Mitral Annular Dimensions and Geometry in Patients With Functional Mitral Regurgitation and Mitral Valve Prolapse

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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agreement;

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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Mitral Annular Dimensions in Mitral Regurgitation

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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9

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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Mitral Annular Dimensions in Mitral Regurgitation

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

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Mitral Annular Dimensions in Mitral Regurgitation

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.