JACC: CARDIOVASCULAR IMAGING
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
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ISSN 1936-878X/$36.00 http://dx.doi.org/10.1016/j.jcmg.2015.08.022
Mitral Annular Dimensions and Geometry in Patients With Functional Mitral Regurgitation and Mitral Valve Prolapse Implications for Transcatheter Mitral Valve Implantation Christopher Naoum, MBBS,a Jonathon Leipsic, MD,a Anson Cheung, MD,a Jian Ye, MD,a Nicolas Bilbey, MD,a George Mak, MBBS,a Adam Berger, MBBS,a Danny Dvir, MD,a Chesnal Arepalli, MD,a Jasmine Grewal, MD,a David Muller, MBBS,b Darra Murphy, MBBS,a Cameron Hague, MD,a Nicolo Piazza, MD,c John Webb, MD,a Philipp Blanke, MDa
ABSTRACT OBJECTIVES The aims of this study were to determine D-shaped mitral annulus (MA) dimensions in control subjects without significant cardiac disease and in patients with moderate to severe mitral regurgitation (MR) being considered for transcatheter mitral therapy and to determine predictors of annular size, using cardiac computed tomography. BACKGROUND The recently introduced D-shaped method of MA segmentation represents a biomechanically appropriate approach for annular sizing prior to transcatheter mitral valve implantation. METHODS Patients who had retrospectively gated cardiac computed tomography performed at our institution (2012 to 2014) and were free of significant cardiac disease were included as controls (n ¼ 88; 56 11 years of age; 47% female) and were compared with patients with moderate or severe MR due to functional mitral regurgitation (FMR) (n ¼ 27) or mitral valve prolapse (MVP) (n ¼ 32). MA dimensions (projected area, perimeter, intercommissural, and septal-to-lateral distance), maximal left atrial (LA) volumes, and phasic left ventricular volumes were measured. RESULTS MA dimensions were larger in patients with FMR or MVP compared with controls (area index 4.7 0.6 cm2/m2, 6.0 1.3 cm2/m2, and 7.3 1.7 cm2/m2; perimeter index 59 5 mm/m2, 67 9 mm/m2, and 75 10 mm/m2; intercommissural distance index 20.2 1.9 mm/m2, 21.2 3.1 mm/m2, and 24.7 3.2 mm/m2; septal-to-lateral distance index 14.8 1.6, 18.1 3.3, and 19.5 3.4 mm/m2 in controls and patients with FMR and MVP, respectively; p < 0.05 between controls and MR subgroups). Absolute MA area was 18% larger in patients with MVP than patients with FMR (13.0 2.9 cm2 vs. 11.0 2.3 cm2; p ¼ 0.006). Although LA and left ventricular volumes were both independently associated with MA area index in controls and patients with MVP, only LA volume was associated with annular size in patients with FMR. CONCLUSIONS Moderate to severe MR was associated with increased MA dimensions, especially among patients with MVP compared with control subjects without cardiac disease. Moreover, unlike in controls and patients with MVP, annular enlargement in FMR was more closely associated with LA dilation. (J Am Coll Cardiol Img 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.
From aSt. Paul’s Hospital and University of British Columbia, Center for Heart Valve Innovation, Vancouver, British Columbia, Canada; bSt. Vincent’s Hospital, Sydney, Australia; and the cDepartment of Medicine, Division of Cardiology, McGill University Health Centre, Montreal, Quebec, Canada. Dr. Leipsic has served as a consultant to Edwards Lifesciences and Neovasc Inc.; and has provided CT core laboratory services to Edwards Lifesciences, Neovasc Inc., and Tendyne Holdings Inc. Dr. Cheung has served as a consultant to Edwards Lifesciences and Neovasc Inc. Drs. Ye and Webb have served as consultants to Edwards Lifesciences. Dr. Piazza has served on scientific advisory boards for Medtronic; has served as a consultant for HighLife SAS; and owns equity shares in HighLife SAS. Dr. Blanke has served as a consultant to Edwards Lifesciences, Neovasc Inc., Tendyne Holdings Inc., and Circle Imaging; and has provided CT core laboratory services to Edwards Lifesciences, Neovasc Inc., and Tendyne Holdings Inc. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 2, 2015; revised manuscript received August 18, 2015, accepted August 20, 2015.
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ABBREVIATIONS AND ACRONYMS BMI = body mass index BSA = body surface area CT = computed tomography FMR = functional mitral regurgitation
IC = intercommissural LA = left atrial/atrium
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Mitral Annular Dimensions in Mitral Regurgitation
ith the rapid innovation and
than mild MA calcification seen on cardiac CT; 2)
growing
of
clinical history of congestive heart failure and/or
transcatheter mitral therapies,
reduced measured left ventricular (LV) ejection
including transcatheter mitral valve implan-
fraction <50%; 3) obstructive coronary artery disease
tation (TMVI), an accurate understanding of
on cardiac CT ($70% in any coronary vessel or >50%
mitral annular (MA) dimensions and geome-
in the left main) or prior coronary revascularization;
try
important.
4) history of atrial fibrillation; 5) prior cardiac surgery;
Given the saddle-shaped, nonplanar configu-
6) complex congenital heart disease; 7) obesity (body
ration of the MA, 3-dimensional (3D) imaging
mass index [BMI] >35 kg/m2 ); 8) increased maximal
is
becoming
clinical
adoption
increasingly
is required for comprehensive assessment.
left atrial (LA) volume index (>78 ml/m 2, a cutoff
LV = left ventricle/ventricular
Although
using
representing 2 SDs from the mean value previously
MA = mitral annular/annulus
computed tomography (CT), with its excel-
reported in healthy subjects [6]); and/or increased LV
MR = mitral regurgitation
lent spatial resolution (1–4), limited data
mass index (>103 g/m 2 for men and >89 g/m 2 for
MVP = mitral valve prolapse
exist describing CT values for MA dimensions
women [7]). Consecutive patients with moderate to
SL = septal-to-lateral
in patients with significant mitral regurgita-
severe MR referred for cardiac CT between November
TMVI = transcatheter mitral
tion (MR) in whom TMVI may be a potential
2013 and June 2015 for workup prior to potential
valve implantation
therapeutic option.
TMVI were included. Patients with MR were divided
this
can
be
achieved
We recently proposed a D-shaped concept
into 2 groups based on MR mechanism (mitral valve
of MA geometry, in which the annulus is truncated
prolapse [MVP] or functional mitral regurgitation
along a virtual line connecting both fibrous trigones,
[FMR]). Patients with a prior aortic and/or mitral
TT = trigone-to-trigone
as a standardized, reproducible, and more biome-
valve prosthesis were excluded from the MR group.
chanically appropriate method for MA sizing prior to
CARDIAC CT DATA ACQUISITION. Cardiac CT was
TMVI (5). An important characteristic of the D-shaped
performed using a 64-slice helical CT scanner (Dis-
segmentation method is that it yields a more planar
covery high-definition 750 or VCT, GE Healthcare,
annulus that closely resembles the cross-sectional
Milwaukee, Wisconsin). For controls, CT acquisition
area of current TMVI devices, which is not achieved
was undertaken according to the institutional proto-
by conventional (saddle-shaped) analyses. Annular
col for performing retrospectively gated clinical car-
size and geometry and the determinants of MA size in
diac CT. For patients with MR, a pre-specified clinical
patients with moderate to severe MR have not been
cardiac CT protocol was used. Imaging was performed
studied using the D-shaped method. Moreover, the
during a single breath-hold following injection of 80
range of D-shaped MA dimensions in patients without
to 110 ml of intravenous contrast media (Visipaque
significant cardiac disease is unknown.
320, GE
Healthcare)
with
a
triphasic
injection
Accordingly, we sought to determine annular di-
(contrast, contrast/saline mix, and saline) for controls
mensions, geometry, and drivers of annular size in
and a biphasic injection (contrast and saline) for pa-
patients with moderate to severe MR and compare
tients with MR. Tube voltage and current were
these findings with those of control subjects without significant
cardiac
disease
using
retrospectively
manually determined (on the basis of BMI) with subsequent ECG modulation of tube current for con-
electrocardiographically (ECG) gated cardiac CT.
trols to minimize radiation dose (median [inter-
METHODS
quartile range] effective dose 9.6 mSv [5.7 to 11.8 mSv] in controls and 14.1 mSv [11.3 to 20.2 mSv] in Review
patients with MR). Scan range extended from the
Board approved this retrospective study with a
carina to just below the inferior cardiac surface. Axial
waiver for informed consent. Two study cohorts were
images were reconstructed at 10% intervals of the
identified. Consecutive patients who underwent
cardiac cycle with a slice thickness of 0.625 mm.
STUDY
POPULATION. The
Institutional
clinically indicated, retrospectively gated cardiac CT
CT DATA ANALYSIS. CT measurements were per-
at our institution between August 2012 and February
formed offline by batch analysis using dedicated
2014 and were identified as being free of significant
software for MA segmentation (3mensio Structural
cardiac disease on the basis of CT findings and review
Heart V7.0; Pie Medical Imaging, Maastricht, the
of available clinical information were included as
Netherlands) and volumetric analyses (Aquarius
controls. Only scans performed with retrospective
iNtuition v4.4, TeraRecon, Foster City, California).
ECG gating were included so that multiphasic data
Different observers separately assessed MA parame-
could be analyzed. Exclusion criteria included: 1)
ters and cardiac volumes (P.B. and C.N. performed
known significant mitral valve disease and/or greater
all MA measurements by co-review and consensus
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Mitral Annular Dimensions in Mitral Regurgitation
N.B.
performed
all
cardiac
volume
saddle-shaped annulus from the posterior, D-shaped
measurements).
compartment. MA area and perimeter were computed
ASSESSMENT OF MR SEVERITY AND MECHANISM IN
for the D-shaped component by projection onto the
THE MR GROUP. MR severity was graded by review
least-squares plane fitted to the 3D annular contour.
of echocardiographic data according to guidelines
Total annular perimeter was calculated by adding the
for the assessment of MR severity (8). The mecha-
TT distance to the posterior 2D perimeter. The septal-
nism of MR was determined by separate review of
to-lateral (SL) distance was defined as the projected
both echocardiographic data and multiphasic (cine)
distance from the TT line to the posterior peak and
CT datasets using multiplanar reconstructions to
the intercommissural (IC) distance as the diameter
generate 2- and 3-chamber views of the LV. MVP was
perpendicular to the SL distance and parallel to the
defined by the presence of systolic excursion of a
TT distance transecting the centroid of the MA. The
mitral leaflet more than 2 mm beyond the annular
IC/SL ratio was also calculated as a measure of overall
plane in either a 2- or 3-chamber view (9). FMR was
MA geometry (Figure 1). Intraobserver and interob-
defined as LV remodeling (dilation and/or global or
server reproducibility of D-shaped MA measurements
regional LV dysfunction) that prevents leaflet coap-
has been recently documented (5).
tation in the absence of a primary mitral valve ab-
VOLUMETRIC
normality (10).
were measured using a threshold-based, region-
ANALYSES. LV
MA ASSESSMENT. The method for segmentation and
growing, 3D segmentation algorithm (Aquarius iNtu-
assessment of the D-shaped MA has been recently
ition). Endocardial and epicardial contours of the LV
described (5,11). Briefly, mid to late diastolic image
were automatically detected with subsequent manual
reconstructions with the least artifact identified by
adjustment of the contours and level of the mitral
visual assessment were used for MA segmentation.
valve plane. LV systolic and diastolic volumes were
The MA contour was generated by cubic-spline-
measured with subsequent calculation of LV stroke
interpolation of 16 seeding points manually placed
volume and ejection fraction. LA size was assessed at
along the insertion of the posterior mitral valve
end-systole corresponding to maximal LA volume by
leaflet and along the anterior peak comprising
using a semiautomated attenuation-based algorithm
the fibrous aortomitral continuity. The lateral and
for
medial fibrous trigones were then manually identified
correction (Aquarius iNtuition). LA volume excluded
and the distance between these 2 points defined
the LA appendage and pulmonary veins (12).
endocardial
border
volumes and mass
detection
with
manual
as the trigone-to-trigone (TT) distance, which sepa-
STATISTICAL ANALYSIS. Continuous variables are
rates the anterior compartment of the traditional
expressed as mean SD and categorical variables as
F I G U R E 1 D-Shaped Mitral Annular Segmentation
Short-axis (A) and long-axis (B) images demonstrating the D-shaped mitral annulus comprising the posterior horn (red contour) and trigoneto-trigone (TT) distance (white line), the latter virtually connecting both fibrous trigones (purple and green dots). The intercommissural (IC) distance (dotted yellow line) runs parallel to the TT distance and transects the centroid, and the septal-to-lateral (SL) distance runs perpendicular to the TT distance and transects the centroid. LA ¼ left atrium; LV ¼ left ventricle.
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number (percentage). Cardiac volumes and MA di-
association between annular size (MA area index)
mensions are indexed to body surface area (BSA)
and LA/LV volumes in patients with FMR or MVP,
calculated using the Mosteller formula (13). Indexed
nonparametric
values were compared between controls and MR
formed, given the smaller sample size in these groups.
(Spearman)
correlation
was
per-
subgroups using an unpaired Student t test or Mann-
Statistical analyses were performed using Graph-
Whitney U test as appropriate (normality determined
Pad Prism V6.0d (GraphPad Software, La Jolla,
using the Kolmogorov-Smirnov method) without
California) and SPSS Statistics 22 (IBM Corp., Armonk,
adjustment for multiple comparisons.
New York). A 2-tailed p value <0.05 was considered
For exploration of the determinants of the size of
statistically significant.
the D-shaped annulus beyond body size (a known correlate of MA dimensions [14]), and in particular to
RESULTS
understand the relative contribution of changes in LA and LV sizes, univariate predictors of MA area indexed
Between August 2012 and February 2014, 163 patients
to BSA were evaluated in the control group using
underwent retrospectively gated cardiac CT of a total
Pearson correlation. Multivariable linear regression
of 2,067 cardiac CT angiograms performed at our
was subsequently performed including univariate
institution during that period. The scans were pri-
predictors (p < 0.10) in the model. In cases of signifi-
marily performed for the evaluation of suspected
cant correlation (R $ 0.60) between 2 covariates, the
coronary artery disease; 75 patients had coronary ar-
variable with more significant univariate association
tery disease and were excluded from the study,
was included to avoid collinearity. Unstandardized
leaving 88 patients in the control cohort. Eighty-five
and standardized beta coefficients are reported for
consecutive patients with moderate to severe MR
individual variables, and the adjusted R2 is re-
being considered for TMVI were referred for cardiac
ported for the overall model. For assessment of the
CT between November 2013 and June 2015, 26 of
F I G U R E 2 Study Flow Chart
Retrospectively-gated cardiac CT performed for clinical indications (2012 and 2014) (N = 163)
Retrospectively-gated cardiac CT performed in patients with MR referred for consideration of transcatheter mitral therapy (2013- 2015) (N = 85)
N = 75 excluded Known mitral valve disease; OR mild or > MAC on CT (n = 5) Prior MI or revascularization (n = 9) CHF and/or LVEF<50% (n = 11) Complex CHD (n = 3) AF (n = 7) Obstructive CAD on CTA (≥ 70%) (n = 9) Prior cardiac surgery (n = 5) Poor image quality (n = 11) BMI > 35 (n = 13) Increased LV mass index or LA volume index (n = 2)
CONTROLS N = 88
N = 26 excluded Poor image quality annular and/or volumetric segmentation (n = 9) Aortic and/or mitral prosthesis (n = 13) Rheumatic mitral disease (n = 1) Unclear mechanism of MR (n = 3)
MVP N = 32
FMR N = 27
Patients included in the control, functional mitral regurgitation (FMR), and mitral valve prolapse (MVP) cohorts and reasons for exclusion. AF ¼ atrial fibrillation; BMI ¼ body mass index; CAD ¼ coronary artery disease; CHD ¼ congenital heart disease; CHF ¼ congestive heart failure; CT ¼ computed tomography; CTA ¼ computed tomography angiography; LVEF ¼ left ventricular ejection fraction; MAC ¼ mitral annular calcification; MI ¼ myocardial infarction; MR ¼ mitral regurgitation; other abbreviations as in Figure 1.
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Mitral Annular Dimensions in Mitral Regurgitation
whom were excluded, resulting in a total of 59 patients in the MR cohort (32 patients with MVP and 27 with FMR) (Figure 2). Baseline characteristics for the control group are presented in Table 1. Age was 56 11 years, and 47% of patients were female. LV and LA volumes and LV ejection fraction were consistent with reported values for healthy individuals (6).
T A B L E 2 Absolute and Indexed Mitral Annular Dimensions in Control Subjects
All (n ¼ 88)
Female (n ¼ 41)
Male (n ¼ 47)
Mean SD
8.9 1.5
8.4 1.2
9.3 1.6
Range
5.5–13.8
5.5–11.2
6.5–13.8
110.0 9.0
107.0 7.0
113.0 10.0
87.0–138.0
87.0–123.0
93.0–138.0
Mitral Annular Dimensions
p Value*
Absolute value Area, cm2 0.004
Perimeter, mm
In control subjects, mean MA area, MA area index, 2
2
and IC/SL ratio were 8.9 1.5 cm , 4.7 0.6 cm/m , and 1.38 0.14, respectively (Table 2). There was wide intersubject variability noted in MA area (Figure 3). Although annular dimensions were gener-
Mean SD Range TT distance, mm Mean SD
28.5 3.4
27.3 2.5
29.5 3.8
Range
20.0–38.0
20.0–33.0
21.0–38.0
27.5 2.7
27.1 2.3
27.8 3.0
21.5–35.1
22.1–31.4
21.5–35.1
0.001
SL distance, mm
ally larger in men compared with women, the differ-
Mean SD
ences largely disappeared after values were indexed
Range
to BSA (Table 2).
0.001
0.21
IC distance, mm
MA dimensions correlated positively with BSA, as expected (Figure 4). Univariate and multivariate predictors of MA area index in controls are presented in Table 3. Age and sex were not associated with MA area index. Both LV and LA volumes were independently associated with MA area index, with LV systolic vol-
Mean SD
37.6 3.7
36.1 2.9
38.8 3.9
Range
28.6–48.6
28.6–42.8
28.8–48.6
Mean SD
4.7 0.6
4.7 0.7
4.8 0.5
Range
3.3–7.4
3.3–7.4
3.7–6.0
59.0 5.0
60.0 6.0
58.0 5.0
47.0–81.0
47.0–69.0
47.0–69.0
Mean SD
15.3 1.9
15.4 1.8
15.2 1.9
Range
10.8–20.3
11.3–20.3
10.8–20.0
Mean SD
14.8 1.6
15.2 1.7
14.4 1.5
Range
11.2–20.6
12.2–20.6
11.2–18.5
20.2 1.9
20.3 2.1
20.0 1.8
16.4–27.3
16.4–27.3
17.0–25.1
Mean SD
1.38 0.14
1.34 0.12
1.41 0.16
Range
1.04–1.75
Value indexed to BSA Area, cm2/m2
ume index (beta ¼ 0.40; p < 0.001) slightly more
Mean SD Range
T A B L E 1 Baseline Characteristics for Control Subjects (n ¼ 105)
Demographics 56 11 55 (47–65)
Female
41 (47)
Body mass index, kg/m2
26.7 3.7
Body surface area, m2
1.88 0.21
Cardiac CT parameters LV diastolic volume index, ml/m2 All
58 13
Female
58 15
Male
59 12
All
21 7
Female
19 7
Male
22 7
Mean SD Range
1.12–1.57
1.04–1.75
*p Value compares differences between women and men. BSA ¼ body surface area; IC ¼ intercommissural; SL ¼ septal-to-lateral; TT ¼ trigone-to-trigone.
MA dimensions and cardiac volumes among MR Controls were younger compared with both patients
51–81
with MVP and FMR and had higher mean BMI and
LV diastolic mass index, g/m2 All
67 12
Female
62 11 72 12
Male 2
Maximal LA volume index, ml/m
BSA values compared with patients with MVP. MA dimensions were generally larger in MR subgroups compared with controls, even after BSA was indexed to account for the differences in BSA. The range of
All
46 8
absolute annular areas observed in patients with FMR
Female
48 9
and MVP is shown in Figure 5.
Male
45 8
Values are mean SD, unless otherwise indicated. CT ¼ computed tomography; LA ¼ left atrial; LV ¼ left ventricular.
0.50
IC/SL ratio
65 7
Range
0.01
IC distance, mm/m2
subgroups and controls are compared in Table 4.
LV ejection fraction, %
0.69
SL distance, mm/m2
LV systolic volume index, ml/m2
Mean SD
0.15
TT distance, mm/m2
index (beta ¼ 0.31; p ¼ 0.001).
Median (interquartile range)
0.66
Perimeter, mm/m2
predictive of MA area index than maximal LA volume
Age, yrs
<0.001
Annular geometry was also modified in patients with moderate to severe MR compared with controls. Whereas IC and SL distances were both increased, the IC/SL ratio was smaller in both patients with FMR and
0.03
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F I G U R E 3 Mitral Annular Size in Control Subjects Stratified by Sex
Men
Women
B 15
14
14
13
13
Mitral Annular Area (cm2)
Mitral Annular Area (cm2)
A 15
12 11 10 9 8
12 11 10 9 8
7
7
6
6
5
5 1
5
9
13
17
21
25
29
33
37
41
45
1
5
9
13
Patient No.
D Mitral Annular Area / BSA (cm2 / m2)
Mitral Annular Area / BSA (cm2 / m2)
C
17
21
25
29
33
37
41
29
33
37
41
Patient No.
8
7
6
5
4
3
8
7
6
5
4
3 1
5
9
13
17
21
25
29
33
37
41
45
1
5
9
13
Patient No.
17
21
25
Patient No. Median
25-75%
5-95%
0-100%
The wide range of absolute (A and B) and indexed (C and D) mitral annular area values in male (green) and female (pink) control subjects without significant cardiac disease.
MVP compared with controls, indicating that annular
MA area index in patients with FMR was associated
remodeling in patients with MR involved relatively
with increasing maximal LA volume index (R ¼ 0.67;
more SL (anteroposterior) rather than lateral (IC)
p < 0.001) but not with LV volumes. In contrast, MA
expansion.
area index in patients with MVP demonstrated a
Differences were noted in annular dimensions be-
positive correlation with both LV systolic volume in-
tween MR subgroups (Table 4). Despite LV volumes
dex (R ¼ 0.48; p ¼ 0.005) and maximal LA volume
being significantly larger in patients with FMR
index (R ¼ 0.48; p ¼ 0.005).
compared with patients with MVP, mean MA area was 18% larger in the MVP group. IC/SL ratio was smaller
DISCUSSION
in the FMR group compared with the MVP group. There were no significant differences in annular di-
In the present study, we reported D-shaped MA di-
mensions between ischemic and nonischemic sub-
mensions using CT in patients with moderate to se-
groups of FMR (Online Table).
vere MR being considered for TMVI and compare
The associations between annular size and LV and
these findings with those of subjects without signifi-
LA volumes were discrepant in patients with MVP and
cant cardiac disease. Among controls, we noted wide
FMR compared with controls (Figure 6). Increasing
interindividual variation in MA dimensions, as well as
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F I G U R E 4 Relationship Between Body Surface Area and Mitral Annular Dimensions in Controls
160 R = 0.66 p < 0.001
R = 0.66 p < 0.001
140
15
Perimeter (mm)
Mitral Annular Area (cm2)
20
10
120
100 5 80 1.0
1.5 2.0 Body-surface Area (m2)
2.5
1.0
40
2.5
55 R = 0.51 p < 0.001
35
30
25
R = 0.64 p < 0.001
50 IC Distance (mm)
SL Distance (mm)
1.5 2.0 Body-surface Area (m2)
45 40 35 30 25
20 1.0
1.5 2.0 Body-surface Area (m2)
2.5
1.0
1.5 2.0 Body-surface Area (m2)
2.5
Pearson correlation plots are shown, with linear regression lines demonstrating a positive association between mitral annular dimensions and body surface area in control subjects. IC ¼ intercommissural; SL ¼ septal-to-lateral.
an independent positive association between MA size
T A B L E 3 Univariate and Multivariate Predictors of Mitral Annulus Area Index in
and LV and LA sizes. Annular dimensions were larger
Control Subjects (n ¼ 88)
in patients with MR and annular geometry distorted
Univariate Analysis
with SL expansion. Although patients with MVP
Multivariate Analysis*
R Value
p Value
B (SE)
Beta
p Value
Age
0.42
size and both LA and LV systolic volumes, in patients
0.09
—
—
—
Female
0.05
0.63
—
—
—
with FMR, annular size appeared to only be associ-
LV diastolic volume index
0.40
<0.001
—
—
—
ated with increasing LA size. Importantly, annular
LV systolic volume index
0.44
<0.001
0.03 (0.008)
0.40
<0.001
dimensions were larger in MVP compared with FMR,
LV ejection fraction
0.27
0.01
—
—
—
which has implications for annular and therefore
LV diastolic mass index
0.04
0.73
—
—
device sizing prior to TMVI.
Maximal LA volume index
0.35
<0.001
0.02 (0.007)
0.31
demonstrated a positive correlation between annular
Whereas traditional descriptions of MA geometry regard the annulus to be a saddle-shaped, nonplanar, 3D structure (15), the concept of a D-shaped MA was recently proposed as being more appropriate for
— 0.001
*LV diastolic volume index and LV ejection fraction were not included due to collinearity with LV systolic volume index (R ¼ 0.83 and R ¼ 0.76, respectively), which was the more significant univariate predictor. Overall model: adjusted R2 ¼ 0.27 (p < 0.001). Abbreviations as in Table 1.
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T A B L E 4 Mitral Annular Dimensions and Cardiac Volumes in Control Subjects and
Patients With MR
but ranging from 5.5 to 13.8 cm 2. Prior studies of MA values have reported a broad range of normal values. Early 2D echocardiographic studies found relatively
Patients With MR
small annular areas, with one study reporting a mean
Controls (n ¼ 88)
MVP (n ¼ 32)
FMR (n ¼ 27)
p Value*
Age, yrs
56 11
78 12†
70 13†
0.02
techniques have reported normal mean values ranging
Female
41 (47)
13 (41)
7 (26)
0.27
from 8.4 to 11.8 cm2 (indexed 4.7 to 5.1 cm 2/m 2)
(17). More recent studies using 3D echocardiographic
Demographics
2
maximal MA area of 7.1 cm 2 (indexed 3.8 cm 2/m 2)
26.7 3.7
24.5 3.5‡
25.4 5.8
0.47
(14,18,19). Cardiac CT studies reporting normative MA
1.88 0.21
1.79 0.21§
1.85 0.27
0.31
values have primarily assessed patients with MR, with
Moderate
—
5 (16)
2 (7)
0.62
Severe
—
27 (84)
25 (93)
0.62
Body mass index, kg/m Body surface area, m2
Mitral regurgitation severity
only small cohorts of healthy subjects included as
Mitral annular dimensions
studies have ranged from 8.4 to 10.2 cm 2 (indexed 4.5 to 5.5 cm 2/m2 ) (1–4,14). In the largest CT series to
Absolute value Area, cm
controls. Mean values for normal MA area in these
2
Perimeter, mm
8.9 1.5
13.0 2.9†
11.0 2.3†
0.006
evaluate healthy subjects (n ¼ 84), Delgado et al. (1)
110 9
132 14†
122 12†
0.004
reported mean MA area, anteroposterior (SL), and IC
TT distance, mm
28.5 3.4
33.9 3.7†
30.1 3.7§
<0.001
distances of 4.8 0.9 cm 2/m 2, 12.5 2.1 mm/m 2, and
SL distance, mm
27.5 2.7
34.5 4.5†
32.9 4.4†
0.18
37.6 3.7
43.8 5.0†
38.9 4.4
<0.001
21.6 2.5 mm/m 2, respectively. Our mean values for
IC distance, mm
4.7 0.6
7.3 1.7†
6.0 1.3†
0.002
Value indexed to BSA 2
Area, cm /m
2 2
MA area are therefore at the lower end of reported values. This would be largely explained by the deliberate truncation of the anterior horn using our
59 5
75 10†
67 9†
TT distance, mm/m2
15.3 1.9
19.1 2.1†
16.4 2.0‡
<0.001
method; however, the broad range of values across
SL distance, mm/m2
14.8 1.6
19.5 3.4†
18.1 3.3†
0.10
studies, allowing for the clinical heterogeneity of
IC distance, mm/m2
20.2 1.9
24.7 3.2†
21.2 3.1§
<0.001
study subjects, highlights the difficulties of and lack of
1.38 0.14
1.28 0.10†
1.19 0.13†
58 13
100 27†
158 59†
LV systolic volume index, ml/m
21 7
48 21†
115 56†
<0.001
LV ejection fraction, %
65 7
52 14†
30 11†
<0.001
Maximal LA volume index, ml/m2
46 8
112 35†
102 34†
0.28
Perimeter, mm/m
IC/SL ratio
0.003
0.008
Cardiac volumes LV diastolic volume index, ml/m2 2
standardized annular evaluation. Sex differences in MA dimensions were also noted
<0.001
in control subjects, with men generally exhibiting larger absolute MA dimensions than women. After correction
for
BSA,
however,
these
differences
largely disappeared, except for SL distance, which Values are mean SD or n (%). *p Value compares means between MVP and FMR groups for continuous variables and chi-square test for categorical variables. For comparison between MR subgroups and controls for continuous variables and chi-square test for trend for categorical variables. †p < 0.01. ‡p < 0.05. §p < 0.001.
was larger in women. Sonne et al. (14) similarly
FMR ¼ functional mitral regurgitation; MR ¼ mitral regurgitation; MVP ¼ mitral valve prolapse; other abbreviations as in Tables 1 and 2.
and women after correction for BSA, with the
noted no difference in MA dimensions between men exception of medial-lateral MA diameter. In contrast, Mihaila et al. (19) noted larger indexed annular
TMVI sizing because it better reflects the planar landing zone of TMVI devices. Importantly, D-shaped MA segmentation eliminates the difficulties associated with defining and segmenting the anterior horn. Historically,
there
has
been
marked
variation
observed between surgical and noninvasive imaging definitions of the anterior horn, with surgeons typi-
dimensions in men compared with women in a larger cohort of 224 healthy volunteers studied with 3D echocardiography. Combined, these data suggest that although sex-related differences in annular dimensions
largely
reflect
differences
in
BSA
between men and women, subtle differences may still exist beyond body size.
cally estimating a less pronounced horn due to their
MA DIMENSIONS AND GEOMETRY IN PATIENTS WITH MR
ability to directly visualize and discriminate between
AND THE
atrial myocardium and fibrous tissue. For these rea-
IMPLICATIONS
FOR
DEVICE
SIZING. MA
dimensions were larger in patients with MR, with MA
sons, the D-shape provides a more standardized and
area measuring 43% larger in patients with MVP and
reproducible method of annular evaluation and is
24% larger in patients with FMR, compared with
now being formally used to screen and provide MA
controls. Annular geometry was also distorted in pa-
sizes in patients being evaluated prior to TMVI (5,16).
tients with MR with greater SL expansion (reduced
MA
SUBJECTS
IC/SL ratio). Although these results are consistent
WITHOUT SIGNIFICANT CARDIAC DISEASE. Wide
with those of previous studies using the saddle-
interindividual variation in MA dimensions was seen
shaped annulus (1,3), our findings provide unique
in control subjects, with a mean value of 8.9 1.5 cm 2,
sizing and geometric information using the D-shaped
MEASUREMENTS
IN
CONTROL
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Mitral Annular Dimensions in Mitral Regurgitation
F I G U R E 5 Mitral Annular Size in Patients With Moderate to Severe MR
B
22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5
19 18 17 16
Mitral Annular Area (cm2)
Mitral Annular Area (cm2)
A
15 14 13 12 11 10 9 8 7 6 5
1
3 2
5 4
7 6
9 8
11 13 15 17 19 21 23 25 27 29 31 10 12 14 16 18 20 22 24 26 28 30 32
1
3 2
5 4
7 6
9 8
11 10
Patient No.
13 12
15 14
17 16
19 18
Patient No.
Median
25-75%
5-95%
0-100%
The range of absolute mitral annular area values in patients with MVP (A) or FMR (B). Abbreviations as in Figure 2.
annulus, which has implications for the development
DETERMINANTS OF ANNULAR SIZE IN CONTROLS
and implantation of TMVI devices. Of particular
AND PATIENTS WITH MR. Age was not associated
importance is the observation of larger MA sizes in
with changes in MA size in control subjects, consis-
patients with MVP compared with patients with FMR
tent with previous studies (14). There was also no
because this has implications in relation to the
association between sex and MA size, likely due to
availability of appropriate device sizes for these
the correction for BSA as discussed above. We did,
clearly different conditions. The finding of larger MA
however, observe an association between MA size
dimensions in patients with MVP is consistent with
and both LA and LV sizes, suggesting independent
previous 3D echocardiographic studies (20) and is
contribution from both chambers to annular size in
thought to be due to increased outward tension on
controls. These findings were different than the ob-
the MA during systole in the setting of excessive
servations in patients with MR. In patients with MVP,
mitral valve tissue (21). Apart from this pathophysi-
a positive correlation between MA area index and
ological mechanism, larger annular dimensions in
both LV and LA sizes was seen; however, in patients
patients with MVP may result from displacement of
with FMR, MA area index was positively associated
the posterior segmentation line into the LA due to
with LA volume only. The cause of FMR has been
disjunction of the mitral valve leaflet insertion from
attributed to various mechanisms, including systolic
the atrioventricular junction (Figure 7), which has
leaflet tethering to displaced papillary muscles in a
been previously reported in association with myxo-
remodeled LV (24), abnormal LV systolic function and
matous mitral valve disease (22,23). Segmentation of
shape (25), and annular remodeling (26). Interest-
the annulus to reflect the anticipated landing zone as
ingly, in a recent study of patients with MR but
opposed to the anatomic site of MV leaflet insertion is
structurally normal mitral valves, an independent
important in the setting of MA disjunction, although
association between LA enlargement and annular
further investigation is needed to better understand
dilation was observed (27), similar to our study, irre-
the impact of disjunction on device sealing and
spective
capture.
dysfunction.
of
the
presence
of
LV
dilation
and
21 20
23 22
25 24
27 26
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F I G U R E 6 Relationship Between Mitral Annular Size and Atrioventricular Remodeling in Patients With Moderate to Severe MR
MVP
150 100 50 0
2
4
6
8
100
50
80 70 60 50 40 30 20 10 0
0
2
4
6
8
0
2
4
6
8
200 100
10 12 14
0
2
4
6
8
10 12 14
6
8
10 12 14
6
8
10 12 14
R = 0.21 p = 0.30 200
100
0 80 70 60 50 40 30 20 10 0
0
2
4
R = 0.10 p = 0.60
0
2
4
200 R = 0.48 p = 0.005
150 100 50
LAVMax /BSA (ml/m2)
250 200
300
300
10 12 14
R = 0.33 p = 0.06
R = 0.21 p = 0.29
0
10 12 14
LV Systolic Volume/BSA (ml/m2)
LV Systolic Volume/BSA (ml/m2)
0
R = 0.48 p = 0.005
0
LV Ejection Fraction (%)
LV Diastolic Volume/BSA (ml/m2)
R = 0.33 p = 0.07
150
FMR
400
LV Ejection Fraction (%)
LV Diastolic Volume/BSA (ml/m2)
200
LAVMax /BSA (ml/m2)
10
0
0 2 4 6 8 10 12 14 Mitral Annular Area / BSA (cm2/m2)
R = 0.67 p < 0.001 150 100 50 0
0 2 4 6 8 10 12 14 Mitral Annular Area / BSA (cm2/m2)
Spearman correlation between mitral annular area index and LA and LV volumes in patients with MVP (left) or FMR (right). Mitral annular area index correlated positively with both LV systolic volume index and LA volume index in patients with MVP but only with LA volume index in patients with FMR. BSA ¼ body surface area; other abbreviations as in Figures 1 and 2.
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F I G U R E 7 Landing Zone Anatomy Examples
Examples of the atrioventricular junction in (A) a control subject showing the normal appearance, (B) a patient with MVP demonstrating disjunction between the MV insertion point and atrioventricular junction (red arrows), and (C) a patient with FMR showing a prominent “atrioventricular shelf” (black arrows) formed by the left ventricular myocardium immediately adjacent to the MV insertion point. Abbreviations as in Figure 2.
STUDY LIMITATIONS. MA dimensions were measured
sample sizes, particularly in the FMR cohort. More-
at mid to late diastole; however, prior studies have
over, the ability of D-shaped annular segmentation to
reported intracycle variation in MA area, with larger
appropriately size the annulus for the purposes of
values previously observed in diastole (2,18). Patients
device selection and the subsequent impact on clin-
with MR were being considered for TMVI because
ical outcomes needs to be addressed in future studies.
they were deemed unfit for surgery. Similarly, controls were only included if they underwent CT with
CONCLUSIONS
retrospective ECG gating, which represented a small proportion of the overall sample. These referral and
Significant interindividual variability in D-shaped MA
selection biases limit the applicability of our data to
dimensions was seen in patients without significant
similar patients. Hypertensive patients were not
cardiac disease. Among patients with moderate to
excluded from the controls cohort (history of hyper-
severe MR, significant MA enlargement was observed
tension present in 44%), and this condition may be
and was associated with SL (anteroposterior) MA
associated with diastolic dysfunction and therefore
expansion. Importantly, patients with MVP exhibited
atrioventricular remodeling. However, patients with
larger MA dimensions than patients with FMR, and
increased LA volume index, which is sensitive for the
the drivers of annular enlargement appeared to be
detection of severe diastolic dysfunction (28), and
different in these cohorts, with LA dilation contrib-
increased LV mass index were excluded. Moreover,
uting more significantly in patients with FMR. Our
we reviewed the electronic charts of controls to
findings provide insights into the size and geometry
ensure that subjects with an echocardiographic report
of the D-shaped annulus and the drivers of MA dila-
did not have evidence of severe diastolic dysfunction,
tion in patients being considered for transcatheter
minimizing the impact of such changes on our results.
mitral therapy.
Although CT provides 3D data with high spatial resolution, it is somewhat limited by its ionizing radia-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
tion. Although the present study provides important
Philipp Blanke, St. Paul’s Hospital, University of
insights into potential interactions between atrio-
British Columbia, 1081 Burrard Street, Vancouver,
ventricular and annular remodeling, our results
British Columbia V6Z 1Y6, Canada. E-mail: phil.
should be interpreted cautiously due to the small
[email protected].
11
12
Naoum et al.
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PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: The
annular enlargement in FMR is more closely associated
D-shaped approach to MA segmentation is considered a
with LA dilation.
more biomechanically appropriate method currently used to screen and size patients being considered for trans-
TRANSLATIONAL OUTLOOK: Further studies are
catheter mitral valve therapy. Patients with moderate to
needed to elucidate the impact of this knowledge of
severe MR exhibit larger D-shaped MA dimensions, as
D-shaped MA dimensions, geometry, and drivers of
well as annular remodeling characterized by SL expan-
annular size on device performance and clinical outcomes
sion, than control subjects, especially patients with MVP.
following TMVI.
Unlike in controls and patients with MVP, D-shaped
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KEY WORDS computed tomography, mitral annulus, mitral regurgitation, TMVI, TMVR, transcatheter mitral valve implantation
A PPE NDI X For a supplemental table, please see the online version of this article.