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\begin{document}

\title{Dimensionless Index of the Mitral Valve for Evaluation of Degenerative
Mitral Stenosis}



\author[1]{Ahmet Afsin Oktay}%
\author[1,2]{Russell Riehl}%
\author[1]{Sergey Kachur}%
\author[1]{Zahoor Khan}%
\author[1]{Vinod Chainani}%
\author[3]{Michael Cash}%
\author[3]{Sangeeta Shah}%
\author[3]{Carl Lavie}%
\author[4]{Daniel Morin}%
\author[3]{Yvonne Gilliland}%
\author[1]{Salima Qamruddin}%
\affil[1]{Ochsner Heart and Vascular Institute}%
\affil[2]{Baylor College of Medicine}%
\affil[3]{Ochsner Medical Center}%
\affil[4]{Ochsner Medical Center - New Orleans}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\selectlanguage{english}
\begin{abstract}
Purpose: Degenerative mitral stenosis (DMS) is an increasingly
recognized cause of mitral stenosis. The goal of this study was to
compare echocardiographic differences between DMS and rheumatic mitral
stenosis (RMS), identify echocardiographic variables reflective of DMS
severity, and propose a dimensionless mitral stenosis index (DMSI) for
assessment of DMS severity. Methods: This is a single-center,
retrospective cohort study. We included patients with at least mild MS
and a mean transmitral pressure gradient (TMPG) [?] 4 mmHg. Mitral valve
area by the continuity equation (MVACEQ) was used as an independent
reference. The DMSI was calculated as follows: DMSI = VTILVOT / VTIMV.
All-cause mortality data were collected retrospectively. Results: A
total of 64 patients with DMS and 24 patients with RMS were identified.
MVACEQ was larger in patients with DMS (1.43 ? 0.4 cm2) than RMS (0.9 ?
0.3 cm2) by \textasciitilde{}0.5 cm2 (p = \textless{}0.001) and mean
TMPG was lower in the DMS group (6.0? 2 vs. 7.9?3 mmHg, p=0.003). A DMSI
of ? 0.50 and [?] 0.351 were associated with MVACEQ [?] 1.5 and MVACEQ [?] 1.0
cm2 (p\textless{}0.001), respectively. With the progression of DMS from
severe to very severe, there was a significant drop in DMSI. There was a
non-significant trend towards worse survival in patients with MVACEQ [?]
1.0 cm2 and DMSI [?] 0.35, suggesting severe stenosis severity.
Conclusion: Our results show that TMPG correlates poorly with MVA in
patients with DMS. Proposed DMSI may serve as a simple echocardiographic
indicator of hemodynamically significant DMS.%
\end{abstract}%



\sloppy


\emph{}

\emph{Introduction:}

Calcification of the mitral valve (MV) annulus and leaflets is an
increasingly common cause of MV stenosis
(MS).\textsuperscript{1,2}Mitral annular calcification (MAC) has four
principal pathophysiological mechanisms: degeneration, atherosclerosis,
increased MV stress, and abnormal calcium phosphate
metabolism.\textsuperscript{3} These processes lead to dystrophic
calcification, increased lipid peroxidation, and chronic expression of
transforming growth factor-\selectlanguage{greek}β \selectlanguage{english}and inflammatory cytokines that promote
phenotypic trans-differentiation of valvular interstitial cells into
osteoblast-like cells.\textsuperscript{3--5} These microscopic changes
can eventually cause the macroscopic changes seen with MAC, including a
larger, flatter annulus with reduced mitral annular dynamism throughout
the cardiac cycle.\textsuperscript{6} As the disease process continues,
the dystrophic calcification extends into the left ventricular (LV)
inflow tract and onto the MV leaflets, thereby obstructing LV inflow
(\textbf{Figure 1} ).\textsuperscript{7} This disease process has
increasingly been recognized as degenerative MS (DMS)

Current guidelines for the management of patients with valvular heart
disease define severe MS with a mitral valve area (MVA) [?] 1.5
cm\textsuperscript{2} independent of the etiology of MS. According to
the guidelines, severe stenosis usually corresponds to a mean
transmitral pressure gradient (TMPG) of 5 to 10 mmHg at normal heart
rates.\textsuperscript{8} It should be noted that these quantification
values have only been validated in patients with rheumatic MS (RMS) and
lack similar validation in DMS populations. The anatomic MVA of DMS can
be estimated with either electrocardiogram-gated multidetector cardiac
computed tomography or three-dimensional echocardiography, but their
availability is limited compared to that of two-dimensional
echocardiography. \textsuperscript{6,9--11}

Transthoracic echocardiography is widely available, but methods commonly
used for evaluating MS severity (\emph{i.e.,} planimetry, pressure
half-time, and color flow Doppler) have not been validated for DMS.
Planimetry is challenging due to difficulty with obtaining the correct
orientation of the image plane.\textsuperscript{11--13} The abnormal LV
compliance that frequently accompanies DMS decreases the accuracy of the
pressure-half time method and limits its
applicability.\textsuperscript{10} The applicability of color flow
Doppler to DMS is limited by the absence of flow contraction secondary
to the MV being distorted into a tubular
morphology.\textsuperscript{10,11,14} Continuity equation method is
usually limited in DMS due to the frequent co-occurrence of mitral
regurgitation (MR), aortic regurgitation, or atrial fibrillation in this
population.\textsuperscript{6} There is ample evidence to support the
TMPG as a surrogate for stenosis severity in RMS, but it is affected by
changes in valve morphology and abnormal atrioventricular compliance as
well as volume overload conditions such as end-stage renal disease
(ESRD), and hence may not be appropriate for
DMS.\textsuperscript{11,14--16}

The goals of this study were to compare echocardiographic
characteristics of DMS and RMS, identify echocardiographic variables
reflective of DMS stenosis severity, propose a dimensionless index of MS
(Dimensionless Mitral Stenosis Index, DMSI) to help with estimation of
DMS severity by transthoracic echocardiography, and examine the
prognostic determinants of all-cause mortality in patients with DMS.

\emph{Materials and Methods:}

This is a single-center, retrospective cohort study that was approved by
the Institutional Review Board at Ochsner Medical Center, New Orleans,
LA. This retrospective study involving human participants was in
accordance with the 1964 Helsinki Declaration and its later amendments
or comparable ethical standards.

Echocardiograms saved in the institutional database (Cardiovascular
Imaging System, New Orleans, LA) between 2007 and 2016 were screened
with the keywords of MS, MAC, rheumatic, or diastolic doming of the
anterior mitral valve leaflet. We obtained demographic and clinical data
from electronic medical records (EPIC, Verona, WI, USA), including age,
body mass index, gender, history of diabetes, hypertension, chronic
kidney disease (eGFR \textless{} 60 mL/min per 1.73
m\textsuperscript{2}), ESRD on dialysis, prior radiation exposure,
coronary artery disease defined by either history of acute coronary
syndrome or abnormal ischemic evaluation, and history of chronic heart
failure. Survival and mortality data were obtained retrospectively from
electronic medical records in July 2020.

Based on echocardiographic findings, DMS was defined in our study with
the presence of severe MAC that extends onto the leaflets causing
restricted leaflet mobility and LV inflow obstruction. Eligible studies
had at least mild MS reported by transthoracic echocardiogram with a
mean TMPG of [?] 4 mmHg. Patients with prior mitral balloon valvuloplasty,
ejection fraction \textless{} 50\%, heart rate [?] 100 bpm, severe aortic
stenosis, and more than mild MR or mild aortic regurgitation were
excluded. Patients with RMS who met inclusion and exclusion criteria
were used as the comparison group. A total of 64 patients with DMS and
24 patients with RMS met the initial inclusion criteria. We excluded
patients with ESRD (6 in DMS and 1 in RMS group) for analyses related to
valve area and pressure gradient because of possibly increased gradients
due to high flow state and volume overload.

Echocardiography studies were performed according to the American
Society of Echocardiography guidelines using either GE Vivid E9 and E95
ultrasound system (GE Vingmed, Horten, Norway) and reviewed and verified
by a Level III-trained echocardiographer.\textsuperscript{17--19} MAC
severity in the DMS cohort was scored as reported in Movva et
al.\textsuperscript{6} The MVA by continuity equation
(MVA\textsubscript{CEQ}) was used as the independent reference and
calculated with the following equation:
MVA\textsubscript{CEQ}(cm\textsuperscript{2}) = (LVOT
diameter)\textsuperscript{2} x 0.785 x (VTI\textsubscript{LVOT} /
VTI\textsubscript{MV}).\textsuperscript{11}.

Continuous-wave Doppler imaging of the MV from the apical four-chamber
view was used to obtain the peak and mean TMPG, as well as the
velocity-time integral (VTI) of the MV. Peak E (early diastolic
velocity), peak A (late diastolic velocity), and deceleration time were
measured with pulse wave Doppler of the MV inflow at the MV tips in the
apical four-chamber view during diastole. The LV outflow tract (LVOT)
diameter was measured in the parasternal long-axis view (inner edge of
the septal endocardium to the inner edge of the anterior mitral leaflet
in mid-systole). The LVOT VTI was measured by tracing the instantaneous
dense modal velocities throughout the systole of the LVOT pulse wave
Doppler sample taken 1 cm below the aortic valve in the apical long-axis
view. LVOT stroke volume (SV) was calculated with the following
equation: SV\textsubscript{LVOT} (cm\textsuperscript{3}) = 0.785 x
Diameter\textsubscript{LVOT}\textsuperscript{2} x
VTI\textsubscript{LVOT}. The DMSI was calculated as follows: DMSI =
VTI\textsubscript{LVOT} / VTI\textsubscript{MV} (\textbf{Figure 2} ).
Three cardiac cycles were averaged for Doppler-related calculations for
patients in sinus rhythm and five cardiac cycles for patients in atrial
fibrillation (AF). A level III trained echocardiographer repeated all of
the measurements for the study purposes. Two separate level-III trained
echocardiographers performed the interclass correlation analysis.

Statistical Analysis

We used SPSS statistical software for all analyses (IBM SPSS Statistics
for Macintosh, Version 20.0. Armonk, NY: IBM Corp.) with a two-sided P
value of less than 0.05 considered statistically significant. A
chi-squared test for association was conducted between MV disease (i.e.,
DMS or RMS) and each categorical/nominal variable; Fisher's exact test
was used instead if a variable had any expected cell frequencies less
than 5. The Shapiro-Wilks test was used to assess the normality of
continuous variables. Independent groups of continuous variables were
compared using Student's t-test if the variable had a normal
distribution or Mann-Whitney U test if the distribution failed to meet
this assumption. Mann-Whitney U tests were used to compare
MVA\textsubscript{CEQ} of DMS and RMS while controlling for mean TMPG.
DMS patients were stratified based on MVA\textsubscript{CEQ} ([?] 1.0
cm\textsuperscript{2}, 1.0 to 1.5 cm\textsuperscript{2}, \textgreater{}
1.5 cm\textsuperscript{2}) to account for the small sample size, and a
Kruskal-Wallis test was used to identify echocardiographic variables
significantly impacted by MVA\textsubscript{CEQ} stratification.
Echocardiographic variables were assessed using simple linear regression
analysis. A receiver operator characteristic (ROC) curve analysis was
created to determine the cutoff value of the DMSI value associated with
MVA\textsubscript{CEQ} [?] 1.5 cm\textsuperscript{2} and
MVA\textsubscript{CEQ} [?] 1.0 cm\textsuperscript{2}. Cox proportional
hazards models were constructed to examine the prognostic determinants
of all-cause mortality in patients with DMS.

\emph{Results:}

Baseline patient characteristics are given in \textbf{Table 1} .
Patients with DMS were older than RMS patients (77 \selectlanguage{ngerman}± 12 vs. 61 ± 15 y, p
\textless{} 0.001). Study subjects were predominantly females (80\% in
DMS vs. 83\% in RMS, p = 0.7). Patients with DMS had a higher prevalence
of hypertension (92\% vs. 70\% in RMS, p = 0.009) and chronic kidney
disease (53\% vs. 29\% in RMS, p = 0.045). There was a higher prevalence
of AF in the RMS group (38\% vs. 14\% in DMS, p = 0.034). Patients with
DMS had a lower mean TMPG (6.0±1.8 vs. 7.9±2.9, p\textless{}0.003) and a
larger MVA\textsubscript{CEQ} (1.4±0.4 vs. 0.98±0.3
cm\textsuperscript{2}) despite a similar LVOT SV (in the absence of
significant MR and aortic regurgitation) (\textbf{Table 2} ). After the
exclusion of patients with ESRD, there were 16 patients in the DMS group
with high LVOT flow defined as LVOT VTI \textgreater{}25 cm. Even after
the exclusion of high LVOT flow, the DMS group still had a larger
MVA\textsubscript{CEQ} (1.3±0.4 vs. 1.0±0.2 cm2, p\textless{}0.001) and
lower TMPG (5.6±2 vs. 8±3 mm HG, p=0.001) compared to RMS group.

The average of mean TMPG in all subjects was 6.3 mmHg. Patients with a
TMPG of \textgreater{} 6.3 mmHg (n=39), had a larger
MVA\textsubscript{CEQ} in the DMS group (n=24) than RMS group (n=14)
(1.4±0.4 vs. 0.8±0.2 cm\textsuperscript{2}, p= 0.001) (\textbf{Figure 3}
). The frequency of low flow state defined as SV index \textless{}35
ml/m\textsuperscript{2} was 41\% (n=24) and 43\% (n=10) in the DMS and
RMS groups, respectively (p=0.8). TMPG was significantly lower in the
DMS group irrespective of the SV index (\textbf{Table 2} ). We
stratified the echocardiographic variables by the presence of AF in the
DMS group. No significant in-between group differences (DMS patients
with AF versus without AF) were observed in mean TMPG (mean difference
-0.50 mmHg~{[}-1.9 - 0.90{]}, p~= 0.475), LVOT SV (mean difference -7.2
ml {[}-17.1 - 2.0{]}, p~= 0.122), and DMSI (mean difference
0.02~{[}-0.06~-~0.87{]}, p~= 0.705).

We stratified DMS patients by MVA\textsubscript{CEQ} to understand the
association of MS severity with other echocardiographic variables
(\textbf{Table 3} ). There was a statistically significant gradual
increase in E velocity with worsening MS severity defined by
MVA\textsubscript{CEQ}. However, A velocity and E/A ratio did not
correlate with MS severity. There was a statistically significant
difference in DMSI between all three groups, and it progressively got
smaller with severe stenosis.

DMSI accounted for 79\% of the variation in
MVA\textsubscript{CEQ}(\textbf{Table 4, Figure 4A} ), whereas the mean
TMPG accounted for only 8\% of the variation in patients with DMS
(\textbf{Figure 4B} ). There was also no correlation between DMSI and
mean TMPG in the DMS group (\textbf{Figure 4C} ).

The ROC curve showed that a DMSI of \selectlanguage{english}[?] 0.50 was associated with
MVA\textsubscript{CEQ} \selectlanguage{english}[?] 1.5 cm\textsuperscript{2} (AUROC 0.971, p =
0.001) and DMSI of \selectlanguage{english}[?] 0.351 was associated with MVA\textsubscript{CEQ} \selectlanguage{english}[?]
1.0 cm\textsuperscript{2} (AUROC 0.965, p = 0.0001).

The interclass correlation (performed in 8 patients) for mean TMPG was
0.909 (CI 0.546 -- 0.982, p~\textless{} 0.001), for
MVA\textsubscript{CEQ} was 0.966~(CI 0.828 -- 0.993, p~\textless{}
0.001), and for DMSI was 0.980 (CI 0.899 -- 0.996, p~\textless{} 0.001)
suggesting excellent~reliability for all measurements. The inter-reader
variability for MVA\textsubscript{CEQ} was 13\%, mean TMPG was 14\%, and
DMSI was 7\%.

Survival and mortality data were available for all subjects in the DMS
group. 27 +-18 months of follow-up was available after the
echocardiography study used for study enrollment. The all-cause
mortality rate was 53\% in the DMS group and 41\% in the RMS group at an
average survival duration of 13 +- 14 vs. 34+-14 months after the
enrolment echocardiography. The Cox hazard regression model revealed
that the left atrial volume index and ESRD were independent predictors
of mortality in patients with DMS. Kaplan-Meier curve analysis showed a
non-significant trend towards worse survival when the cutoff values of
MVA\textsubscript{CEQ} \selectlanguage{english}[?] 1.0 cm\textsuperscript{2} and DMSI \selectlanguage{english}[?] 0.35 were
used (\textbf{Figure 5} ). Other echocardiographic parameters such as
MVA\textsubscript{CEQ} \selectlanguage{english}[?] 1.5 cm\textsuperscript{2}, mean TMPG
\textgreater{} 7 mmHg, or SV index \selectlanguage{english}[?] 0.35 did not predict mortality
risk.

\emph{Discussion:}

The results of our study suggest that TMPG correlates poorly with the
severity of MS in patients with DMS. Moreover, DMSI may be a viable
alternative for the evaluation of DMS. The potential inadequacy of mean
TMPG reported here agrees with previous
guidelines.\textsuperscript{2,17} However, our results note a
significant discordance between TMPG and MVA in DMS patients.
Differences in MV morphology and net atrioventricular compliance between
DMS and RMS may, in part, explain this observation. The flat plate
geometry caused by MAC, compared to the dome-shape of RMS, increases the
contraction coefficient.\textsuperscript{14} An increased contraction
coefficient causes a lower pressure drop across the valve, accounting
for the low transvalvular gradient.\textsuperscript{10,11,14} Also, risk
factors for an increased net atrioventricular compliance are much more
common in the patients with DMS than RMS.\textsuperscript{11,20--23} An
increased net atrioventricular compliance accelerates the rate of
transvalvular pressure decay, hence lowering the mean
TMPG.\textsuperscript{20,24} A recent study suggested the presence of
diastolic dysfunction as a potential cause of low TMPG in patients with
very severe RMS.\textsuperscript{25} The above factors may be
responsible for lower mean TMPG seen in DMS patients in our study. The
use of mean TMPG as an index for MS severity carries a 1B
recommendation, but it may not accurately reflect MS severity in the
setting of DMS.\textsuperscript{15--17}.

The patients in our RMS and DMS groups were similar to each other
regarding some of the hemodynamic (i.e., pulmonary artery systolic
pressure, SV index) and structural (i.e., left atrial volume index)
parameters. Despite this similarity between groups, DMS was associated
with a larger MVA and lower mean TMPG compared to RMS. Consistent with
our findings, Pressman et al. recently reported in a retrospective
cohort study that DMS is associated with a larger MVA relative to mean
TMPG when compared to RMS.\textsuperscript{26}

The DMSI proposed here denotes an increased velocity across the stenotic
MV relative of the LVOT velocity. Similar to the continuity equation,
the DMSI relies on the rule of conservation of mass. The strong
correlation between MVA\textsubscript{CEQ} and the DMSI relies on the
fact that the DMSI is a large component of the
MVA\textsubscript{CEQ}formula. Despite these similarities, this DMSI has
several theoretical advantages. It avoids the variability of the LVOT
cross-sectional area and reduces error risk driven by LVOT diameter
measurement and assumptions of LVOT shape. Thus, the index would be most
useful in cases with suboptimal visualization of the LVOT.

The DMSI is relatively flow independent in the absence of significant
valvular regurgitation. Therefore it would not be affected by the heart
rate or flow state. The concept of the velocity ratio was previously
described in the assessment of prosthetic aortic and mitral valve
stenoses.\textsuperscript{27--29} The former utilized the ratio of LVOT
VTI to prosthetic valve VTI with \textless{} 0.30 denoting severe
prosthetic aortic valve stenosis, and the latter utilized ratio of
mitral prosthesis VTI to LVOT VTI denoting \textgreater{} 2.5 as a
significant valve dysfunction.\textsuperscript{29} Furthermore, the
dimensionless index for the native aortic valve is calculated as a ratio
of LVOT VTI to aortic valve VTI. Moreover, an index of \textless{} 0.25
is consistent with severe aortic valve stenosis.

A recent study by Cho et al. including RMS patients with very severe MS
(MVA \selectlanguage{english}[?] 1 cm2) undergoing MV replacement showed that patients with low
mean TMPG (\selectlanguage{english}[?] 10 mmHg) were more likely to be older, and females, and
have diabetes or AF compared to those with high mean TMPG (\selectlanguage{english}[?]10
mmHg).\textsuperscript{25} The authors noted that this might be related
to higher atrial compliance and lower atrial pressure seen in RMS
patients. Interestingly, LV SV was higher in the low mean TMPG group in
the study mentioned above. The frequency of low-flow state (SV index
\textless{}35 ml/m\textsuperscript{2}) was similar in our DMS and RMS
groups. Therefore, between-group differences (mean TMPG and
MVA\textsubscript{CEQ}) observed in our study is unlikely to originate
from differences in flow-states. We did not perform further subgroup
analyses for patients with low-flow states because of the small sample
size. Cho et al. reported an association between AF and low mean TMPG in
patients with RMS.\textsuperscript{25} Absence of such a relationship in
our study might be due to the small number of patients with AF in our
DMS group (14\%).

Our study shows that mean TMPG does not correlate well with
MVA\textsubscript{CEQ} and that a practical tool such as DMSI proposed
in this study may serve as a simile echocardiographic parameter in the
identification of patients with significant DMS.

Our survival analysis indicated that patients with DMS have a poor
prognosis, and more than 50\% of the patients with DMS died over an
average of 13 months. The small sample size was a limitation for the
detailed evaluation of predictors of mortality among patients with DMS.
According to the cox-regression model, the left atrial volume index and
ESRD were the only two independent predictors of mortality among DMS
patients. A non-significant trend towards increased mortality risk was
observed with MVA\textsubscript{CEQ} \selectlanguage{english}[?] 1.0 cm\textsuperscript{2} and
DMSI \selectlanguage{english}[?] 0.35. Other echocardiographic parameters such as
MVA\textsubscript{CEQ} \selectlanguage{english}[?] 1.5 cm\textsuperscript{2}, mean TMPG
\textgreater{} 7 mmHg, or SV index \selectlanguage{english}[?] 0.35 did not predict mortality
risk.

Medical management of DMS includes heart rate control, and diuretic
therapy that may cause provide some symptomatic
relief.\textsuperscript{2} Surgical treatment for severe DMS is
significantly challenging due to older age of these patients with
multiple comorbidities.\textsuperscript{2} Emerging transcatheter
approach for mitral valve replacement is feasible, but further
advancement is needed to improve outcomes.\textsuperscript{30}

Limitations

This is a single-center study of MS patients obtained. The
generalizability of our results will require a multicenter study where
this new parameter can be validated. The study design diminishes the
reliability of results from linear regression modeling in this study.
Due to the small sample size, we had to use stratification to control
for confounding and could account for the effect of diastolic
dysfunction on the echocardiographic characteristics. There are
significant differences in the demographic profile of the two groups.
DMS group had a high frequency of chronic kidney disease and ESRD. We
excluded patients with ESRD and hyperdynamic LV from analysis to
minimize confounding.

Our study utilized the continuity equation method as an independent
standard. The continuity equation valve area in the DMS population was
comparable to that of 3-Dimensional MVA in one
study.\textsuperscript{10} The retrospective nature of our study
prevented us from using an alternative imaging modality to corroborate
these findings, which is a significant limitation.

In the presence of significant MR and aortic regurgitation, our results
may not be applicable. Therefore, DMSI should be avoided in the
assessment of stenosis severity if there is more than mild MR or AR.
Also, VTI can show beat-to-beat variability with irregular heart rhythm.
Thus, in the setting of cardiac arrhythmia, DMSI can only be reliable if
the average of multiple VTI values is used.

Our study included a limited number of DMS patients with AF. Therefore,
our results may not accurately capture the impact of AF on TMPG and
transmitral flow, both of which were shown to be affected by AF in RMS
patients.\textsuperscript{25} Given the retrospective nature of the
data, the ROC curves shown are the best-case scenario and that
association strength may be variable in a larger cohort of patients.
Also, there is a lack of validation of these cutoff values.

The presence of at least mild MS on the official echocardiography report
was an eligibility criterion for our study. Moreover, some interpreters
may avoid calling MS in the setting of MAC since these patients usually
have normal-appearing leaflet excursion on 2D echocardiography.
Therefore, our subjects might not represent the full spectrum of DMS. It
is also a limitation that men were underrepresented in our DMS and RMS
groups.

Conclusion

Our results suggest that TMPG correlates poorly with MVA in patients
with DMS. The DMSI, which denotes an increased velocity across the
stenotic MV relative of the LVOT velocity, may serve as a useful and
practical screening tool in the evaluation of DMS. Future studies using
multimodality imaging techniques and evaluating clinical outcomes are
needed to validate and further explore these findings.

\textbf{Author Contributions:}

\selectlanguage{polish}\textbf{Ahmet Afşin Oktay}\selectlanguage{english} : Conceptualization, writing -- original
draft, writing -- reviewing \& editing

\textbf{Russell Riehl} : Writing -- reviewing \& editing, formal
analysis, visualization

\textbf{Sergey Kachur} : Formal analysis, visualization

\textbf{Zahoor Khan} : Investigation, data curation

\textbf{Vinod Chainani:} Investigation, data curation

\textbf{Michael E. Cash:} Writing -- reviewing \& editing

\textbf{Sangeeta Shah:} Writing -- reviewing \& editing

\textbf{Carl J. Lavie:} Writing -- reviewing \& editing

\textbf{Daniel P. Morin:} Methodology, writing -- reviewing \& editing

\textbf{Yvonne E. Gilliland:} Methodology, writing -- reviewing \&
editing, supervision

\textbf{Salima Qamruddin:} Conceptualization, investigation,
methodology, writing -- reviewing \& editing, supervision, project
administration

\emph{References:}

1. Oktay AA, Gilliland YE, Lavie CJ, Ramee SJ, Parrino PE, Bates M, et
al. Echocardiographic Assessment of Degenerative Mitral Stenosis: A
Diagnostic Challenge of an Emerging Cardiac Disease. Curr Probl Cardiol.
2017/01/10. 2017;42(3):71--100.

2. Sud K, Agarwal S, Parashar A, Raza MQ, Patel K, Min D, et al.
Degenerative Mitral Stenosis: Unmet Need for Percutaneous Interventions.
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\emph{Figure Legends}

\textbf{Figure 1.} Transthoracic Echocardiogram showing severe Mitral
annular calcification (MAC) and Degenerative Mitral stenosis (DMS).
Parasternal Long axis (A) showing calcification of the posterior mitral
annulus (arrow) and color flow acceleration across the mitral valve;
Parasternal short axis (B) showing an extensive calcification of
posterior mitral annular ring (arrow); Apical 4 chamber view (C) shows
the extension of calcium on to the mitral valve leaflets (arrowheads)
causing restriction; Continuous wave doppler across Mitral valve (D)
shows a peak and mean gradient of 24 and 12 mmHg consistent with severe
degenerative Mitral stenosis)

\textbf{Figure 2.} DMSI (Dimensionless Mitral Stenosis Index) sample
calculation.

LVOT VTI (27 cm) / MV VTI (78 cm) = DMSI (0.35). LVOT-left ventricular
outflow tract; MV VTI-Mitral valve velocity time integral; DMSI-
Dimensionless Mitral Stenosis Index

\textbf{Figure 3} . MVA\textsubscript{CEQ} stratified by high (\selectlanguage{english}[?] 7 mmHg)
and low (\textless{} 7 mmHg) TMPG.

\textbf{Figure 4.}

\textbf{A.} Linear regression analysis of MVA\textsubscript{CEQ} as a
function of the DMSI in DMS patients

\textbf{B.} Linear regression analysis of MVA\textsubscript{CEQ} as a
function of the mean TMPG in DMS patients

C. Linear regression analysis of mean TMPG as a function of DMSI

\textbf{Figure 5.}

Kaplan-Meier survival curve using a cutoff value of \textless{} 1
cm\textsuperscript{2} for MVA\textsubscript{CEQ} (A) and \textless{}0.35
for DMSI (B) in patients with DMS.

\textbf{Hosted file}

\verb`DMS FIGURES 1.pptx`  available at \url{https://authorea.com/users/331473/articles/475084-dimensionless-index-of-the-mitral-valve-for-evaluation-of-degenerative-mitral-stenosis}

\textbf{Hosted file}

\verb`DMS FIGURES 2.pptx`  available at \url{https://authorea.com/users/331473/articles/475084-dimensionless-index-of-the-mitral-valve-for-evaluation-of-degenerative-mitral-stenosis}

\textbf{Hosted file}

\verb`DMS FIGURES 3.pptx`  available at \url{https://authorea.com/users/331473/articles/475084-dimensionless-index-of-the-mitral-valve-for-evaluation-of-degenerative-mitral-stenosis}

\textbf{Hosted file}

\verb`DMS FIGURES 4.pptx`  available at \url{https://authorea.com/users/331473/articles/475084-dimensionless-index-of-the-mitral-valve-for-evaluation-of-degenerative-mitral-stenosis}

\textbf{Hosted file}

\verb`DMS FIGURES 5.pptx`  available at \url{https://authorea.com/users/331473/articles/475084-dimensionless-index-of-the-mitral-valve-for-evaluation-of-degenerative-mitral-stenosis}

\selectlanguage{english}
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