[}6{]}}, which
represents the majority of our patients.

It had been widely accepted that leaflet tethering plays a fundamental
role in the pathogenesis of FMR\textsuperscript{{[}12, 21{]}}, whereas
leaflet tethering in MVP patients was not commonly recognized until
Otani et al. Although Otani et al\textsuperscript{{[}12{]}} firstly
elaborated the mechanism, limitations existed with the small population
and narrow spectrum of MR severity in the previous study. Furthermore,
data on clinical and echocardiographic characteristics MVPt+ patients
are sparse. One of the reasons may be attributed to lack of specific
criteria for differentiating normal from pathological leaflet tethering
in MVP patients.

Under normal physiological circumstances, longitudinal LV fiber
contraction translates the posterior annulus apically during the systole
as to fold the annulus into a saddle shape. Accordingly, the anterior
annulus has to tilt posteriorly, thus made the anterior leaflet tethered
at the aortic root.\textsuperscript{{[}24, 25{]}}The value of TVi in
healthy controls and MVPt- group represents the above conformational
changes of the anterior leaflet.

Our study also suggested that within MVP patients both AML and PML could
occur secondary leaflet tethering, as quantitated by TVi and leaflet
angle. Reduction of PML TVi and leaflet angle in MVPt- patients was
probably a morphological consequence of PML prolapse.

\textbf{Characteristics of MVP patients with pathological leaflet
tethering}

In patients categorized by MVN analysis as MVPt+, we demonstrated more
severe clinical and echocardiographic characteristics. Apart from marked
LV and annular enlargement, MVPt+ group presented significantly greater
MR severity, elevated plasma levels of NT-proBNP and sPAP. All these
factors have been shown to be correlated with adverse outcome in MVP
patients.\textsuperscript{{[}26{]}} \textsuperscript{{[}27{]}}

Patients in our study with 3D VCA \textless{} 0.55
cm\textsuperscript{2}had a very low likelihood of being categorized as
MVPt+ with a calculated negative predictive value of 98\%. Herein,
occurrence of leaflet tethering is a specific marker for severe MR (3D
VCA \selectlanguage{english}[?]0.55 cm\textsuperscript{2}) within MVP patients.

\textbf{Clinical Implications}

The concept that secondary leaflet tethering is a significant mechanism
behind severe degenerative mitral regurgitation has several clinical
consequences. First of all, our study corroborated a pathophysiologic
rationale for early surgical repair. Secondly, emphasis may be given to
leaflet tethering quantification for MVP patients during the routine
echocardiographic evaluation as to assist in MR severity grading and
risk stratification. Finally, MV repair for PML prolapse is an
established procedure\textsuperscript{{[}1{]}}, whereas studies
regarding MV repair for MVPt+ patients are sparse. Otani et al.
demonstrated that MV repair for MVPt+ patients alleviate leaflet
tethering and even restore it to normal range, reflecting a favorable
surgical result. \textsuperscript{{[}8{]}} Sakaguchi et al. reported
leaflet tethering in MVP could pose challenge to surgical repair as a
risk factor for MR occurrence.\textsuperscript{{[}9{]}} As the above
studies were limited with small sample size, whether secondary leaflet
tethering in MVP impacts the result of MV repair or whether it could be
a complementary therapeutic target should be further investigated in a
larger patient group.

\textbf{Limitations}

First of all, this is a cross-sectional study without longitudinal
follow-up. To fully understand the prognostic role of leaflet tethering
in patients with MVP, follow-up studies in valvular determinants for the
adverse outcome should be carried out. In addition, the study sample,
featuring with a majority of FED etiology, presence of symptoms, is
derived from patients enrolled in a multicenter registry to assess
suitability for transcatheter edge-to-edge repair. Thus, selection bias
cannot be ruled out in the present study. The majority presented
symptomatic severe mitral regurgitation requiring MV surgery. Finally,
as is previously described, the last-systolic frame was chosen to
analyze 3D morphological parameters as it typically presented the
largest prolapse magnitude and the minimal tenting magnitude.

\textbf{Conclusion}

In MVP patients, tenting volume index, an indicator of leaflet
tethering, is strongly associated with MR severity, giving rise to an
MVP with secondary leaflet tethering phenotype featuring more advanced
morphological and hemodynamical characteristics\textbf{.} Whether
secondary leaflet tethering in MVP impacts the result of surgical repair
or whether it could be a complementary therapeutic target should be
further investigated in a larger patient group.

\textbf{Acknowledgements}

The data supporting this study are available on request from the
corresponding author. The protocol of this study was approved by the
institutional review board of Zhongshan Hospital. Written informed
consent was obtained at the time of consent for the clinical TEE
procedure in all of the patients.

\textbf{Data Available Statement}

Data Are available upon request from the authors.

\textbf{Funding Statement:} This work was supported in part by the
Shanghai Municipal Health Commission (N0. 202140291), the Clinical
Research Plan of Shanghai Hospital Development Center (Grant No.
SHDC2020CR4071) and the Youth Fund Program in Zhongshan Hospital, Fudan
University (Grant No.2021ZSQN16 \& 2021-006ZP)

\textbf{Conflict of Interest: None}

\textbf{Reference}

{[}1{]} Adams D H, Rosenhek R, Falk V. Degenerative mitral valve
regurgitation: best practice revolution {[}J{]}. Eur Heart J, 2010,
31(16): 1958-66.

{[}2{]} Zoghbi W A, Adams D, Bonow R O, et al. Recommendations for
Noninvasive Evaluation of Native Valvular Regurgitation A Report from
the American Society of Echocardiography Developed in Collaboration with
the Society for Cardiovascular Magnetic Resonance {[}J{]}. J Am Soc
Echocardiog, 2017, 30(4): 303-71.

{[}3{]} Grayburn P A, Berk M R, Spain M G, et al. Relation of
echocardiographic morphology of the mitral apparatus to mitral
regurgitation in mitral valve prolapse: Assessment by Doppler color flow
imaging {[}J{]}. Am Heart J, 1990, 119(5): 1095-102.

{[}4{]} Enriquez-Sarano M, Basmadjian A-J, Rossi A, et al. Progression
of mitral regurgitation A prospective Doppler echocardiographic study
{[}J{]}. J Am Coll Cardiol, 1999, 34(4): 1137-44.

{[}5{]} Uretsky S, Supariwala A, Nidadovolu P, et al. Quantification of
left ventricular remodeling in response to isolated aortic or mitral
regurgitation {[}J{]}. J Cardiov Magn Reson, 2010, 12(1): 32.

{[}6{]} Clavel M-A, Mantovani F, Malouf J, et al. Dynamic phenotypes of
degenerative myxomatous mitral valve disease: quantitative 3-dimensional
echocardiographic study {[}J{]}. Circulation Cardiovasc Imaging, 2015,
8(5): e002989.

{[}7{]} Lee A P-W, Hsiung M C, Salgo I S, et al. Quantitative Analysis
of Mitral Valve Morphology in Mitral Valve Prolapse With Real-Time
3-Dimensional Echocardiography {[}J{]}. Circulation, 2013, 127(7):
832-41.

{[}8{]} Otani K, Takeuchi M, Kaku K, et al. Evidence of a Vicious Cycle
in Mitral Regurgitation With Prolapse {[}J{]}. Circulation, 2012,
126(11\_suppl\_1): S214-S21.

{[}9{]} Sakaguchi T, Kagiyama N, Toki M, et al. Residual Mitral
Regurgitation After Repair for Posterior Leaflet Prolapse-Importance of
Preoperative Anterior Leaflet Tethering {[}J{]}. J Am Heart Assoc, 2018,
7(11).

{[}10{]} Oguz D, Eleid M F, Dhesi S, et al. Quantitative
Three-Dimensional Echocardiographic Correlates of Optimal Mitral
Regurgitation Reduction during Transcatheter Mitral Valve Repair
{[}J{]}. J Am Soc Echocardiogr, 2019, 32(11): 1426-35 e1.

{[}11{]} Ge Z, Pan W, Li W, et al. Impact of Leaflet Tethering on
Residual Regurgitation in Patients With Degenerative Mitral Disease
After Interventional Edge-to-Edge Repair {[}J{]}. Front Cardiovasc Med,
2021, 8: 647701.

{[}12{]} Saito K, Okura H, Watanabe N, et al. Influence of Chronic
Tethering of the Mitral Valve on Mitral Leaflet Size and Coaptation in
Functional Mitral Regurgitation {[}J{]}. Jacc Cardiovasc Imaging, 2012,
5(4): 337-45.

{[}13{]} Kagiyama N, Hayashida A, Toki M, et al. Insufficient Leaflet
Remodeling in Patients With Atrial Fibrillation {[}J{]}. Circulation
Cardiovasc Imaging, 2018, 10(3): e005451.

{[}14{]} Ge Z, Pan W, Zhou D, et al. Effect of a novel transcatheter
edge-to-edge repair device on the three-dimensional geometry of mitral
valve in degenerative mitral regurgitation {[}J{]}. Catheter Cardiovasc
Interv, 2021, 97(1): 177-85.

{[}15{]} Malkowski M J, Boudoulas H, Wooley C F, et al. Spectrum of
structural abnormalities in floppy mitral valve echocardiographic
evaluation {[}J{]}. Am Heart J, 1996, 132(1): 145-51.

{[}16{]} Delling F N, Kang L L, Yeon S B, et al. CMR Predictors of
Mitral Regurgitation in Mitral Valve Prolapse {[}J{]}. Jacc Cardiovasc
Imaging, 2010, 3(10): 1037-45.

{[}17{]} El-Tallawi K C, Kitkungvan D, Xu J, et al. Resolving the
Disproportionate Left Ventricular Enlargement in Mitral Valve Prolapse
Due to Barlow Disease Insights From Cardiovascular Magnetic Resonance
{[}J{]}. Jacc Cardiovasc Imaging, 2021, 14(3): 573-84.

{[}18{]} Gaasch W H, Meyer T E. Left Ventricular Response to Mitral
Regurgitation {[}J{]}. Circulation, 2008, 118(22): 2298-303.

{[}19{]} Morningstar J E, Gensemer C, Moore R, et al. Mitral Valve
Prolapse Induces Regionalized Myocardial Fibrosis {[}J{]}. J Am Heart
Assoc, 2021, 10(24): e022332.

{[}20{]} Kitkungvan D, Nabi F, Kim R J, et al. Myocardial Fibrosis in
Patients With Degenerative Mitral Regurgitation With and~Without
Prolapse {[}J{]}. J Am Coll Cardiol, 2018, 72(8): 823-34.

{[}21{]} Otsuji Y, Kumanohoso T, Yoshifuku S, et al. Isolated annular
dilation does not usually cause important functional mitral
regurgitation Comparison between patients with lone atrial fibrillation
and those with idiopathic or ischemic cardiomyopathy {[}J{]}. J Am Coll
Cardiol, 2002, 39(10): 1651-6.

{[}22{]} Lee A P-W, Jin C-N, Fan Y, et al. Functional Implication of
Mitral Annular Disjunction in Mitral Valve Prolapse A Quantitative
Dynamic 3D Echocardiographic~Study {[}J{]}. Jacc Cardiovasc Imaging,
2017, 10(12): 1424-33.

{[}23{]} Tang Z, Fan Y-T, Wang Y, et al. Mitral Annular and Left
Ventricular Dynamics in Atrial Functional Mitral Regurgitation: A
Three-Dimensional and Speckle-Tracking Echocardiographic Study {[}J{]}.
J Am Soc Echocardiog, 2019, 32(4): 503-13.

{[}24{]} Ormiston J A, Shah P M, Tei C, et al. SIZE AND MOTION OF THE
MITRAL-VALVE ANNULUS IN MAN .1. A TWO-DIMENSIONAL ECHOCARDIOGRAPHIC
METHOD AND FINDINGS IN NORMAL SUBJECTS {[}J{]}. Circulation, 1981,
64(1): 113-20.

{[}25{]} Komoda T, Hetzer R, Oellinger J, et al. Mitral Annular
Flexibility {[}J{]}. J Cardiac Surg, 1997, 12(2): 102-9.

{[}26{]} Detaint D, Messika-Zeitoun D, Avierinos J-F o, et al. B-Type
Natriuretic Peptide in Organic Mitral Regurgitation {[}J{]}.
Circulation, 2005, 111(18): 2391-7.

{[}27{]} Pizarro R, Bazzino O O, Oberti P F, et al. Prospective
Validation of the Prognostic Usefulness of Brain Natriuretic Peptide in
Asymptomatic Patients With Chronic Severe Mitral Regurgitation {[}J{]}.
J Am Coll Cardiol, 2009, 54(12): 1099-106.

Table 1 Determinants of Severity of Mitral Regurgitation (3D Vena
Contracta Area)\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Variables & Univariable & Univariable & Multivariable & Multivariable &
Multivariable\tabularnewline
\midrule
\endhead
& \selectlanguage{greek}β & P Value & \selectlanguage{greek}β & P Value & Partial
R\textsuperscript{2}\tabularnewline
Annular Area index & 0.396 & 0.000 & -0.142 & 0.314 &
-0.110\tabularnewline
Prolapse Volume index & 0.214 & 0.050 & 0.391 & 0.000 &
0.390\tabularnewline
Tenting Volume index & 0.464 & 0.000 & 0.585 & 0.000 &
0.562\tabularnewline
PVi + TVi & 0.243 & 0.026 & 0.163 & 0.074 & -0.190\tabularnewline
AHCWR & -0.262 & 0.017 & -0.167 & 0.067 & -0.184\tabularnewline
\bottomrule
\end{longtable}

Univariate and multivariate linear regression analyses were performed.

Table 2 Clinical and two-Dimensional Echocardiographic Characteristics\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Control (N=20)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
MVPt- (N=63)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
MVPt+ (N=31)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P-Value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age, years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66.5 (8.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
74.1 (6.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
73.7 (6.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Men, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11(55)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25 (40)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13 (42)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
BSA, m\textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.7 (0.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.5 (0.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.6 (0.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
NYHA, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23 (100.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0(0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0(0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0(0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15 (23.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 (12.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0(0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
39 (61.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (64.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0(0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9 (14.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 (22.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
NT-proBNP\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
885.2\selectlanguage{ngerman}±1298.76\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1870.35\selectlanguage{ngerman}±2266.97\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
VCA, cm\textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0 (0.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.6 (0.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.9 (0.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVEDVi, mL/m\textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
46.1 (10.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
72.3 (15.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
86.4 (22.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVESVi, mL/m\textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
17.5 (4.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
28.2 (10.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
35.0 (14.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVEF, \%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
63.2 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60.4 (11.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56.4 (17.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.13\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
VCW, mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0 (0.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8.9 (2.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8.8 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Etiology, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.274\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
FED\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55 (87)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30 (97)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Barlow\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Flail, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0(0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
46 (73.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (93.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Flail width, mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0 (0.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.8 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12.5 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Flail gap, mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0 (0.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.3 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9.2 (2.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AML length, mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21.6 (3.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24.5 (3.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25.6 (3.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.001*\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
PML length, mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.9 (1.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16.5 (3.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18.1 (3.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AP diameter(2D), mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30.3 (6.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33.3 (4.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36.0 (3.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVEDD, mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
46.2 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
52.1 (4.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55.1 (5.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVESD, mm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29.3 (3.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31.7 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
35.4 (6.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LAA, cm\textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18.0 (5.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29.1 (8.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33.0 (9.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001*\textbar{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
sPAP, mmHg\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
51.8\selectlanguage{ngerman}±18.9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60.8\selectlanguage{ngerman}±17.5\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.052\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

AML, anterior mitral leaflet; PML, posterior mitral leaflet; FED,
fibroelastic deficiency; BD, barlow disease; LVEDVi, left ventricular
end-diastolic volume index; LVESVi, left ventricular end-systolic volume
index; LVEF, left ventricular ejection fraction; VCW, vena contracta
width; sPAP, systolic pulmonary artery pressure; LAA, left atrial area.
* P \textless{} 0.05 for MVPt- versus control, \textbar{} P \textless{}
0.05 for MVPt+ versus control, \selectlanguage{ngerman}¶ P \textless{} 0.05 for MVPt+ versus
MVPt-.

Table 3 3D Geometry of Mitral Complex in healthy controls, MVPt- and
MVPt+ patients\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& Control (n=20) & MVPt- (n=63) & MVPt+ (n=31) & ANOVA\tabularnewline
\midrule
\endhead
ALPMi, mm/m\textsuperscript{2} & 20.2 (2.1) & 23.0 (3.0) & 24.5 (3.1) &
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\tabularnewline
APi, mm/m\textsuperscript{2} & 18.5 (2.1) & 21.2 (2.6) & 23.1 (2.7) &
\textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\tabularnewline
Annular Height, mm & 5.6 (1.4) & 6.3 (1.7) & 6.6 (1.6) &
0.142\textbar{}\tabularnewline
AAi, mm\textsuperscript{2}/m\textsuperscript{2} & 494.6 (79) & 616.5
(109.6) & 734.7 (128.1) & \textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\tabularnewline
AML Angle, \selectlanguage{english}* & 19.1 (6.7) & 16.7 (6.5) & 24.8 (5.0) &
\textless{}0.001\selectlanguage{ngerman}¶\textbar{}\tabularnewline
PML Angle, \selectlanguage{english}* & 25.0 (6.3) & 23.9 (7.4) & 31.0 (5.6) &
\textless{}0.001\selectlanguage{ngerman}¶\textbar{}\tabularnewline
THi, mm\textsuperscript{2}/m\textsuperscript{2} & 2.3 (0.7) & 2.6 (1.1)
& 4.8 (1.4) & \textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\tabularnewline
PHi, mm\textsuperscript{2}/m\textsuperscript{2} & 0.8 (0.5) & 3.6 (1.7)
& 2.9 (1.5) & \textless{}0.001*\textbar{}\tabularnewline
TVi, mL/m\textsuperscript{2} & 0.4 (0.2) & 0.4 (0.2) & 1.2 (0.4) &
\textless{}0.001\selectlanguage{ngerman}¶\textbar{}\tabularnewline
PVi, mL/m\textsuperscript{2} & 0.1 (0.1) & 0.4 (0.3) & 0.3 (0.3) &
\textless{}0.001*\textbar{}\tabularnewline
ACi, mm\textsuperscript{2}/m\textsuperscript{2} & 61.0 (6.1) & 73.0
(8.3) & 78.7 (9.4) & \textless{}0.001*\selectlanguage{ngerman}¶\textbar{}\tabularnewline
Ellipticity, (\%) & 115.2 (11.3) & 109.1 (10.7) & 106.4 (8.4) &
0.008*\textbar{}\tabularnewline
TVi + PVi, mL/m\textsuperscript{2} & 0.4 (0.1) & 0.9 (0.5) & 1.1 (0.5) &
\textless{}0.001*\textbar{}\tabularnewline
AHCWR (\%) & 16.2 (4.3) & 18.2(5.3) & 17.3(4.0) & 0.117\tabularnewline
\bottomrule
\end{longtable}

ALPM, anterior-lateral/posterior-medial diameter index; AP,
anterior--posterior diameter index; THi, tenting height index; PHi,
prolapse volume index; TVi, tenting volume index; PVi, prolapse volume
index; ACi, annular circumference index; AML, anterior mitral leaflet;
PML, posterior mitral leaflet

\textbf{Figure 1} 3D parametric models (D) of patient's mitral valve by
MVN analysis. Three orthogonal mitral annulus images, including
two-chamber view (A), long-axis view (B) and short-axis view (C)were
displayed and subsequently used to model the entire annulus and mitral
valve.

\textbf{Figure 2} A: Scatterplots demonstrating the distribution of
tenting volume index among healthy controls and MVP patients and the
cutoff value of 0.7 mL/m\textsuperscript{2} (horizontal dashed line) to
distinguish the occurrence of secondary leaflet tethering in MVP
patients. B to E: Histograms comparing the tenting volume index (B),
annular area index, prolapse volume index and AHCWR between the healthy
controls, MVPt- and MVP+ group.

\textbf{Figure 3} Correlations of tenting volume index with NT-proBNP
and 3D VCA. The scatterplot demonstrates a mild correlation between
tenting volume index and NT-proBNP (A) and 3D VCA (B). C: ROC curve for
3D VCA to predict the occurrence of secondary leaflet tethering.

\textbf{Figure 4} Illustrative examples of mitral valve prolapse
patients without and with secondary leaflet tethering. A mitral valve
prolapse patients without secondary leaflet tethering (PVi = 0.69
mL/m\textsuperscript{2}, tenting volume index = 0.19
mL/m\textsuperscript{2}, VCA = 0.32 cm\textsuperscript{2}) B and C
mitral valve prolapse patients with secondary leaflet tethering and
larger regurgitant orifices. Case B PVi =0.02 mL/m\textsuperscript{2},
tenting volume index = 1.46 mL/m\textsuperscript{2}, VCA = 0.95
cm\textsuperscript{2}; Case C PVi = 0.25 mL/m\textsuperscript{2},
tenting volume index = 2.2 mL/m\textsuperscript{2}, VCA = 1.48
cm\textsuperscript{2})

\textbf{Figure 1}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}



\textbf{Figure 2}

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/612415/articles/640321-secondary-leaflet-tethering-in-patients-with-degenerative-mitral-regurgitation-and-its-association-with-the-severity-of-mitral-regurgitation}



\textbf{Figure 3}

\textbf{Hosted file}

\verb`image3.emf`  available at \url{https://authorea.com/users/612415/articles/640321-secondary-leaflet-tethering-in-patients-with-degenerative-mitral-regurgitation-and-its-association-with-the-severity-of-mitral-regurgitation}

\textbf{Figure 4}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

