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Mitral Annular Dimensions and Geometryin Patients With Functional MitralRegurgitation and Mitral Valve ProlapseImplications 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

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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 appro-

priate 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;9:269–80)

© 2016 by the American College of Cardiology Foundation.

m aSt. Paul’s Hospital and University of British Columbia, Center for Heart Valve Innovation, Vancouver, British Columbia,

nada; bSt. Vincent’s Hospital, Sydney, Australia; and the cDepartment of Medicine, Division of Cardiology, McGill University

alth Centre, Montreal, Quebec, Canada. Dr. Leipsic has served as a consultant to Edwards Lifesciences and Neovasc Inc.;

d has provided CT core laboratory services to Edwards Lifesciences, Neovasc Inc., and Tendyne Holdings Inc. Dr. Cheung

s served as a consultant to Edwards Lifesciences and Neovasc Inc. Drs. Ye and Webb have served as consultants to Edwards

esciences. Dr. Piazza has served on scientific advisory boards for Medtronic; has served as a consultant for HighLife SAS;

d owns equity shares in HighLife SAS. Dr. Blanke has served as a consultant to Edwards Lifesciences, Neovasc Inc., Tendyne

ldings Inc., and Circle Imaging; and has provided CT core laboratory services to Edwards Lifesciences, Neovasc Inc., and

ndyne Holdings Inc. All other authors have reported that they have no relationships relevant to the contents of this paper

disclose.

nuscript received July 2, 2015; revised manuscript received August 18, 2015, accepted August 20, 2015.

ABBR EV I A T I ON S

AND ACRONYMS

BMI = body mass index

BSA = body surface area

CT = computed tomography

FMR = functional mitral

regurgitation

IC = intercommissural

LA = left atrial/atrium

LV = left ventricle/ventricular

MA = mitral annular/annulus

MR = mitral regurgitation

MVP = mitral valve prolapse

SL = septal-to-lateral

TMVI = transcatheter mitral

valve implantation

TT = trigone-to-trigone

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W ith the rapid innovation andgrowing clinical adoption oftranscatheter mitral therapies,

including transcatheter mitral valve implan-tation (TMVI), an accurate understanding ofmitral annular (MA) dimensions and geome-try is becoming increasingly important.Given the saddle-shaped, nonplanar configu-ration of the MA, 3-dimensional (3D) imagingis required for comprehensive assessment.Although this can be achieved usingcomputed tomography (CT), with its excel-lent spatial resolution (1–4), limited dataexist describing CT values for MA dimensionsin patients with significant mitral regurgita-tion (MR) in whom TMVI may be a potentialtherapeutic option.

We recently proposed a D-shaped concept

of MA geometry, in which the annulus is truncatedalong a virtual line connecting both fibrous trigones,as a standardized, reproducible, and more biome-chanically appropriate method for MA sizing prior toTMVI (5). An important characteristic of the D-shapedsegmentation method is that it yields a more planarannulus that closely resembles the cross-sectionalarea of current TMVI devices, which is not achievedby conventional (saddle-shaped) analyses. Annularsize and geometry and the determinants of MA size inpatients with moderate to severe MR have not beenstudied using the D-shaped method. Moreover, therange of D-shaped MA dimensions in patients withoutsignificant cardiac disease is unknown.

SEE PAGE 281

Accordingly, we sought to determine annular di-mensions, geometry, and drivers of annular size inpatients with moderate to severe MR and comparethese findings with those of control subjects withoutsignificant cardiac disease using retrospectivelyelectrocardiographically (ECG) gated cardiac CT.

METHODS

STUDY POPULATION. The Institutional ReviewBoard approved this retrospective study with awaiver for informed consent. Two study cohorts wereidentified. Consecutive patients who underwentclinically indicated, retrospectively gated cardiac CTat our institution between August 2012 and February2014 and were identified as being free of significantcardiac disease on the basis of CT findings and reviewof available clinical information were included ascontrols. Only scans performed with retrospectiveECG gating were included so that multiphasicdata could be analyzed. Exclusion criteria included:

1) known significant mitral valve disease and/orgreater than mild MA calcification seen on cardiac CT;2) clinical history of congestive heart failure and/orreduced measured left ventricular (LV) ejectionfraction <50%; 3) obstructive coronary artery diseaseon cardiac CT ($70% in any coronary vessel or >50%in the left main) or prior coronary revascularization;4) history of atrial fibrillation; 5) prior cardiac surgery;6) complex congenital heart disease; 7) obesity (bodymass index [BMI] >35 kg/m2); 8) increased maximalleft atrial (LA) volume index (>78 ml/m2, a cutoffrepresenting 2 SDs from the mean value previouslyreported in healthy subjects [6]); and/or increased LVmass index (>103 g/m2 for men and >89 g/m2 forwomen [7]). Consecutive patients with moderate tosevere MR referred for cardiac CT between November2013 and June 2015 for workup prior to potentialTMVI were included. Patients with MR were dividedinto 2 groups based on MR mechanism (mitral valveprolapse [MVP] or functional mitral regurgitation[FMR]). Patients with a prior aortic and/or mitralvalve prosthesis were excluded from the MR group.

CARDIAC CT DATA ACQUISITION. Cardiac CT wasperformed using a 64-slice helical CT scanner (Dis-covery high-definition 750 or VCT, GE Healthcare,Milwaukee, Wisconsin). For controls, CT acquisitionwas undertaken according to the institutional proto-col for performing retrospectively gated clinical car-diac CT. For patients with MR, a pre-specified clinicalcardiac CT protocol was used. Imaging was performedduring a single breath-hold following injection of 80to 110 ml of intravenous contrast media (Visipaque320, GE Healthcare) with a triphasic injection(contrast, contrast/saline mix, and saline) for controlsand a biphasic injection (contrast and saline) for pa-tients with MR. Tube voltage and current weremanually determined (on the basis of BMI) withsubsequent ECG modulation of tube current for con-trols to minimize radiation dose (median [inter-quartile range] effective dose 9.6 mSv [5.7 to 11.8mSv] in controls and 14.1 mSv [11.3 to 20.2 mSv] inpatients with MR). Scan range extended from thecarina to just below the inferior cardiac surface. Axialimages were reconstructed at 10% intervals of thecardiac cycle with a slice thickness of 0.625 mm.

CT DATA ANALYSIS. CT measurements were per-formed offline by batch analysis using dedicatedsoftware for MA segmentation (3mensio StructuralHeart V7.0, Pie Medical Imaging, Maastricht, theNetherlands) and volumetric analyses (AquariusiNtuition v4.4, TeraRecon, Foster City, California).Different observers separately assessed MA parame-ters and cardiac volumes (P.B. and C.N. performed

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all MA measurements by co-review and consensusagreement; N.B. performed all cardiac volumemeasurements).

ASSESSMENT OF MR SEVERITY AND MECHANISM IN

THE MR GROUP. MR severity was graded by reviewof echocardiographic data according to guidelinesfor the assessment of MR severity (8). The mecha-nism of MR was determined by separate review ofboth echocardiographic data and multiphasic (cine)CT datasets using multiplanar reconstructions togenerate 2- and 3-chamber views of the LV. MVP wasdefined by the presence of systolic excursion of amitral leaflet more than 2 mm beyond the annularplane in either a 2- or 3-chamber view (9). FMR wasdefined as LV remodeling (dilation and/or global orregional LV dysfunction) that prevents leaflet coap-tation in the absence of a primary mitral valve ab-normality (10).

MA ASSESSMENT. The method for segmentation andassessment of the D-shaped MA has been recentlydescribed (5,11). Briefly, mid to late diastolic imagereconstructions with the least artifact identified byvisual assessment were used for MA segmentation.The MA contour was generated by cubic-spline-interpolation of 16 seeding points manually placedalong the insertion of the posterior mitral valveleaflet and along the anterior peak comprisingthe fibrous aortomitral continuity. The lateral andmedial fibrous trigones were then manually identifiedand the distance between these 2 points definedas the trigone-to-trigone (TT) distance, which sepa-rates the anterior compartment of the traditional

FIGURE 1 D-Shaped Mitral Annular Segmentation

Short-axis (A) and long-axis (B) images demonstrating the D-shaped mi

to-trigone (TT) distance (white line), the latter virtually connecting both

distance (dotted yellow line) runs parallel to the TT distance and trans

perpendicular to the TT distance and transects the centroid. LA ¼ left a

saddle-shaped annulus from the posterior, D-shapedcompartment. MA area and perimeter were com-puted for the D-shaped component by projectiononto the least-squares plane fitted to the 3D annularcontour. Total annular perimeter was calculated byadding the TT distance to the posterior 2D perimeter.The septal-to-lateral (SL) distance was defined asthe projected distance from the TT line to the pos-terior peak and the intercommissural (IC) distanceas the diameter perpendicular to the SL distance andparallel to the TT distance transecting the centroidof the MA. The IC/SL ratio was also calculated asa measure of overall MA geometry (Figure 1). In-traobserver and interobserver reproducibility ofD-shaped MA measurements has been recentlydocumented (5).

VOLUMETRIC ANALYSES. LV volumes and masswere measured using a threshold-based, region-growing, 3D segmentation algorithm (Aquarius iNtu-ition). Endocardial and epicardial contours of the LVwere automatically detected with subsequent manualadjustment of the contours and level of the mitralvalve plane. LV systolic and diastolic volumes weremeasured with subsequent calculation of LV strokevolume and ejection fraction. LA size was assessed atend-systole corresponding to maximal LA volume byusing a semiautomated attenuation-based algorithmfor endocardial border detection with manualcorrection (Aquarius iNtuition). LA volume excludedthe LA appendage and pulmonary veins (12).

STATISTICAL ANALYSIS. Continuous variables areexpressed as mean � SD and categorical variables as

tral annulus comprising the posterior horn (red contour) and trigone-

fibrous trigones (purple and green dots). The intercommissural (IC)

ects the centroid, and the septal-to-lateral (SL) distance runs

trium; LV ¼ left ventricle.

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number (percentage). Cardiac volumes and MA di-mensions are indexed to body surface area (BSA)calculated using the Mosteller formula (13). Indexedvalues were compared between controls and MRsubgroups using an unpaired Student t test or Mann-Whitney U test as appropriate (normality determinedusing the Kolmogorov-Smirnov method) withoutadjustment for multiple comparisons.

For exploration of the determinants of the size ofthe D-shaped annulus beyond body size (a knowncorrelate of MA dimensions [14]), and in particular tounderstand the relative contribution of changes in LAand LV sizes, univariate predictors of MA area indexedto BSA were evaluated in the control group usingPearson correlation. Multivariable linear regressionwas subsequently performed including univariatepredictors (p < 0.10) in the model. In cases of signifi-cant correlation (R $ 0.60) between 2 covariates, thevariable with more significant univariate associationwas included to avoid collinearity. Unstandardizedand standardized beta coefficients are reported forindividual variables, and the adjusted R2 is re-ported for the overall model. For assessment of the

FIGURE 2 Study Flow Chart

Retrospectively-gated cardiac CTperformed for clinical indications

(2012 and 2014)(N = 163)

CONTROLSN = 88

N = 75 excludedKnown 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 indexor LA volume index (n = 2)

Patients included in the control, functional mitral regurgitation (FMR), a

AF ¼ atrial fibrillation; BMI ¼ body mass index; CAD ¼ coronary artery dis

CT ¼ computed tomography; CTA ¼ computed tomography angiograph

calcification; MI ¼ myocardial infarction; MR ¼ mitral regurgitation; oth

association between annular size (MA area index)and LA/LV volumes in patients with FMR or MVP,nonparametric (Spearman) correlation was per-formed, given the smaller sample size in these groups.

Statistical analyses were performed using Graph-Pad Prism V6.0d (GraphPad Software, La Jolla,California) and SPSS Statistics 22 (IBM Corp., Armonk,New York). A 2-tailed p value <0.05 was consideredstatistically significant.

RESULTS

Between August 2012 and February 2014, 163 patientsunderwent retrospectively gated cardiac CT of a totalof 2,067 cardiac CT angiograms performed at ourinstitution during that period. The scans were pri-marily performed for the evaluation of suspectedcoronary artery disease; 75 patients had coronary ar-tery disease and were excluded from the study,leaving 88 patients in the control cohort. Eighty-fiveconsecutive patients with moderate to severe MRbeing considered for TMVI were referred for cardiacCT between November 2013 and June 2015, 26 of

Retrospectively-gated cardiac CT performed in patientswith MR referred for consideration of

transcatheter mitral therapy (2013- 2015)(N = 85)

MVPN = 32

FMRN = 27

N = 26 excludedPoor image quality annular and/orvolumetric segmentation (n = 9)

Aortic and/or mitral prosthesis (n = 13)Rheumatic mitral disease (n = 1)Unclear mechanism of MR (n = 3)

nd mitral valve prolapse (MVP) cohorts and reasons for exclusion.

ease; CHD ¼ congenital heart disease; CHF ¼ congestive heart failure;

y; LVEF ¼ left ventricular ejection fraction; MAC ¼ mitral annular

er abbreviations as in Figure 1.

TABLE 2 Absolute and Indexed Mitral Annular Dimensions in Control Subjects

Mitral Annular DimensionsAll

(n ¼ 88)Female(n ¼ 41)

Male(n ¼ 47) p Value*

Absolute value

Area, cm2

Mean � SD 8.9 � 1.5 8.4 � 1.2 9.3 � 1.6 0.004

Range 5.5–13.8 5.5–11.2 6.5–13.8

Perimeter, mm

Mean � SD 110.0 � 9.0 107.0 � 7.0 113.0 � 10.0 0.001

Range 87.0–138.0 87.0–123.0 93.0–138.0

TT distance, mm

Mean � SD 28.5 � 3.4 27.3 � 2.5 29.5 � 3.8 0.001

Range 20.0–38.0 20.0–33.0 21.0–38.0

SL distance, mm

Mean � SD 27.5 � 2.7 27.1 � 2.3 27.8 � 3.0 0.21

Range 21.5–35.1 22.1–31.4 21.5–35.1

IC distance, mm

Mean � SD 37.6 � 3.7 36.1 � 2.9 38.8 � 3.9 <0.001

Range 28.6–48.6 28.6–42.8 28.8–48.6

Value indexed to BSA

Area, cm2/m2

Mean � SD 4.7 � 0.6 4.7 � 0.7 4.8 � 0.5 0.66

Range 3.3–7.4 3.3–7.4 3.7–6.0

Perimeter, mm/m2

Mean � SD 59.0 � 5.0 60.0 � 6.0 58.0 � 5.0 0.15

Range 47.0–81.0 47.0–69.0 47.0–69.0

TT distance, mm/m2

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whom were excluded, resulting in a total of 59patients in the MR cohort (32 patients with MVP and27 with FMR) (Figure 2).

Baseline characteristics for the control group arepresented in Table 1. Age was 56 � 11 years, and 47%of patients were female. LV and LA volumes and LVejection fraction were consistent with reported valuesfor healthy individuals (6).

In control subjects, mean MA area, MA area index,and IC/SL ratio were 8.9 � 1.5 cm2, 4.7 � 0.6 cm/m2,and 1.38 � 0.14, respectively (Table 2). There waswide intersubject variability noted in MA area(Figure 3). Although annular dimensions were gener-ally larger in men compared with women, the differ-ences largely disappeared after values were indexedto BSA (Table 2).

MA dimensions correlated positively with BSA, asexpected (Figure 4). Univariate and multivariate pre-dictors of MA area index in controls are presented inTable 3. Age and sex were not associated with MA areaindex. Both LV and LA volumes were independentlyassociated with MA area index, with LV systolic vol-ume index (beta ¼ 0.40; p < 0.001) slightly morepredictive of MA area index than maximal LA volumeindex (beta ¼ 0.31; p ¼ 0.001).

TABLE 1 Baseline Characteristics for Control Subjects (n ¼ 105)

Demographics

Age, yrs 56 � 11

Median (interquartile range) 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

LV systolic volume index, ml/m2

All 21 � 7

Female 19 � 7

Male 22 � 7

LV ejection fraction, %

Mean � SD 65 � 7

Range 51–81

LV diastolic mass index, g/m2

All 67 � 12

Female 62 � 11

Male 72 � 12

Maximal LA volume index, ml/m2

All 46 � 8

Female 48 � 9

Male 45 � 8

Values are mean � SD, unless otherwise indicated.

CT ¼ computed tomography; LA ¼ left atrial; LV ¼ left ventricular.

Mean � SD 15.3 � 1.9 15.4 � 1.8 15.2 � 1.9 0.69

Range 10.8–20.3 11.3–20.3 10.8–20.0

SL distance, mm/m2

Mean � SD 14.8 � 1.6 15.2 � 1.7 14.4 � 1.5 0.01

Range 11.2–20.6 12.2–20.6 11.2–18.5

IC distance, mm/m2

Mean � SD 20.2 � 1.9 20.3 � 2.1 20.0 � 1.8 0.50

Range 16.4–27.3 16.4–27.3 17.0–25.1

IC/SL ratio

Mean � SD 1.38 � 0.14 1.34 � 0.12 1.41 � 0.16 0.03

Range 1.04–1.75 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 MRsubgroups and controls are compared in Table 4.Controls were younger compared with both patientswith MVP and FMR and had higher mean BMI andBSA values compared with patients with MVP. MAdimensions were generally larger in MR subgroupscompared with controls, even after BSA was indexedto account for the differences in BSA. The range ofabsolute annular areas observed in patients with FMRand MVP is shown in Figure 5.

Annular geometry was also modified in patientswith moderate to severe MR compared with controls.Whereas IC and SL distances were both increased, theIC/SL ratio was smaller in both patients with FMR and

FIGURE 3 Mitral Annular Size in Control Subjects Stratified by Sex

15

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Mit

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(cm

2 )

5 9 13 17 21 25 29 33 37 41 45Patient No.

AMen

1

8

7

6

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4

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7

6

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cm2 / m

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Patient No.

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itra

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SA

(cm

2 / m

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5 9 13 17 21 25 29 33 37 41Patient No.

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1

0-100%5-95%25-75%Median

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.

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MVP compared with controls, indicating that annularremodeling in patients with MR involved relativelymore SL (anteroposterior) rather than lateral (IC)expansion.

Differences were noted in annular dimensions be-tween MR subgroups (Table 4). Despite LV volumesbeing significantly larger in patients with FMRcompared with patients with MVP, mean MA area was18% larger in the MVP group. IC/SL ratio was smallerin the FMR group compared with the MVP group.There were no significant differences in annular di-mensions between ischemic and nonischemic sub-groups of FMR (Online Table).

The associations between annular size and LV andLA volumes were discrepant in patients with MVP andFMR compared with controls (Figure 6). Increasing

MA area index in patients with FMR was associatedwith increasing maximal LA volume index (R ¼ 0.67;p < 0.001) but not with LV volumes. In contrast, MAarea index in patients with MVP demonstrated apositive correlation with both LV systolic volume in-dex (R ¼ 0.48; p ¼ 0.005) and maximal LA volumeindex (R ¼ 0.48; p ¼ 0.005).

DISCUSSION

In the present study, we reported D-shaped MA di-mensions using CT in patients with moderate to se-vere MR being considered for TMVI and comparethese findings with those of subjects without signifi-cant cardiac disease. Among controls, we noted wideinterindividual variation in MA dimensions, as well as

FIGURE 4 Relationship Between Body Surface Area and Mitral Annular Dimensions in Controls

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15

10

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Mit

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nn

ula

r A

rea

(cm

2 )

Body-surface Area (m2)1.0 1.5 2.0 2.5

R = 0.66p < 0.001

160

140

120

100

80P

erim

eter

(m

m)

Body-surface Area (m2)1.0 1.5 2.0 2.5

R = 0.66p < 0.001

40

35

30

25

20

SL

Dis

tan

ce (

mm

)

Body-surface Area (m2)1.0 1.5 2.0 2.5

R = 0.51p < 0.001

55

50

45

40

35

30

25

IC D

ista

nce

(m

m)

Body-surface Area (m2)1.0 1.5 2.0 2.5

R = 0.64p < 0.001

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.

TABLE 3 Univariate and Multivariate Predictors of Mitral Annulus Area Index in

Control Subjects (n ¼ 88)

Univariate Analysis Multivariate Analysis*

R Value p Value B (SE) Beta p Value

Age �0.09 0.42 — — —

Female �0.05 0.63 — — —

LV diastolic volume index 0.40 <0.001 — — —

LV systolic volume index 0.44 <0.001 0.03 (0.008) 0.40 <0.001

LV ejection fraction �0.27 0.01 — — —

LV diastolic mass index 0.04 0.73 — — —

Maximal LA volume index 0.35 <0.001 0.02 (0.007) 0.31 0.001

*LV diastolic volume index and LV ejection fraction were not included due to collinearity with LV systolic volumeindex (R¼ 0.83 and R¼ �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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an independent positive association between MA sizeand LV and LA sizes. Annular dimensions were largerin patients with MR and annular geometry distortedwith SL expansion. Although patients with MVPdemonstrated a positive correlation between annularsize and both LA and LV systolic volumes, in patientswith FMR, annular size appeared to only be associ-ated with increasing LA size. Importantly, annulardimensions were larger in MVP compared with FMR,which has implications for annular and thereforedevice sizing prior to TMVI.

Whereas traditional descriptions of MA geometryregard the annulus to be a saddle-shaped, nonplanar,3D structure (15), the concept of a D-shaped MA wasrecently proposed as being more appropriate for

TABLE 4 Mitral Annular Dimensions and Cardiac Volumes in Control Subjects and

Patients With MR

Controls(n ¼ 88)

Patients With MR

MVP(n ¼ 32)

FMR(n ¼ 27) p Value*

Demographics

Age, yrs 56 � 11 78 � 12† 70 � 13† 0.02

Female 41 (47) 13 (41) 7 (26) 0.27

Body mass index, kg/m2 26.7 � 3.7 24.5 � 3.5‡ 25.4 � 5.8 0.47

Body surface area, m2 1.88 � 0.21 1.79 � 0.21§ 1.85 � 0.27 0.31

Mitral regurgitation severity

Moderate — 5 (16) 2 (7) 0.62

Severe — 27 (84) 25 (93) 0.62

Mitral annular dimensions

Absolute value

Area, cm2 8.9 � 1.5 13.0 � 2.9† 11.0 � 2.3† 0.006

Perimeter, mm 110 � 9 132 � 14† 122 � 12† 0.004

TT distance, mm 28.5 � 3.4 33.9 � 3.7† 30.1 � 3.7§ <0.001

SL distance, mm 27.5 � 2.7 34.5 � 4.5† 32.9 � 4.4† 0.18

IC distance, mm 37.6 � 3.7 43.8 � 5.0† 38.9 � 4.4 <0.001

Value indexed to BSA

Area, cm2/m2 4.7 � 0.6 7.3 � 1.7† 6.0 � 1.3† 0.002

Perimeter, mm/m2 59 � 5 75 � 10† 67 � 9† 0.003

TT distance, mm/m2 15.3 � 1.9 19.1 � 2.1† 16.4 � 2.0‡ <0.001

SL distance, mm/m2 14.8 � 1.6 19.5 � 3.4† 18.1 � 3.3† 0.10

IC distance, mm/m2 20.2 � 1.9 24.7 � 3.2† 21.2 � 3.1§ <0.001

IC/SL ratio 1.38 � 0.14 1.28 � 0.10† 1.19 � 0.13† 0.008

Cardiac volumes

LV diastolic volume index, ml/m2 58 � 13 100 � 27† 158 � 59† <0.001

LV systolic volume index, ml/m2 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

Values are mean � SD or n (%). *p Value compares means between MVP and FMR groups for continuous variablesand chi-square test for categorical variables. For comparison between MR subgroups and controls for continuousvariables and chi-square test for trend for categorical variables. †p < 0.01. ‡p < 0.05. §p < 0.001.

FMR ¼ functional mitral regurgitation; MR ¼ mitral regurgitation; MVP ¼ mitral valve prolapse; otherabbreviations as in Tables 1 and 2.

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TMVI sizing because it better reflects the planarlanding zone of TMVI devices. Importantly, D-shapedMA segmentation eliminates the difficulties associ-ated with defining and segmenting the anterior horn.Historically, there has been marked variationobserved between surgical and noninvasive imagingdefinitions of the anterior horn, with surgeons typi-cally estimating a less pronounced horn due to theirability to directly visualize and discriminate betweenatrial myocardium and fibrous tissue. For these rea-sons, the D-shape provides a more standardized andreproducible method of annular evaluation and isnow being formally used to screen and provide MAsizes in patients being evaluated prior to TMVI (5,16).

MA MEASUREMENTS IN CONTROL SUBJECTS

WITHOUT SIGNIFICANT CARDIAC DISEASE. Wideinterindividual variation in MA dimensions was seenin control subjects, with a mean value of 8.9 � 1.5 cm2,

but ranging from 5.5 to 13.8 cm2. Prior studies of MAvalues have reported a broad range of normal values.Early 2D echocardiographic studies found relativelysmall annular areas, with one study reporting a meanmaximal MA area of 7.1 cm2 (indexed 3.8 cm2/m2)(17). More recent studies using 3D echocardiographictechniques have reported normal mean values rangingfrom 8.4 to 11.8 cm2 (indexed 4.7 to 5.1 cm2/m2)(14,18,19). Cardiac CT studies reporting normative MAvalues have primarily assessed patients with MR, withonly small cohorts of healthy subjects included ascontrols. Mean values for normal MA area in thesestudies have ranged from 8.4 to 10.2 cm2 (indexed 4.5to 5.5 cm2/m2) (1–4,14). In the largest CT series toevaluate healthy subjects (n ¼ 84), Delgado et al. (1)reported mean MA area, anteroposterior (SL), and ICdistances of 4.8 � 0.9 cm2/m2, 12.5 � 2.1 mm/m2, and21.6 � 2.5 mm/m2, respectively. Our mean values forMA area are therefore at the lower end of reportedvalues. This would be largely explained by the delib-erate truncation of the anterior horn using ourmethod; however, the broad range of values acrossstudies, allowing for the clinical heterogeneity ofstudy subjects, highlights the difficulties of and lack ofstandardized annular evaluation.

Sex differences in MA dimensions were also notedin control subjects, with men generally exhibitinglarger absolute MA dimensions than women. Aftercorrection for BSA, however, these differenceslargely disappeared, except for SL distance, whichwas larger in women. Sonne et al. (14) similarlynoted no difference in MA dimensions between menand women after correction for BSA, with theexception of medial-lateral MA diameter. In contrast,Mihaila et al. (19) noted larger indexed annulardimensions in men compared with women in a largercohort of 224 healthy volunteers studied with 3Dechocardiography. Combined, these data suggestthat although sex-related differences in annulardimensions largely reflect differences in BSAbetween men and women, subtle differences maystill exist beyond body size.

MA DIMENSIONS AND GEOMETRY IN PATIENTS WITH MR

AND THE IMPLICATIONS FOR DEVICE SIZING. MAdimensions were larger in patients with MR, with MAarea measuring 43% larger in patients with MVP and24% larger in patients with FMR, compared withcontrols. Annular geometry was also distorted in pa-tients with MR with greater SL expansion (reducedIC/SL ratio). Although these results are consistentwith those of previous studies using the saddle-shaped annulus (1,3), our findings provide uniquesizing and geometric information using the D-shaped

FIGURE 5 Mitral Annular Size in Patients With Moderate to Severe MR

22

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Mit

ral A

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Patient No.

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1920

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2526

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m2 )

Patient No.

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910

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1516

1718

1920

2122

2324

2526

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0-100%5-95%25-75%Median

The range of absolute mitral annular area values in patients with MVP (A) or FMR (B). Abbreviations as in Figure 2.

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annulus, which has implications for the developmentand implantation of TMVI devices. Of particularimportance is the observation of larger MA sizes inpatients with MVP compared with patients with FMRbecause this has implications in relation to theavailability of appropriate device sizes for theseclearly different conditions. The finding of larger MAdimensions in patients with MVP is consistent withprevious 3D echocardiographic studies (20) and isthought to be due to increased outward tension onthe MA during systole in the setting of excessivemitral valve tissue (21). Apart from this pathophysi-ological mechanism, larger annular dimensions inpatients with MVP may result from displacement ofthe posterior segmentation line into the LA due todisjunction of the mitral valve leaflet insertion fromthe atrioventricular junction (Figure 7), which hasbeen previously reported in association with myxo-matous mitral valve disease (22,23). Segmentation ofthe annulus to reflect the anticipated landing zone asopposed to the anatomic site of MV leaflet insertion isimportant in the setting of MA disjunction, althoughfurther investigation is needed to better understandthe impact of disjunction on device sealing andcapture.

DETERMINANTS OF ANNULAR SIZE IN CONTROLS

AND PATIENTS WITH MR. Age was not associatedwith changes in MA size in control subjects, consis-tent with previous studies (14). There was also noassociation between sex and MA size, likely due tothe correction for BSA as discussed above. We did,however, observe an association between MA sizeand both LA and LV sizes, suggesting independentcontribution from both chambers to annular size incontrols. These findings were different than the ob-servations in patients with MR. In patients with MVP,a positive correlation between MA area index andboth LV and LA sizes was seen; however, in patientswith FMR, MA area index was positively associatedwith LA volume only. The cause of FMR has beenattributed to various mechanisms, including systolicleaflet tethering to displaced papillary muscles in aremodeled LV (24), abnormal LV systolic function andshape (25), and annular remodeling (26). Interest-ingly, in a recent study of patients with MR butstructurally normal mitral valves, an independentassociation between LA enlargement and annulardilation was observed (27), similar to our study, irre-spective of the presence of LV dilation anddysfunction.

FIGURE 6 Relationship Between Mitral Annular Size and Atrioventricular Remodeling in Patients With Moderate to Severe MR

MVP200

150

100

50

0

LV D

iast

olic

Vo

lum

e/B

SA

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R = 0.33p = 0.07

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0 2 4 6 8 10 12 14

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ysto

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olu

me/

BS

A(m

l/m2 )

0 2 4 6 8 10 12 14

R = 0.48p = 0.005

300

200

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olu

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0 2 4 6 8 10 12 14

R = 0.21p = 0.30

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VM

ax/B

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l/m2 )

Mitral Annular Area/BSA (cm2/m2)0 2 4 6 8 10 12 14

R = 0.48p = 0.005

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150

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50

0

LA

VM

ax/B

SA

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l/m2 )

Mitral Annular Area/BSA (cm2/m2)0 2 4 6 8 10 12 14

R = 0.67p < 0.001

LV E

ject

ion

Fra

ctio

n (

%)

0 2 4 6 8 10 12 14

R = 0.33p = 0.06

80

70

60

50

40

30

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10

0 LV E

ject

ion

Fra

ctio

n (

%) 80

70

60

50

40

30

20

10

00 2 4 6 8 10 12 14

R = 0.10p = 0.60

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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FIGURE 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.

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STUDY LIMITATIONS. MA dimensions were measuredat mid to late diastole; however, prior studies havereported intracycle variation in MA area, with largervalues previously observed in diastole (2,18). Patientswith MR were being considered for TMVI becausethey were deemed unfit for surgery. Similarly, con-trols were only included if they underwent CT withretrospective ECG gating, which represented a smallproportion of the overall sample. These referral andselection biases limit the applicability of our data tosimilar patients. Hypertensive patients were notexcluded from the controls cohort (history of hyper-tension present in 44%), and this condition may beassociated with diastolic dysfunction and thereforeatrioventricular remodeling. However, patients withincreased LA volume index, which is sensitive for thedetection of severe diastolic dysfunction (28), andincreased LV mass index were excluded. Moreover,we reviewed the electronic charts of controls toensure that subjects with an echocardiographic reportdid not have evidence of severe diastolic dysfunction,minimizing the impact of such changes on our results.Although CT provides 3D data with high spatial res-olution, it is somewhat limited by its ionizing radia-tion. Although the present study provides importantinsights into potential interactions between atrio-ventricular and annular remodeling, our resultsshould be interpreted cautiously due to the small

sample sizes, particularly in the FMR cohort. More-over, the ability of D-shaped annular segmentation toappropriately size the annulus for the purposes ofdevice selection and the subsequent impact on clin-ical outcomes needs to be addressed in future studies.

CONCLUSIONS

Significant interindividual variability in D-shaped MAdimensions was seen in patients without significantcardiac disease. Among patients with moderate tosevere MR, significant MA enlargement was observedand was associated with SL (anteroposterior) MAexpansion. Importantly, patients with MVP exhibitedlarger MA dimensions than patients with FMR, andthe drivers of annular enlargement appeared to bedifferent in these cohorts, with LA dilation contrib-uting more significantly in patients with FMR. Ourfindings provide insights into the size and geometryof the D-shaped annulus and the drivers of MA dila-tion in patients being considered for transcathetermitral therapy.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Philipp Blanke, St. Paul’s Hospital, University ofBritish Columbia, 1081 Burrard Street, Vancouver,British Columbia V6Z 1Y6, Canada. E-mail: phil.blanke@googlemail.com.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: The

D-shaped approach to MA segmentation is considered a

morebiomechanically appropriatemethodcurrently usedto

screen and size patients being considered for transcatheter

mitral valve therapy. Patients with moderate to severe MR

exhibit larger D-shaped MA dimensions, as well as annular

remodeling characterized by SL expansion, than control

subjects, especially patients with MVP. Unlike in controls

and patients with MVP, D-shaped annular enlargement

in FMR is more closely associated with LA dilation.

TRANSLATIONAL OUTLOOK: Further studies are

needed to elucidate the impact of this knowledge of

D-shaped MA dimensions, geometry, and drivers of

annular size on device performance and clinical outcomes

following TMVI.

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KEY WORDS computed tomography, mitralannulus, mitral regurgitation, TMVI, TMVR,transcatheter mitral valve implantation

APPENDIX For a supplemental table, pleasesee the online version of this article.