Valvular Heart Disease
Quantitative Analysis of Mitral Valve Morphology in Mitral
Valve Prolapse With Real-Time 3-Dimensional Echocardiography
Importance of Annular Saddle Shape in the Pathogenesis of
Mitral Regurgitation
Alex Pui-Wai Lee, MBChB; Ming C. Hsiung, MD; Ivan S. Salgo, MD; Fang Fang, MD, PhD;
Jun-Min Xie, MD, PhD; Yan-Chao Zhang, MD; Qing-Shan Lin, MD; Jen-Li Looi, MBChB;
Song Wan, MD, PhD; Randolph H.L. Wong, MBChB; Malcolm J. Underwood, MD;
Jing-Ping Sun, MD; Wei-Hsian Yin, MD; Jeng Wei, MD; Shen-Kou Tsai, MD; Cheuk-Man Yu, MD
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Background—Few data exist on the relation of the 3-dimensional morphology of mitral valve and degree of mitral
regurgitation (MR) in mitral valve prolapse.
Methods and Results—Real-time 3-dimensional transesophageal echocardiography of the mitral valve was acquired in
112 subjects, including 36 patients with mitral valve prolapse and significant MR (≥3+; MR+ group), 32 patients with
mitral valve prolapse but no or mild MR (≤2+; MR− group), 12 patients with significant MR resulting from nonprolapse
pathologies (nonprolapse group), and 32 control subjects. The 3-dimensional geometry of mitral valve apparatus was
measured with dedicated quantification software. Compared with the normal and MR− groups, the MR+ group had more
dilated mitral annulus (P<0.0001), a reduced annular height to commissural width ratio (AHCWR) (P<0.0001) indicating
flattening of annular saddle shape, redundant leaflet surfaces (P<0.0001), greater leaflet billow volume (P<0.0001) and
billow height (P<0.0001), longer lengths from papillary muscles to coaptation (P<0.0001), and more frequent chordal
rupture (P<0.0001). Prevalence of chordal rupture increased progressively with annulus flattening (7% versus 24% versus
42% for AHCWR >20%, 15%--20%, and <15%, respectively; P=0.004). Leaflet billow volume increased exponentially
with decreasing AHCWR in patients without chordal rupture (r2=0.66, P<0.0001). MR severity correlated strongly
with leaflet billow volume (r2=0.74, P<0.0001) and inversely with AHCWR (r2=0.44, P<0.0001). In contrast, annulus
dilatation but not flattening occurred in nonprolapse MR patients. An AHCWR <15% (odds ratio=7.1; P=0.0004) was
strongly associated with significant MR in mitral valve prolapse.
Conclusion—Flattening of the annular saddle shape is associated with progressive leaflet billowing and increased frequencies of
chordal rupture and may be important in the pathogenesis of MR in mitral valve prolapse. (Circulation. 2013;127:832-841.)
Key Words: echocardiography, three-dimensional ◼ mitral valve ◼ mitral valve insufficiency
◼ mitral valve prolapse
M
itral valve prolapse (MVP) is a common disorder with a
variable clinical course that is determined by the presence
and magnitude of mitral regurgitation (MR).1 Given the prognostic
implication of MR, identification of factors associated with
progression is important for risk stratification and surgical decision
making. Conventional 2-dimensional tomographic imaging has
shown that the progression of MR is determined primarily by the
degree of deformation of valvular structure.2–4 However, the mitral
valve has a complex 3-dimensional (3D) morphology that may not
be completely assessed with 2-dimensional imaging techniques. In
particular, the normal mitral annulus has a nonplanar saddle shape
that has been suggested to be important for alleviating mechanical
stress on mitral leaflets and chordae tendinae imposed by left
ventricular pressure.5,6 Moreover, the geometry of leaflet surface
and coaptation, magnitude of leaflet billowing, and deformation
of subvalvular structures are important morphological features
of MVP that cannot be adequately assessed with 2-dimensional
tomographic imaging.
Editorial see p 766
Clinical Perspective on p 841
With the advances of real-time 3D transesophageal echocardiography (RT3DE), high-resolution, full-volume imaging
Received May 21, 2012; accepted December 7, 2012.
From the Li Ka Shing Institute of Health Sciences (A.P.-W.L., F.F., J.-M.X., Y.-C.Z., Q.-S.L., J.-L.L., J.-P.S., C.-M.Y.) and Division of Cardiothoracic
Surgery, Department of Surgery (S.W., R.H.L.W., M.J.U.), Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong SAR; Division of
Cardiology, Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan (M.C.H., W.-H.Y., J.W., S.-K.T.); Philips Healthcare, Andover, MA (I.S.S.); and
Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan (W.-H.Y.).
Correspondence to Cheuk-Man Yu, MD, Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Li Ka Shing
Institute of Health and Sciences, Chinese University of Hong Kong, Hong Kong. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.112.118083
832
Lee et al 3D Echocardiographic Morphology of Mitral Valve Prolapse 833
and quantification of morphology of the entire mitral apparatus have become feasible.7–9 More recently, systolic deepening
of the annular saddle shape has been shown to be decreased
in MVP.10 Furthermore, topographical assessment of leaflet
geometry in patients with MVP allows accurate diagnostic
evaluation of the degree of leaflet billowing and anticipated
complexity of repair.9 RT3DE study of leaflet surface geometry has led to a new understanding of the pathogenesis of
functional MR.11 To date, few data exist on the relation of
3D morphology of the mitral valve to the degree of MR in
MVP. Therefore, we undertook a prospective transesophageal
RT3DE study in patients with MVP, comparing the 3D mitral
valve morphology associated with clinically significant MR
and that associated with no or mild MR, as well as normal reference subjects. We sought to identify 3D echocardiographic
factors associated with MR in patients with MVP.
Methods
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Patient Population
A total of 100 subjects, including 68 consecutive patients with MVP
and 32 control subjects referred for transesophageal echocardiography, were prospectively studied. MVP was identified on echocardiography as systolic displacement (>2 mm) of 1 or both mitral
leaflets into the left atrium, below the plane of mitral annulus, as
indicated in the parasternal long-axis view. The indications of referral for transesophageal echocardiography included determination of
regurgitation severity, evaluation of suitability of valve repair, suboptimal transthoracic images, exclusion of endocarditis, and evaluation of cardiac source of embolic event. Exclusion criteria included
contraindications to transesophageal echocardiography and the presence of mitral stenosis, aortic valve disease, pericardial or congenital
diseases, endocarditis, and cardiomyopathy. Patients with clinically
significant MR (defined as ≥3+; MR+ group) were compared with
those with no or mild MR (≤2+; MR− group). Patients referred for
transesophageal echocardiography and found to have no underlying
structural cardiac disease or arrhythmia were included as the normal
reference. The annular geometry of a nonprolapse group (n=12) referred for transesophageal echocardiography and found to have significant MR (≥3+) as a result of nonprolapse leaflet pathologies was
examined to see whether any annular flattening effect observed in the
MVP groups is specific to prolapse pathology or nonspecifically associated with the annulus-dilating effect of MR. The local Institutional
Review Board approved the study. Written informed consent was obtained from all subjects.
Imaging
Transesophageal RT3DE of the mitral valve was performed with an
iE33 ultrasound system (Philips Healthcare, Andover, MA) equipped
with a fully sampled matrix transducer (X7-2t). Zoomed RT3DE
images of the entire mitral complex, including annulus, leaflets,
papillary muscles, and aortic valve, were then acquired. The region
of interest was adjusted to the smallest pyramidal volume that encompassed the entire mitral complex to maximize frame rates (>20
Hz). Acquisition of 3D data sets was repeated several times to ensure optimal image quality without stitching artifact. Left ventricular
ejection fraction and end-systolic and end-diastolic dimensions were
determined following the American Society of Echocardiography
recommendations.12 The effective regurgitant orifice (ERO) of MR
was quantified by the proximal isovelocity surface area method.13 In
eccentric flow convergence patients, correction for flow constraint
was performed, multiplying ERO by the ratio of the angle formed by
the walls adjacent to the regurgitant orifice and 180°. Clinically significant MR (≥3+) was defined as ERO ≥0.3cm2 and mild MR (≤2+)
as ERO ≤0.29 cm.2 An ERO ≥0.4cm2 signified grade 4+ MR. In addition, supportive parameters, including jet area, continuous-wave
Doppler jet configuration, pulsed-wave Doppler transmitral flow, and
pulmonary venous flow, were examined as an integrative approach
to the evaluation of MR severity as recommended.13 Criteria for the
diagnosis of ruptured chordae tendinae included a fluctuating chordae
in the left atria1 cavity during systole manifested by a linear echo
with high-frequency fluttering in association with a flail leaflet segment. The latter was defined as a portion of a leaflet edge with erratic
motion and consistent loss of coaptation.
Mapping of 3D Morphology of Mitral Valve
Images were analyzed offline on an Xcelera workstation (Philips
Healthcare) by an investigator (A.P.L.). The quantitative morphological analysis on the mitral valve was performed with custom software
(QLAB MVQ, Philips; Figure 1). The images were presented in 4
quadrants, including 3 orthogonal planes, each representing an anatomic plane derived from the 3D data, and a volume-rendered view.
The end-systolic frame, defined as the last frame just before aortic
valve closure, was tagged in the cine-loop sequence. The image was
oriented by adjusting the rotation of image data in the orthogonal
planes, ensuring that the mitral valve was bisected by the 2 long-axis
planes and that the short-axis plane was parallel to the plane of the
valve. Initially, the 4 major annulus reference points were tagged on
the appropriate planes. The annulus shape was then manually outlined by defining intermediate reference points in 18 radial planes
(ie, 36 reference points) rotated around the long axis. The mitral
valve was then segmented to map the leaflet contour and coaptation
by manually tracing the leaflets in multiple parallel long-axis planes
spanning the valve from commissure to commissure (6 trace points
per centimeter). Finally, the 2 groups of papillary muscles were identified by adjusting the long- and short-axis planes.
Quantitative Assessment of Mitral Morphology
The reconstructed valve was displayed as a color-coded 3D-rendered
surface representing a topographical map. Measurements of the
key 3D parameters were automatically generated. Specifically,
annular geometry was described by its anteroposterior diameter,
commissural width (the intercommissure distance between the
posteromedial and anterolateral horns of the annulus), height (the
maximal vertical distance between the highest and lowest annular
points), circumference, and projected area. The annular ellipticity
was calculated as the ratio of anteroposterior diameter to commissural
width. The ratio of annular height to commissural width (AHCWR)
was computed as a surrogate of annular saddle-shaped nonplanarity.
A deeper saddle shape of the annulus is characterized by a more
apical position of the medial and lateral aspects of the annulus,
whereas the anterior and posterior aspects remain basal in position
and thus translate as a higher percentage of AHCWR. We studied the
3D leaflet surface topography by assessing the leaflet dimensions,
coaptation, and billowing. Areas of the exposed (noncoaptation)
surfaces and lengths of the anterior and posterior leaflets were
measured. Coaptation length was measured as the arc length of the
coaptation line. We define billowing of the leaflet as abnormal bowing
of the leaflet toward the left atrium without involving the leaflet edge.
We describe billowing with respect to a 3D minimal surface that was
mathematically defined to fit to the nonplanar annulus (can be thought
of as a soap film fitted to the annulus).6 The leaflet billow height is the
height above this minimal surface as in a mountain peak, and billow
volume is the volume of the mountain. The length from papillary
muscles to coaptation was measured from the anterolateral and
posteromedial papillary muscle tips to markers manually placed on
either side of the midthird of coaptation line on the leaflets. The aortic
annulus point marked in the long-axis plane was used to measure the
angle between the mitral and aortic annuli (Figure 2). Reproducibility
of measurement was determined by repeating measurements on stored
3D data sets at least 1 week after the initial measurement by the same
observer (intraobserver) and a different observer (interobserver).
Statistical Analysis
Data are expressed as mean±SD, mean rank, or number of patients
(percentages) as appropriate. Normality of all continuous data was
834 Circulation February 19, 2013
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Figure 1. Three-dimensional (3D) mapping of mitral valve geometry. Initially, anterolateral (AL), posteromedial (PM), anterior (A), and
posterior (P) mitral annulus; aortic annulus (Ao); and coaptation (Nadir) points were tagged in the 2 orthogonal long-axis planes (A and B).
Then, the 2 commissures were marked in the short-axis plane (arrows), and 2 markers were placed on both sides of the midthird segment of the coaptation line (arrowheads) as reference points for the measurement of distances from papillary muscles to leaflet coaptation (C). Contours of the mitral leaflets and coaptation (arrowhead) were traced plane by plane from commissure to commissure (D).
Papillary muscles were identified by adjusting the views on the orthogonal long-axis (E) and short-axis (F) planes. Visual clues from the
3D volume are used to aid the operator in identifying the correct anatomic landmarks. A cropped 3D full-volume data set shows the spatial relationship of the mapped mitral valve to adjacent anatomic structures (G). A surgeon’s view of mitral valve mapping is superimposed
on the volumetric data set (H), and the final mapping is displayed as a color-coded 3D-rendered topographical surface (I). The asterisk
indicates left atrial appendage. AML indicates anterior mitral leaflet; AV, aortic valve; and PML, posterior mitral leaflet.
Figure 2. Parameters of mitral valve 3-dimensional geometry. A, Commissural width (CW) and anteroposterior diameter (APD). B, Annular
height (AH). C, Annular area on the projection plane. D, Length of anterior (AL) and posterior (PL) leaflets. E and F, Areas of the exposed
AL and PL surfaces. G, Coaptation line (green dotted line). H, Leaflet billowing is represented in red scale on the topographical display. I,
Lengths from the anterolateral (Al) and posteromedial (Pm) papillary muscles (PPM) to the coaptation markers. Ao indicates aortic annulus.
Lee et al 3D Echocardiographic Morphology of Mitral Valve Prolapse 835
confirmed with the Kolmogorov-Smirnov test. Group comparisons
used ANOVA, the Kruskal-Wallis test, or the χ2 test as appropriate.
Intraobserver and interobserver variabilities of measurements of the
3D mitral valve morphology were assessed by intraclass correlation
coefficient. Correlations between continuous variables were explored
by use of Pearson analysis or exponential growth model. Strengths
of association with significant MR (≥3+) for key 3D geometric
variables, including annular area, annular nonplanarity, leaflet
billow volume, and chordal rupture, were examined. These factors
were tested because they are the primary variables of mitral valve
morphology shown to be associated with MR in MVP.1–4 Analyses
were performed with SPSS 20.0 (IBM Inc, Armonk, NY). A value of
P<0.05 was considered statistically significant.
Results
Study Population
Characteristics of MVP patients in the MR+ group (n=36) are
compared with those of the MR− group (n=32), the nonprolapse
group (n=12), and control subjects (n=32) in Table 1. Compared
with control subjects, most clinical characteristics of MVP
patients were similar except for more symptoms and higher blood
pressure in the MVP groups. Ejection fraction was identical
among all groups, but left ventricular volumes were larger in
the MR+ group as a result of volume overload. Trivial MR was
Table 1. Participant Characteristics
MVP
Variable
Normal (n=32)
MR− Group (n=32)
MR+ Group (n=36)
Nonprolapse Group
(n=12)
P
Clinical
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Age, y
58±15
59±11
61±12
62±10
0.77
Women, n (%)
13 (41)
10 (31)
16 (44)
5 (42)
0.50‡
1.64±0.15
1.68±0.17
1.67±0.16
1.65±0.12
0.75
68±9
72±12
71±11
70±13
0.51
Systolic blood pressure, mm Hg
123±14
133±19*
131±17*
135±9*
0.045
Diastolic blood pressure, mm Hg
75±8
79±9
84±11*
82±8
0.001
I
32 (100)
30 (94)
9 (25)
2 (17)
II
0 (0)
2 (6)
9 (25)
4 (33)
III/IV
0 (0)
0 (0)
18 (50)
6 (50)
Mean rank
37.0
39.75
79.75*†
83.42*†
Body surface area, m2
Heart rate, bpm
NYHA class, n (%)
<0.0001
Echocardiography
Left ventricle
Ejection fraction, %
62±5
64±9
63±8
65±7
0.59
End-diastolic volume, ml
91±17
91±19
119±31*†
110±28*†
0.001
End-systolic volume, ml
35±11
32±10
45±19*†
42±20*†
0.002
Mitral regurgitation, n (%)
Grade
0
32 (100)
5 (16)
0 (0)
0 (0)
1+
0 (0)
16 (50)
0 (0)
0 (0)
2+
0 (0)
11 (34)
0 (0)
0 (0)
3+/4+
0 (0)
0 (0)
36 (100)
12 (100)
Mean rank
19.0
46.0*
88.5*†
88.5*†
<0.0001
ERO, cm2
0±0
0.14±0.09
0.79±0.43*†
0.60±0.10*†
<0.0001
Bileaflet prolapse, n (%)
NA
6 (19)
4 (11)
NA
Site of lesions, n (%)
0.498‡
0.944‡
A1
NA
1 (3)
0 (0)
NA
A2
NA
1 (3)
1 (3)
NA
A3
NA
2 (6)
2 (6)
NA
P1
NA
0 (0)
4 (11)
NA
P2
NA
11 (34)
12 (33)
NA
P3
NA
5 (16)
3 (8)
NA
Multisegment
NA
12 (38)
14 (39)
NA
ERO indicates effective regurgitant orifice; MR, mitral regurgitation; MVP, mitral valve prolapse; NA, not applicable; and NYHA, New York Heart Association. Data are
expressed as mean±SD, mean rank, or number of patients (percentage) as appropriate.
*P<0.05 versus control subjects.
†P<0.05 versus MR− group.
‡P value from the Fisher exact test.
836 Circulation February 19, 2013
Table 2. Strength of Agreement of the Interobserver and
Intraobserver Analysis for Each Mitral Valve Parameter
Measured by 3D Echocardiography
Intraclass Correlation Coefficients
Parameters
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Intraobserver
Interobserver
Annular height
0.840
0.829
Commissural width
0.912
0.838
AHCWR
0.816
0.810
Annular circumference
0.967
0.891
Annular area
0.966
0.907
Anterior leaflet area
0.952
0.877
Posterior leaflet area
0.880
0834
Leaflet billow volume
0.954
0.931
Length from anterolateral papillary
muscle to coaptation
0.930
0.885
Length from posteromedial papillary
muscle to coaptation
0.893
0.857
0.14±0.09 cm2; P<0.001). The majority of patients (75%) in the
MR+ group had severe (4+) MR, whereas most patients (66%)
in the MR− group had either no or 1+ MR. Mitral valve lesions
were located mostly in the P2 segment or involved multiple
segments in both groups of MVP patients (P=0.944). Chordal
rupture was diagnosed on transesophageal echocardiography
in 15 patients (41%) in the MR+ group compared with only 2
(6%; both had 2+ MR with a small flail segment) in the MR−
group (P=0.0008). In the nonprolapse group, significant MR
(ERO=0.60±0.10 cm2; P=0.11 versus MR+ patients with MVP)
was the result of endocarditic leaflet perforation in 9 patients
and congenital cleft mitral leaflet (1 isolated posterior leaflet
cleft, 2 associated with primum atrial septal defect) in 3 patients.
There was no evidence of leaflet prolapse in these patients.
3D Mitral Valve Geometry
AHCWR indicates annular height to commissural width ratio.
documented in 6 control subjects; all the others were free of
MR. As the definition implies, ERO was significantly larger
in the MR+ compared with the MR− group (0.79±0.43 versus
The intraclass correlation coefficient was good for the interobserver analysis and excellent for the intraobserver analysis
in 3D measurements of mitral valve morphology (Table 2).
Intergroup comparisons of mitral valve geometry are shown
in Table 3. Compared with control subjects, patients of the
MR− group had dilated mitral annulus with significantly
increased anteroposterior diameter, commissural width, and
annular area and circumference, all of which were further
Table 3. Three-Dimensional Mitral Valve Geometry
MVP
Normal
(n=32)
MR− Group
(n=32)
MR+ Group
(n=36)
Nonprolapse
Group
(n=12)
P
Commissural width, mm
33.3±3.7
37.7±3.9*
42.2±5.9*†
39.2±3.3*
<0.0001
Anteroposterior diameter, mm
28.0±2.5
33.4±4.0*
38.8±6.4*†
36.6±2.9*
<0.0001
Ellipticity
0.0023
Variables
Annulus
0.84±0.07
0.91±0.09*
0.91±0.11*
0.93±0.06*
Height, mm
7.9±1.9
6.5±1.6*
5.6±1.6*†
8.2±1.2†‡
AHCWR, %
23.7±5.4
17.3±4.6*
13.2±4.2*†
21.0±1.9‡
<0.0001
0 (0)
6 (19)
24 (77)
0 (0)
<0.0001§
AHCWR <15%, n (%)
<0.0001
Circumference, mm
106±10
122±14*
136±19*†
133±11*
<0.0001
Area, mm2
738±125
1039±241*
1343±392*†
1032±124*‡
<0.0001
Aortic-mitral angle, °†
118±8
121±9
120±9
Anterior leaflet length, mm
21.2±3.0
24.0±4.9*
26.3±6.1*
NA
Posterior leaflet length, mm
9.8±2.0
13.1±4.3*
16.0±5.0*†
NA
<0.0001
Anterior leaflet surface area, mm2
519±108
705±189*
913±297*†
NA
<0.0001
Posterior leaflet surface area, mm2
355±71
571±178*
764±247*†
NA
<0.0001
Coaptation length, mm
29.9±6.6
37.7±7.2*
43.2±11.5*†
NA
<0.0001
Billow volume, mL
0.07±0.07
0.9±0.9*
2.4±1.9*†
NA
<0.0001
Billow height, mm
1.8±0.9
5.0±1.8*
7.8±2.6*†
NA
<0.0001
119±7
0.55
Leaflet
Chordae tendinae
Chordal rupture, n (%)
<0.0001
NA
0 (0)
2 (6)
15 (42)
NA
0.0008§
Length from anterolateral papillary muscle to coaptation, mm
18.8±3.3
20.4±4.9
23.8±4.4*†
NA
<0.0001
Length from posteromedial papillary muscle to coaptation, mm
19.3±3.8
21.2±4.6
25.1±5.4*†
NA
<0.0001
AHCWR indicates annular height to commissural width ratio; and NA, not applicable. Data are expressed as mean±SD or number of patients (percentage) as appropriate.
*P<0.05 versus control subjects.
†P<0.05 versus MR− group.
‡P<0.05 versus MR+ group.
§P value from Fisher’s Exact method.
Lee et al 3D Echocardiographic Morphology of Mitral Valve Prolapse 837
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increased in the MR+ group (all P<0.0001). Annular ellipticity was significantly greater in both MVP groups compared
with control subjects (both P<0.05 versus reference; P=1.0
between MVP groups). The mitral annulus of all control subjects conformed to a saddle configuration with elevation of
anterior and posterior annular segments and nadirs of the saddle near the commissures. In the normal population, AHCWR
was 23.7±5.4% (normal range, 15%--33%). Progressive dilatation of mitral annulus in MVP groups was accompanied
by paradoxical reduction in annular height (all P<0.05) and
AHCWR (all P<0.005), representing progressive flattening of
the mitral annulus. Furthermore, in patients who had prolapse
and minimal (0/1+) MR (n=21), annular height (7.0±1.2 versus 7.9±1.0 mm; P=0.041) and AHCWR (18.7±3.8% versus
23.7±5.4%; P=0.0003) were also reduced compared with control subjects. On the other hand, the mitral annulus of the nonprolapse group was dilated (P=0.01 versus control subjects),
but annular height (P=0.90 versus normal; P<0.0001 versus
MR+ group) and AHCWR (P=0.23 versus normal; P<0.0001
versus MR+ group) were not significantly reduced (Table 3).
No difference in mitral-aortic angle was observed.
The leaflet coaptation line could be clearly recognized
as the mitral smile in all control subjects. In normal valves,
anterior leaflets were 2.3±0.6 times longer and 1.5±0.4 times
larger than posterior leaflets; the surface area of both leaflets
taken together was 140±10% of the annular area, indicating
a large natural surplus of leaflet surfaces to cover the mitral
orifice in normal valves. Compared with control subjects, the
length and surface area of both mitral leaflets increased significantly in the MR− group (P<0.05 versus the reference group)
and further increased in the MR+ group (P<0.005 versus the
reference and MR− groups). Consistently, the coaptation
length was significantly longer in the MR− group compared
with control subjects but was most increased in MR+ patients
(all P<0.01). Patients who had bileaflet prolapse (n=10) tend
to have longer coaptation lengths than those with single-leaflet prolapse (n=58; 46.0±9.6 versus 39.8±9.9 mm; P=0.07),
but the difference was not statistically significant. By definition, there was no leaflet billowing in control subjects. Leaflet
billow height (P<0.0001) and billow volume (P<0.0001) of
MR+ patients were both significantly greater than those of
MR− patients. Papillary muscle distances to coaptation were
similar (P=0.22) between the reference and MR− group
but were significantly longer in the MR+ group (P<0.001).
Illustrative examples of 3D mitral valve geometry are shown
in Figure 3.
Figure 3. Illustrative examples of mitral valve deformation in mitral valve prolapse. A, A control subject with a saddle-shaped annulus
(annular height to commissural width ratio [AHCWR]=23%). B, A patient with mild posterior leaflet billowing with mild mitral regurgitation (MR) on 2-dimensional echocardiography (2DE). Real-time 3-dimensional echocardiography (RT3DE) reveals isolated P2 billowing
(arrow). The saddle shape of mitral annulus decreases (AHCWR=18%), and the leaflet topography shows a light-red hue localized to P2
with a leaflet billow volume of 0.2 mL. C, A patient with chordal rupture resulting in flail P2 segment and severe eccentric MR on 2DE. The
ruptured chord (arrowheads) can be clearly visualized on RT3DE. The annular saddle shape is lost with an AHCWR of 14%, presumably
predisposing to the chordal rupture. Leaflet topography shows a deep-red hue at P2, indicating P2 prolapse with a large coaptation gap
(asterisk). Leaflet billow volume=0.8 mL. Bottom, A patient with bileaflet billowing and severe MR. The MR jet is central and large with
an elongated vena contracta, as shown on biplane imaging. Substantial leaflet billowing and increased total leaflet surface area are well
appreciated on RT3DE. The mitral annulus is large and extremely flat (AHCWR=10%), and the leaflet topography shows diffuse deep-red
discoloration over multiple segments, illustrating extensive leaflet billowing (leaflet billow volume=7.8 mL). A indicates anterior; AL, anterolateral; Ao, aortic annulus; P, posterior; and PM, posteromedial.
838 Circulation February 19, 2013
Figure 4. Annulus saddle shape in relation to chordal rupture.
The frequencies of chordal rupture progressively increased with
lower annular height to commissural width ratio (AHCWR).
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Anatomic Relationships of Annular, Leaflet, and
Subvalvular Apparatus in MVP
MVP patients with multisegment prolapse had significantly
greater billow volume than those with single-segment prolapse
(2.5±1.9 versus 1.2±1.3 mL; P=0.002). AHCWR correlated
inversely with total leaflet surface area (r2=0.39, P<0.0001)
and billow volume (r2=0.36, P<0.0001). Tertiles of AHCWR
in relation to subvalvular geometry showed an increase in
the lengths from papillary muscles to leaflet coaptation with
lower AHCWR (19.6±3.6 versus 22.3±4.9 versus 22.7±5.2
mm for AHCWR >20%, 15%--20%, and <15%, respectively;
P<0.05, ANOVA). The frequency of chordal rupture increased
progressively with flattening of the annular saddle (7% versus
24% versus 42% for AHCWR >20%, 15%--20%, and <15%,
respectively; P=0.004, Fisher exact test; Figure 4). In a subset
of patients with intact chordae tendinae (n=87), a strong inverse
correlation (r2=0.66, P<0.0001) existed between AHCWR
and leaflet billow volume, which increased exponentially
when AHCWR decreased below 15%, in association with a
Figure 6. Correlations of effective regurgitant orifice (ERO) area
with leaflet billow volume and annular height to commissural
width ratio (AHCWR). The scatterplot demonstrates a strong
correlation between ERO and leaflet billow volume (A) and an
inverse correlation between ERO and AHCWR (B).
significantly higher prevalence of MR ≥3+ (80% versus 32%;
P<0.0001; Figure 5).
3D Mitral Valve Morphology Associated With
Clinically Significant MR
Structural deformation of mitral valve increased with a
higher degree of MR. The strongest correlation with ERO
was observed with leaflet billow volume (r2=0.74, P<0.0001;
Figure 6A). Larger EROs were also associated with lower
AHCWR (r2=0.44, P<0.0001; Figure 6B); greater annular
area (r2=0.56, P<0.0001), anteroposterior diameter (r2=0.55,
P<0.0001), and commissural width (r2=0.46, P<0.0001);
larger leaflet surface area (r2=0.59, P<0.0001); higher leaflet
billow height (r2=0.54, P<0.0001); and longer coaptation line
(r2=0.32, P<0.0001). There were no significant correlations for
ERO with age, body surface area, blood pressure, or heart rate
(all P>0.05). Table 4 shows the results of individual-variable
Table 4. Predictors for Clinically Significant Mitral
Regurgitation in Mitral Valve Prolapse
Variables
Figure 5. Scatterplot demonstrating a strong inverse correlation
between annular height to commissural width ratio (AHCWR)
and leaflet billow volume in subjects without chordal rupture.
Solid line represents the regression line of a negative exponential
growth model. Open circles, solid dots, and open triangles represent reference group, group with no mitral regurgitation, and
group with mitral regurgitation, respectively.
Annular flattening (AHCWR <15%)
Chordal rupture
Leaflet billow volume
Annular area
Odds Ratio (95% CI)
P
7.1 (2.4–21.2)
0.0004
10.7 (2.2–51.9)
0.0032
2.2 (1.4–4.0)
1.003 (1.001–1.006)
0.0006
0.003
AHCWR indicates annular height to commissural width ratio; and CI,
confidence interval.
Lee et al 3D Echocardiographic Morphology of Mitral Valve Prolapse 839
analysis of key 3D geometric parameters of the annulus, leaflet, and chordae in association with MR ≥3+.
Discussion
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To the best of our knowledge, the present study is the first
prospective series to examine quantitatively the complete
3D echocardiographic morphology of the mitral apparatus
in patients with MVP. Our results confirmed the findings of
pathological studies that MVP is associated with annular
dilatation, increased leaflet size, progressive leaflet billowing,
and chordal rupture, with resultant mitral valve incompetence.
Notably, our study demonstrated for the first time that
AHCWR, a surrogate of the annular saddle shape, has strong
negative associations with leaflet redundancy, volume of
leaflet billowing, and frequencies of chordal rupture and that
extreme flattening of the annular saddle with an AHCWR
<15% (which happens to be the lower limit of normal) is
independently associated with the presence of clinically
significant MR in patients with MVP.
Pioneering work by Levine et al5 revealed >2 decades ago
that the normal mitral annulus has a saddle shape. Using
echocardiography and sonomicrometry-based measurement,
Salgo et al6 showed that AHCWR is preserved across mammalian species (15%≈20%), suggesting that nature conserves the saddle-shaped annulus for a mechanical benefit.
Calculated by Gorman et al14 in the normal human subjects
and studied by Kaplan et al15 by gated 3D echocardiography,
AHCWR is ≈22% to 23%. However, in a recent RT3DE study
by Maffessanti et al,8 AHCWR in control subjects was only
12.7%. Other RT3DE studies10,16 showed that AHCWR in normal humans during systole is about 20%≈26%. The normal
range of AHCWR in our larger study population values is
≈15% to 33% (mean±SD, 23.7±5.4%). Discrepancies among
studies may stem from the number of reference points used to
define the annular plane (36 in our study and only 16 in the
Maffessanti et al study). A lower density of annular points preset during mapping is likely to yield an annulus that appeared
flatter than actual.
It has been postulated that the saddle shape of the annulus
in systole may provide a configuration more capable of
withstanding the stresses imposed by left ventricular pressure.5,6
As demonstrated by Salgo et al6 using finite-element analysis,
the optimal leaflet stress reductions occur with AHCWRs in
the range of 15% to 20%. Leaflet stress becomes minimum
once AHCWR exceeds 20% to 25% and, on the other hand,
rises steeply when AHCWR falls to <15%. In our study, mitral
annulus was flattened in patients with MVP, and about one
third of the MVP population had AHCWR <15%. Of note,
leaflet size and leaflet billow volume rose exponentially when
AHCWR fell below 15%, bearing intriguing resemblances
to a previously reported computational model relating
AHCWR and leaflet stresses.6 In vivo, physiological loading
on porcine heart increases anterior leaflet areal strain17 by
19% and P2 segment areal strain18 by 78% when a saddleshaped annulus becomes flattened. Moreover, a saddleshaped annulus optimizes force distribution on the chordal
system because a larger number of chordae are extended and
load is divided more evenly among them.19 Our discovery
of an association between annular flattening and increased
frequencies of chordal rupture in human patients is clinically
provoking. Increased distance from the papillary muscle to
leaflet coaptation in patients with significant MR in our study
may be a combined effect of left ventricular and annular
remodeling: A flattened annulus may lift the leaflet coaptation
site toward the atrium, whereas left ventricular dilatation
pulls the papillary muscles away from the mitral valve. The 2
opposing forces may act together to cause chordal lengthening
and rupture. Our study has provided new data suggesting that
loss of the annular saddle shape may predispose to chordal
elongation and rupture as a result of excessive chordal
tension. From these findings, we postulated that flattening
of the annular saddle shape might play a fundamental role
in the pathogenesis of MVP-related MR by potentiating the
deformation of intrinsically abnormal leaflets and chordae in
association with the excessive mechanical stress. Previous
autopsy findings suggested that valve degeneration, in which
the leaflets may be larger and thicker than normal, could be
explained by the increased production of connective tissue in
response to altered mechanical conditions that is contributed
by mitral annulus disjunction.20–22
Several other groups have studied the 3D annular geometry
in MVP. Ennis et al,23 using magnetic resonance, reported a
greater annular height (11.5 mm) in 25 MVP patients. The
majority of their patients, however, were white (80%) with a
large body size (average body mass index, 25.8 kg/m2). It is
possible that the normal range of annular height, as with other
measurement of cardiac dimensions, varies with body size
and ethnicity. It is also questionable whether annular height
measurements by echocardiography and magnetic resonance
are interchangeable, given that the annular height measured
by the Ennis group was also greater than that measured
by other investigators using 3D echocardiography.8,10,15,16
Without a normal reference group, it is difficult to conclude
whether annular height was reduced, increased, or normal
in the MVP subjects in the Ennis et al23 study. In contrast,
Mahmood et al24 reported a larger nonplanarity angle (another
measure of annular nonplanarity) in 40 MVP patients (133°)
compared with control subjects (127°). This finding supports
the contention of annular flattening, although this difference
was not statistically significant, presumably because of
the small size of the reference group (n=8). More recently,
Grewal et al10 reported a loss of systolic annular contraction
and decreased deepening of the saddle shape in MVP despite
normal ventricular contraction, suggestive of primary annular
dysfunction independent of ventricular function.
Clinical Implications
The natural history of MVP is variable,1,2 and valvular lesions
progression is usually unpredictable.25 Our findings suggested
that the annulus flattening detected by RT3DE might be a risk
marker for the progression of leaflet lesions and occurrence of
chordal rupture. Measures to avoid excessive hemodynamic
burden such as aggressive treatment for hypertension and
overweight may be advisable in some of these patients.26 With
rapid advances in RT3DE technologies, accurate, quantitative
analysis of mitral valve morphology by transthoracic RT3DE
would become feasible for repeated monitoring and preoperative assessment of mitral valve reparability.27,28
840 Circulation February 19, 2013
Limitations
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One could envisage that MR, by enlarging annular size, would
reduce the height of the annulus. It is arguable that annular flattening may be an effect rather than a cause of increased MR. It is
important to note that the AHCWR is decreased in large part by
increased annular area and therefore width in patients with MR.
Even the decrease in annular height itself may be secondary to
in-plane annular stretching, reducing out-of-plane height. Our
study, limited by a cross-sectional design, albeit demonstrating a strong association of annular flattening with MR, would
not establish a causal relationship. Longitudinal studies with a
proper design showing that annular flattening precedes progression of MR may be able to further clarify whether annular flattening is a cause or an effect of MR. Nevertheless, the finding of
decreased annular height in patients with MVP and no or mild
MR suggests the possibility of primary annular pathology. On
the other hand, pure severe MR in the nonprolapse group did not
reduce annular height but caused annular dilatation. In an ovine
model, Nguyen et al29 found that pure MR produced by a hole
in the leaflets did not decrease annular height, which suggests
that MR alone may not be the dominant cause of annular flattening and that primary annular pathology may play a contributory role in clinical settings. Taken together, the findings of both
Nguyen et al and the present study have lent strong support to
our hypothesis that the annular flattening observed in MVP was
not an epiphenomenon of MR but a determinant factor. Moreover, a decrease in annular nonplanarity, whatever its cause, will
exert increased tension on the leaflets and chords,30–32 promoting rupture of mechanically weakened chords and the progressive disease seen clinically. MR begets MR.
Conclusions
The complex structure of mitral valve demands a 3D imaging solution. Transesophageal RT3DE of the mitral valve is
capable of quantitatively defining the structural deformities of
MVP. Our study demonstrated for the first time in humans that
flattening of the annular saddle shape is associated with progressive leaflet billowing and increased frequencies of chordal
rupture and may be important in the pathogenesis of clinically
significant MR in patients with MVP.
Acknowledgment
The authors wish to thank the cardiac sonographers of the Echo­
cardiography Laboratory, Prince of Wales Hospital for their help in
transthoracic image acquisition.
Disclosures
Dr Lee received unrestricted educational support and speaker honorarium from Philips Healthcare. The other authors report no conflicts.
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Clinical PERSPECTIVE
Mitral valve prolapse is a common disorder with a prognosis determined by the development of mitral regurgitation (MR).
Decades of echocardiography and cardiac surgery have shown that degenerative MR is a consequence of pathologically
altered valve morphology. However, attempts to use 2-dimensional slices to comprehend a complex 3-dimensional structure
of the mitral valve have provided an incomplete picture. We undertook a quantitative 3-dimensional echocardiographic
study in patients with mitral valve prolapse with a wide spectrum of MR severity to characterize the link between mitral
morphology and MR severity. For the first time in humans, we demonstrated that annular flattening, represented by a reduced
ratio of annular height to commissural width, is strongly associated with progressive leaflet billowing, higher frequencies
of chordal rupture, and greater regurgitant orifices. The lower limit of the ratio of annular height to commissural width in
healthy population appears to be 15%, and a ratio <15% is strongly associated with moderate or severe MR among patients
with mitral valve prolapse. Importantly, annular height and ratio of annular height to commissural width are reduced even
in patients with mitral valve prolapse and no or mild MR, suggesting the possibility of primary annular abnormality. Such
annular flattening was not observed in patients with organic MR due to nonprolapse leaflet pathologies. We proposed annular
flattening as a novel geometric mechanism in the pathogenesis of degenerative MR, adding to our understanding of how MR
begets MR: A decrease in annular nonplanarity will exert increased tension on the leaflets and chordae, promoting rupture
of mechanically weakened chords and the progressive disease seen clinically.
Quantitative Analysis of Mitral Valve Morphology in Mitral Valve Prolapse With
Real-Time 3-Dimensional Echocardiography: Importance of Annular Saddle Shape in the
Pathogenesis of Mitral Regurgitation
Alex Pui-Wai Lee, Ming C. Hsiung, Ivan S. Salgo, Fang Fang, Jun-Min Xie, Yan-Chao Zhang,
Qing-Shan Lin, Jen-Li Looi, Song Wan, Randolph H.L. Wong, Malcolm J. Underwood,
Jing-Ping Sun, Wei-Hsian Yin, Jeng Wei, Shen-Kou Tsai and Cheuk-Man Yu
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation. 2013;127:832-841; originally published online December 24, 2012;
doi: 10.1161/CIRCULATIONAHA.112.118083
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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