Three-Dimensional Transthoracic Static and Dynamic Normative Values of the Mitral Valve Apparatus: Results from the Multicenter World Alliance Societies of Echocardiography Study

Abstract

Background:

Recent advances in mitral valve (MV) percutaneous interventions have escalated the need for a more quantitative and comprehensive assessment of the MV, which can be best achieved using three-dimensional echocardiography. Understanding normal valve size, structure, and function is essential for differentiation of healthy from disease states. The aims of this study were to establish normative values for MV apparatus size and morphology and to determine how they vary across age, sex, and race groups using data from the World Alliance Societies of Echocardiography Normal Values Study.

Methods:

Three-dimensional volumetric data sets obtained on transthoracic echocardiography in 748 normal subjects (51% men) were analyzed using commercial MV analysis software (TomTec Imaging Systems) to determine annular and leaflet dimensions and areas. The subjects were divided into groups by sex (378 men and 370 women) and age (18 to 40 years [n = 266], 41 to 65 years [n = 249], and >65 years [n = 233]) to identify sex- and age-related differences. In addition, differences among black, white, and Asian populations were studied. Inter- and intraobserver variability was assessed in a subset of 30 subjects and expressed as mean absolute difference between pairs of repeated measurements.

Results:

Compared with women, men had larger annular size measurements, larger tenting size parameters, and larger leaflet length and area. Compared with the black and white populations, the Asian population showed significantly smaller mitral annular size. Although many of the age, sex, and race differences in MV parameters were statistically significant, they were comparable with or smaller than the corresponding measurement variability. Indexing to body surface area and height did not eliminate these differences consistently, suggesting that parameters may need to be indexed according to their dimensionality.

Conclusions:

This analysis of the World Alliance Societies of Echocardiography data provides normative values of mitral apparatus size and morphology. Although sex- and age-related differences were noted, they need to be interpreted with caution in view of the associated measurement variability.

Defining the normal geometry and dynamics of the mitral valve (MV) is essential to the understanding of pathology and planning of therapeutic interventions to diminish patient morbidity and mortality. Transthoracic echocardiography (TTE) has been the primary modality used to define MV geometry, largely as a result of its ease of use, reproducibility, and near universal availability.

However, most data regarding echocardiographic reference values are based on observational studies from specific ethnic groups, generally focused on healthy subjects in the fourth to sixth decades of life. Most of these existing data come from single-center studies that did not include multiethnic populations^1–7 and focused on the cardiac chambers and great vessels rather than specifically on the MV. Also, meaningful comparisons of the results of these studies are confounded by the use of different protocols and analysis software. As a consequence, robust reference values describing the MV apparatus are scarce. Although some studies have reported two-dimensional (2D) echocardiographic measurements,⁸ other studies used cardiac computed tomography or magnetic resonance in small cohorts, making the generalization of their results difficult.^9,10

The MV has a complex three-dimensional (3D) geometry, which limits the applicability of geometric assumptions and the reproducibility of 2D measurements. In contrast, 3D echocardiography avoids these assumptions, allowing anatomically correct measurements on reproducible MV cut planes.¹¹ Analysis of MV anatomy using 3D transesophageal echocardiography (TEE) has been shown to be accurate compared with surgical measurements and superior to 2D measurements.^12,13 Furthermore, analysis using 3D TTE offers additional important advantages, mainly its noninvasive nature, wide availability, and lower cost. Although 3D echocardiography–derived normative values for static and dynamic MV parameters have been reported,^14–16 these analyses have been performed in single-race cohorts.

Therefore, we sought to determine normative values for both static and dynamic measurements of the MV apparatus geometry. To achieve this goal, 2D and 3D transthoracic echocardiographic images were obtained from a large, racially diverse population of normal subjects of both sexes with a broad distribution of ages, in which a standardized image acquisition protocol was used as part of the World Alliance Societies of Echocardiography (WASE) study.^17–20

METHODS

The rationale and design of the WASE Normal Values Study have been previously described.¹⁷ Briefly, this was a multicenter international, observational, prospective, cross-sectional study of healthy adult individuals. The American Society of Echocardiography invited representatives of member societies of the American Society of Echocardiography International Alliance Partners (as of March 2016) to participate in this study by enrolling 100 “normal” local healthy adult volunteers at each of the 19 participating sites. A “normal” subject was defined as one without a history or clinical evidence of heart, lung, or kidney disease. Only participants >65 years of age were allowed to have histories of hypertension or hyperlipidemia, as long as blood pressure and lipids were well controlled with no more than two medications and there was no evidence of left ventricular (LV) hypertrophy on echocardiography. Individuals were evenly distributed among three age subgroups (young, 18–40 years; middle aged, 41–65 years; and elderly, >65 years) and both sexes.

A single encounter with each subject was required for the collection of basic demographic information and a comprehensive transthoracic echocardiographic examination that included 2D and 3D imaging. The definitions of race were adapted from those proposed for the 2020 US census, the US Food and Drug Administration, and the 2011 UK census.²¹ The study was approved by local ethics committees, and subjects provided informed consent, as mandated by each of the enrolling centers’ institutional review board or ethics committee.

Comprehensive transthoracic echocardiographic data sets were acquired following a study-specific standardized acquisition protocol created by the WASE core laboratories (MedStar Health Research Institute and the University of Chicago) on the basis of recent American Society of Echocardiography recommendations.^14,15 Ultrasound imaging systems used for data acquisition could be from any vendor but had to be able to acquire 2D, Doppler, and 3D images using uniform settings.

Image Analysis

Digital Imaging and Communications in Medicine images were analyzed by the core laboratory at the University of Chicago using commercial software for MV quantitative analysis (4D-MV Assessment version 2.3; TomTec Imaging Systems, Unterschleissheim, Germany). Analysis was performed by two observers (M.P.H. and J.C.) on data sets of a randomly selected subset of 900 subjects from the WASE data set, whose data sets included 3D images of the MV. The quality of MV data sets was judged subjectively considering the signal-to-noise ratio, the degree of blood-tissue contrast, and the quality of mitral annular (MA) tracking. After 152 data sets were excluded for inadequate image quality, the final analysis included 748 studies (378 men and 370 women; mean age, 50 ± 18 years; mean frame rate, 33 ± 19 frames/sec; i.e., feasibility of 83%). Basic demographic data of these 748 subjects are shown in Table 1.

Table 1.

Baseline demographic characteristics

	All subjects	Men	Women
	(N = 748)	(n = 378)	(n = 370)
Age, y	50 ± 18	50 ± 18	51 ± 18
Height, cm	168 ± 10	174 ± 8	161 ± 7*
Weight, kg	68 ± 14	75 ± 13	62 ± 11*
BSA, m2	1.78 ± 0.22	1.90 ± 0.20	1.65 ± 0.17*
Systolic BP, mm Hg	122 ± 12	124 ± 12	119 ± 13*
Diastolic BP, mm Hg	74 ± 9	75 ± 8	73 ± 9*
Race
White	302 (40.4)	151 (39.9)	151 (40.8)
Black	148 (19.8)	79 (20.9)	69 (18.6)
Asian	295 (39.4)	147 (38.9)	148 (40.0)
Other	3 (0.4)	1 (0.3)	2 (0.5)

BP, Blood pressure.

Data are expressed as mean ± SD or as number (percentage).

^*P < .05 between men and women.

The analysis began with the identification of three time points in the cardiac cycle: early systole (the frame after MV closure), end-systole (the frame just before MV opening), and mid-systole (the frame halfway way between MV closure and end-systole). Early systole was chosen as the reference frame used for the static measurements, as the program automatically selected this timing to perform these measurements, because easy identification of the frame corresponding to early systole (MV closing) would facilitate more reproducible measurements. Anatomic landmarks for the MA, aorta, and leaflet coaptation point were manually selected. Then the software automatically created a static 3D model of the mitral annulus and leaflets at early systole (Figure 1). Afterward, the mitral annulus was automatically tracked in each systolic frame (dynamic analysis). Manual adjustments were performed on both static and dynamic models to ensure adequate tracking of MV structures.

Figure 1.

Three-dimensional measurements of the MV size and shape parameters (see text for details).

MA measurements were classified into three categories: annular size, annular shape, and leaflet geometry. Annular size measurements included the following: anteroposterior (AP) diameter (defined as the shortest distance between the highest anterior and posterior MA points) and anterolateral (AL)–posteromedial (PM) diameter (defined as the longest distance between two points on the mitral annulus that are derived by intersecting the annulus and a line perpendicular to AP diameter). Then, using a polynomial spline interpolation within the multiplanar reconstruction, the software automatically calculated the MA circumference and 2D and 3D area measurements.

Annular shape measurements included nonplanar angle (NPA; defined as the angle between a vector originating from the two higher points of the annulus in the AP plane and the center axis of the AL-PM plane), annular height (defined as the distance between the lowest and the highest points of the saddle-shaped annulus), tenting height (defined as the distance between intersecting plane between the AP diameter and the nadir of the closure line), the corresponding tenting area and volume, and sphericity index (defined as the ratio between AP and AL-PM diameters).

Leaflet measurements included both anterior and posterior leaflet area and length. Leaflet area was calculated as the area defined by the closure line and the anterior or posterior part of the mitral annulus, whereas leaflet length was defined as the total length of the anterior or posterior leaflet contours in the AP direction, including the coaptation length.

Measurements were normalized to body surface area (BSA), calculated using the DuBois formula, and separately to body height. Measurements independent of body size, such as the dimensionless sphericity index, and NPA measured in degrees, were not indexed.

Measurements included in the dynamic analysis were AL-PM and AP diameters, 2D annular area, annular circumference, and sphericity index. Changes in these parameters over time were expressed as a function of the percentage of total systolic time (from 0% to 100% of systole).

Reproducibility Analysis

Thirty echocardiograms from subjects evenly distributed between the two sexes and among the three age groups were randomly selected and used to assess measurement variability. Intraobserver absolute differences were calculated from repeated measurements made by the same reader, while interobserver absolute differences were calculated from measurements made by a second independent observer, both blinded to all prior measurements. These differences were also expressed as a percentage of the mean of the corresponding repeated measurements as a standard measure of variability.

Statistical Analysis

All measurements are presented as mean ± SD. Group differences were evaluated using the unpaired two-tailed Student’s t test. In cases of three-group comparisons, analysis of variance was first used to identify significant differences. Statistical significance was defined as P < .05. The upper limits of normal for the measurements were calculated as the 97.5th percentile and the lower limits of normal as the 2.5th percentile of the corresponding sex and age groups for each measurement technique. This is in accordance with the definition of “normal” as falling within 95% of the normal population, with the remaining 5% being distributed equally between the two tails of the distribution, irrespective of whether the distribution is Gaussian. The results of the dynamic analysis were plotted as mean values with standard error bars, to allow visualization of the small variations throughout the systolic contraction.

RESULTS

Static Measurements

Comparison between Sex Groups.

The results of the MV analysis according to sex are shown in Tables 2 to 4. As expected, the male population had larger BSA and was taller than the female population. MA size, shape, and leaflet measurements were all larger in men than in women (Table 2). The only parameters not significantly different between sexes were NPA, sphericity index, and annular height. Interestingly, the statistical significance of the differences between sexes in length measurements were mostly eliminated after indexing to height, and that of volume or area measurements was lost after indexing to BSA (Tables 3 and 4). Tables 5 to 7 present the normal ranges of MV parameters without indexing (Table 5) and with indexing to BSA and by height (Tables 6 and 7).

Table 2.

Early systolic MV measurements obtained in the entire study group and separately in men and women

	All subjects	Men	Women
	(N = 748)	(n = 378	(n = 370)	P
BSA, m2	1.78 ± 0.22	1.90 ± 0.20	1.65 ± 0.17	*
Height, cm	168 ± 10	174 ± 8	161 ± 7	*
MA size
AP diameter, cm	3.3 ± 0.4	3.4 ± 0.4	3.1 ± 0.4	*
AL-PM diameter, cm	3.7 ± 0.5	3.8 ± 3.8	3.5 ± 0.4	*
Circumference, cm	11.8 ± 1.4	12.2 ± 1.4	11.3 ± 1.3	*
2D area, cm2	9.7 ± 2.4	10.5 ± 2.3	9.0 ± 2.2	*
3D area, cm3	10.3 ± 5.2	11.3 ± 6.9	9.4 ± 2.2	*
MA shape
NPA, °	141 ± 16	141 ± 17	140 ± 15
Annular height, cm	0.88 ± 0.25	0.89 ± 0.24	0.86 ± 0.25
Tenting volume, cm3	3.3 ± 1.5	3.6 ± 1.5	2.9 ± 1.4	*
Tenting area, cm2	2.1 ± 0.7	2.2 ± 0.7	2.0 ± 0.7	*
Tenting height, mm	9.7 ± 2.8	10.1 ± 2.8	9.3 ± 2.8	*
Sphericity index, AP/AL-PM	0.89 ± 0.08	0.89 ± 0.08	0.89 ± 0.07
Mitral leaflets
Anterior leaflet area, cm2	6.9 ± 1.7	7.3 ± 1.8	6.4 ± 1.5	*
Posterior leaflet area, cm2	5.9 ± 1.8	6.4 ± 1.8	5.4 ± 1.8	*
Anterior leaflet length, cm	2.6 ± 0.4	2.7 ± 0.3	2.5 ± 0.4	*
Posterior leaflet length, cm	1.5 ± 0.4	1.6 ± 0.4	1.5 ± 0.4	*

Data are expressed as mean ± SD.

^*P < .05, men versus women.

Table 4.

Early systolic MV measurements indexed to body height, by sex

	Men	Women
	(n = 378)	(n = 370)	P
MA size
AP diameter, cm/m	2.0 ± 0.2	1.9 ± 0.2
AL-PM diameter, cm/m	2.2 ± 2.2	2.2 ± 0.3
Circumference, cm/m	7.0 ± 0.7	7.0 ± 0.8
2D area, cm2/m	6.0 ± 1.3	5.6 ± 1.3	*
3D area, cm3/m	6.4 ± 3.8	5.8 ± 1.3	*
Mitral annular shape
Annular height, cm/m	0.51 ± 0.13	0.53 ± 0.15	*
Tenting volume, cm3/m	2.1 ± 0.8	1.8 ± 0.8	*
Tenting area, cm2/m	1.3 ± 0.4	1.2 ± 0.4	*
Tenting height, mm/m	5.8 ± 1.7	5.6 ± 2.0
Mitral leaflets
Anterior leaflet area, cm2/m	4.2 ± 1.0	4.0 ± 0.9	*
Posterior leaflet area, cm2/m	3.7 ± 1.0	3.4 ± 1.1	*
Anterior leaflet length, cm/m	1.6 ± 0.2	1.6 ± 03
Posterior leaflet length, cm/m	0.9 ± 0.2	0.9 ± 0.2

Data are expressed as mean ± SD. NPA and sphericity index were not indexed.

^*P < .05, men versus women.

Table 3.

Early systolic MV measurements indexed to BSA, by sex

	Men	Women
	(n = 378)	(n = 370)	P
MA size
AP diameter, cm/m2	1.8 ± 0.2	1.9 ± 0.3	*
AL-PM diameter, cm/m2	2.0 ± 2.0	2.1 ± 0.3	*
Circumference, cm/m2	6.5 ± 0.8	6.9 ± 0.9	*
2D area, cm2/m2	5.5 ± 1.1	5.5 ± 1.3
3D area, cm2/m2	5.9 ± 3.3	5.7 ± 1.3
MA shape
Annular height, cm/m2	0.47 ± 0.13	0.52 ± 0.15	*
Tenting volume, cm2/m2	1.9 ± 0.7	1.8 ± 0.8	*
Tenting area, cm2/m2	1.2 ± 0.3	1.2 ± 0.4
Tenting height, mm/m2	5.3 ± 1.6	5.5 ± 1.9
Mitral leaflets
Anterior leaflet area, cm2/m2	3.9 ± 0.9	3.9 ± 0.9
Posterior leaflet area, cm2/m2	3.4 ± 0.9	3.3 ± 1.0
Anterior leaflet length, cm/m2	1.4 ± 0.2	1.5 ± 0.3	*
Posterior leaflet length, cm/m2	0.8 ± 0.2	0.9 ± 0.2	*

Data are expressed as mean ± SD. NPA and sphericity index were not indexed.

^*P < .05, men versus women.

Table 5.

Normal ranges of nonindexed early systolic MV parameters for men and women

	Men	Women
Mitral annular size
AP diameter, cm	2.7–4.2	2.4–3.9
AL-PM diameter, cm	3.0–4.7	2.8–4.5
Circumference, cm	9.8–14.9	9.1–14.1
2D area, cm2	6.5–15.7	5.7–14.2
3D area, cm3	6.9–16.4	6.1–14.5
MA shape
NPA, °	116–173	113–174
Annular height, cm	0.42–1.37	0.39–1.45
Tenting volume, cm3	1.1–6.9	0.9–6.2
Tenting area, cm2	1.0–3.6	0.9–3.5
Tenting height, mm	4.9–15.9	4.6–15.8
Sphericity index (AP/AL-PM)	0.74–1.04	0.76–1.05
Mitral leaflets
Anterior leaflet area, cm2	4.2–11.3	3.8–9.8
Posterior leaflet area, cm2	3.2–10.4	2.6–9.4
Anterior leaflet length, cm	2.1–3.4	1.9–3.3
Posterior leaflet length, cm	0.9–2.4	0.8–2.4

Table 7.

Normal ranges of early systolic MV measurements for men and women, indexed to body height

	Men	Women
MA size
AP diameter, cm/m	1.6–2.4	1.5–2.5
AL-PM diameter, cm/m	1.7–2.7	1.8–2.8
Circumference, cm/m	5.6–8.5	5.7–8.8
2D area, cm2/m	3.8–8.8	3.7–8.8
3D area, cm3/m	4.0–9.0	3.9–9.0
MA shape
Annular height, cm/m	0.25–0.79	0.25–0.87
Tenting volume, cm3/m	0.6–3.8	0.6–3.8
Tenting area, cm2/m	0.6–2.0	0.5–2.1
Tenting height, mm/m	2.5–8.9	0.0–9.8
MA leaflets
Anterior leaflet area, cm2/m	2.4–6.2	2.4–6.0
Posterior leaflet area, cm2/m	1.9–5.7	1.6–5.7
Anterior leaflet length, cm/m	1.2–1.9	1.22.0
Posterior leaflet length, cm/m	0.5–1.4	0.5–1.5

NPA and sphericity index were not indexed.

Table 6.

Normal ranges of early systolic MV measurements for men and women, indexed to BSA

	Men	Women
Mitral annular size
AP diameter, cm/m2	1.4–2.3	1.4–2.4
AL-PM diameter, cm/m2	1.6–2.5	1.6–2.7
Circumference, cm/m2	5.1–8.2	5.4–8.8
2D area, cm2/m2	3.5–8.0	3.6–8.6
3D area, cm3/m2	3.7–8.4	3.8–8.7
MA shape
Annular height, cm3/m2	0.22–0.73	0.24–0.84
Tenting volume, cm3/m2	0.6–3.4	0.6–3.5
Tenting area, cm3/m2	0.6–1.8	0.5–2.0
Tenting height, mm/m2	2.5–8.3	0.0–9.3
Mitral leaflets
Anterior leaflet area, cm2/m2	2.3–5.9	2.4–6.0
Posterior leaflet area, cm2/m2	1.7–5.3	1.6–5.4
Anterior leaflet length, cm/m2	1.1–1.9	1.1–2.0
Posterior leaflet length, cm/m2	0.5–1.2	0.5–1.4

NPA and sphericity index were not indexed.

Comparison among Age Groups.

The results of the MV analysis according to age are shown in Tables 8 to 10. BSA in the oldest group (>65 years) was smaller compared with the young (18–40 years) and middle-aged (41–65 years) groups. Age-related differences in multiple parameters were statistically significant (Table 8). Most MV parameters showed larger absolute values in the middle-aged group, with a subtle decrease in the oldest group, particularly for NPA, tenting measurements, and leaflet size parameters. Some (but not all) statistical significance was lost after BSA and height indexing (Tables 9 and 10). The NPA and the annular height in the middle-aged group were consistent with a tendency toward a flatter annulus compared with younger and older adults. AP diameter showed bigger values in the elderly population after BSA indexing, without losing statistical significance (Table 9). After both BSA and height indexing, smaller anterior leaflet area values were still noticed in the oldest age group, without losing statistical significance, compared with both the young and middle-aged groups (Tables 9 and 10).

Table 8.

Early systolic MV measurements obtained in the three age groups

	All subjects
	18–40 y	41–65y	>65 y
	(n = 266)	(n = 249)	(n = 233)	P
BSA, m2	1.79 ± 0.24	1.81 ± 0.22	1.72 ± 0.19	* ,†,‡
Height, cm	170 ± 11	168 ± 10	164 ± 9	* ,†,‡
MA size
AP diameter, cm	3.3 ± 0.4	3.3 ± 0.4	3.2 ± 0.5
AL-PM diameter, cm	3.7 ± 0.5	3.7 ± 0.5	3.6 ± 0.5	* ,†
Circumference, cm	11.8 ± 1.4	11.9 ± 1.4	11.6 ± 1.5	* ,†
2D area, cm2	9.7 ± 2.3	10.0 ± 2.5	9.5 ± 2.5	* ,†
3D area, cm3	10.2 ± 2.4	10.4 ± 2.4	10.4 ± 8.7
MA shape
NPA, °	139 ± 17	143 ± 15	140 ± 15	* ,‡,§
Annular height, cm	0.91 ± 0.24	0.85 ± 0.26	0.86 ± 0.23	* ,†,§
Tenting volume, cm3	3.0 ± 1.5	3.9 ± 1.5	2.9 ± 1.3	* ,‡,§
Tenting area, cm2	2.0 ± 0.7	2.3 ± 0.7	1.9 ± 0.6	* ,‡,§
Tenting height, mm	9.0 ± 2.8	10.7 ± 2.7	9.6 ± 2.6	* ,†,‡,§
Sphericity index (AP/AL-PM)	0.89 ± 0.08	0.89 ± 0.08	0.90 ± 0.07	* ,†,‡
Mitral leaflets
Anterior leaflet area, cm2	7.2 ± 1.8	7.1 ± 1.7	6.2 ± 1.7	* ,†,‡
Posterior leaflet area, cm2	5.4 ± 1.7	6.3 ± 1.8	6.0 ± 1.8	* ,†,‡,§
Anterior leaflet length, cm	2.7 ± 0.3	2.7 ± 0.4	2.5 ± 0.4	* ,†,‡,§
Posterior leaflet length, cm	1.4 ± 0.4	1.6 ± 0.4	1.6 ± 0.3	* ,†,§

Data are expressed as mean ± SD.

^*Three-way analysis of variance.

^†Student’s t test for 18 to 40 versus >65 years.

^‡Student’s t test for 41 to 65 versus >65 years.

^§Student’s t test for 18 to 40 versus 41 to 65 years.

Table 10.

Early systolic MV measurements indexed to body height, by age groups

	All subjects
	18–40 y	41–65y	>65 y
	(n = 266)	(n = 249)	(n = 233)	P
MA shape
AP diameter, cm/m	1.9 ± 0.2	2.0 ± 0.2	2.0 ± 0.3	* ,†,‡
AL-PM diameter, cm/m	2.2 ± 0.2	2.2 ± 0.2	2.2 ± 0.2	* ,†
Circumference, cm/m	6.9 ± 0.7	7.1 ± 0.7	7.1 ± 0.8	* ,†
2D area, cm2/m	5.7 ± 1.2	5.9 ± 1.3	5.7 ± 1.4	* ,†
3D area, cm3/m	6.0 ± 1.2	6.2 ± 1.3	6.3 ± 4.8	* ,†
MA shape
Annular height, cm/m	0.54 ± 0.14	0.51 ± 0.15	0.52 ± 0.14	* ,†
Tenting volume, cm3/m	1.8 ± 0.8	2.3 ± 0.8	1.8 ± 0.8	* ,†,§
Tenting area, cm2/m	1.2 ± 0.4	1.4 ± 0.4	1.2 ± 0.3	* ,†,§
Tenting height, mm/m	5.3 ± 1.7	6.0 ± 2.1	5.9 ± 1.6	* ,†,‡
Mitral leaflets
Anterior leaflet area, cm2/m	4.2 ± 0.9	4.2 ± 0.9	3.8 ± 1.0	* ,‡,§
Posterior leaflet area, cm2/m	3.2 ± 1.0	3.8 ± 1.0	3.6 ± 1.1	* ,†,‡
Anterior leaflet length, cm/m	1.6 ± 0.2	1.6 ± 0.3	1.5 ± 0.2	* ,†,‡,§
Posterior leaflet length, cm/m	0.8 ± 0.2	1.0 ± 0.2	1.0 ± 0.2	* ,†,‡

Data are expressed as mean ± SD. NPA and sphericity index were not indexed.

^*Three-way analysis of variance.

^†Student’s t test for 18 to 40 versus 41 to 65 years.

^‡Student’s t test for 18 to 40 versus >65 years.

^§Student’s t test for 41 to 65 versus >65 years.

Table 9.

Early systolic MV measurements indexed to BSA, by age groups

	All subjects
	18–40 y	41–65y	>65 y
	(n = 266)	(n = 249)	(n = 233)	P
MA size
AP diameter, cm/m2	1.8 ± 0.2	1.8 ± 0.3	1.9 ± 0.3	* ,†,‡
AL-PM diameter, cm/m2	2.1 ± 0.3	2.1 ± 0.3	2.1 ± 0.3
Circumference, cm/m2	6.6 ± 0.8	6.6 ± 0.8	6.8 ± 0.9
2D area, cm2/m2	5.4 ± 1.1	5.5 ± 1.2	5.5 ± 1.3
3D area, cm3/m2	5.7 ± 1.1	5.8 ± 1.2	6.0 ± 4.2
MA shape
Annular height, cm/m2	0.51 ± 0.14	0.47 ± 0.14	0.50 ± 0.14	* ,‡,§
Tenting volume, cm/m2	1.7 ± 0.8	2.1 ± 0.7	1.7 ± 0.7	* ,‡,§
Tenting area, cm2/m2	1.1 ± 0.4	1.3 ± 0.4	1.1 ± 0.3	* ,‡,§
Tenting height, mm/m2	5.1 ± 1.6	5.6 ± 2.0	5.6 ± 1.6	* ,†,§
Mitral leaflets
Anterior leaflet area, cm2/m2	4.0 ± 0.9	3.9 ± 0.8	3.6 ± 0.9	* ,†,‡
Posterior leaflet area, cm2/m2	3.0 ± 0.9	3.5 ± 0.9	3.5 ± 1.0	* ,†,§
Anterior leaflet length, cm/m2	1.5 ± 0.2	1.5 ± 0.3	1.5 ± 0.2	* ,†,§
Posterior leaflet length, cm/m2	0.8 ± 0.2	0.9 ± 0.2	0.9 ± 0.2	* ,†,§

Data are expressed as mean ± SD. NPA and sphericity index were not indexed.

^*Three-way analysis of variance.

^†Student’s t test for 18 to 40 versus >65 years.

^‡Student’s t test for 41 to 65 versus >65 years.

^§Student’s t test for 18 to 40 versus 41 to 65 years.

Comparison among Races.

Results of the MV analysis according to race are shown in Table 11. Asians had smaller BSA, height, and weight compared with the black and white subjects. Asian individuals, both men and women, showed significantly lower values in all MA size measurements compared with the white and black populations. NPA was the only parameter that was larger (more obtuse) in Asians and statistically significant compared with the other races, in both men and women.

Table 11.

Early systolic MV measurements obtained in men and separately in women of the three races

	Men				Women
	Asian	White	Black		Asian	White	Black
	(n = 147)	(n = 151)	(n = 79)	P	(n = 148)	(n = 151)	(n = 69)	P
BSA, m2	1.80 ± 0.15	1.98 ± 0.17	1.94 ± 0.23	* ,†,‡	1.54 ± 0.12	1.72 ± 0.15	1.76 ± 0.17	* ,†,‡
Height, cm	171 ± 6	176 ± 8	176 ± 9	* ,†,‡	157 ± 6	164 ± 7	162±6	* ,†,‡
MA size
AP diameter, cm	3.3 ± 0.4	3.4 ± 0.4	3.5 ± 0.4	* ,†,‡	3.0 ± 0.4	3.2 ± 0.4	3.3 ± 0.4	* ,†,‡
AL-PM diameter, cm	3.7 ± 0.5	3.9 ± 0.5	3.9 ± 0.4	* ,†,‡	3.4 ± 0.5	3.6 ± 0.5	3.7 ± 0.4	* ,†,‡
Circumference, cm	11.8 ± 1.3	12.4 ± 1.5	12.6 ± 1.1	* ,†,‡	10.8 ± 1.1	11.6 ± 1.4	11.8 ± 1.2	* ,†,‡
2D area, cm2	9.8 ± 2.1	10.8 ± 2.7	11.0 ± 1.9	* ,†,‡	8.2 ± 1.8	9.4 ± 2.5	9.8 ± 2.2	* ,†,‡
3D area, cm3	10.2 ± 2.2	12.1 ± 10.6	11.6 ± 2.0	* ,†,‡	8.6 ± 1.8	9.8 ± 24	10.2 ± 2.2	* ,†,‡
MA shape
NPA, °	144 ± 19	140 ± 17	137 ± 13	* ,†,‡	144 ± 14	138 ± 16	140 ± 14	* ,†,‡
Annular height, cm	0.82 ± 0.24	0.90 ± 0.22	1.00 ± 0.20	* ,†,‡,§	0.78 ± 0.23	0.91 ± 0.28	0.90 ± 0.20	* ,†
Tenting volume, cm3	3.3 ± 1.4	3.6 ± 1.6	4.1 ± 1.5	* ,‡	2.6 ± 1.2	3.1 ± 1.5	3.2 ± 1.2	* ,†,‡
Tenting area, cm2	2.1 ± 0.6	2.3 ± 0.7	2.4 ± 0.6	* ,†,‡	1.8 ± 0.5	2.1 ± 0.7	2.0 ± 0.6	* ,†,‡
Tenting height, mm	10.2 ± 2.6	10.0 ± 3.1	10.3 ± 2.4	* ,†	8.9 ± 2.5	9.8 ± 3.2	9.3 ± 2.2
Sphericity index (AP/AL-PM)	0.90 ± 0.08	0.89 ± 0.08	0.89 ± 0.06		0.89 ± 0.07	0.89 ± 0.08	0.89 ± 0.06
Mitral leaflets
Anterior leaflet area, cm2	6.9 ± 1.6	7.5 ± 1.9	7.7 ± 1.7	* ,†,‡	6.0 ± 1.5	6.6 ± 1.7	6.6 ± 1.2	* ,†,‡
Posterior leaflet area, cm2	6.2 ± 1.7	6.5 ± 2.0	6.4 ± 1.5		4.8 ± 1.4	5.9 ± 1.9	5.7 ± 1.7	* ,†,‡
Anterior leaflet length, cm	2.6 ± 0.3	2.7 ± 0.3	2.8 ± 0.4	* ,‡	2.5 ± 0.3	2.6 ± 0.4	2.6 ± 0.3	* ,†,‡
Posterior leaflet length, cm	1.6 ± 0.3	1.6 ± 0.4	1.6 ± 0.3		1.4 ± 0.4	1.5 ± 0.4	1.5 ± 0.3	* ,†,‡

Data are expressed as mean ± SD.

^*P < .05 by three-way analysis of variance.

^†Student’s t test for Asian versus white.

^‡Student’s t test for Asian versus black.

^§Student’s t test for black versus white.

Reproducibility Analysis.

Reproducibility data in terms of inter- and intraobserver differences between repeated measurements and the corresponding percentage variabilities are summarized in Table 12. For almost every parameter, interobserver differences were larger than intraobserver differences. Most differences in length measurements were smaller as a percentage of the measured values than the differences in area and volume measurements (Table 12, columns 4 and 5).

Table 12.

Inter- and intraobserver differences (columns 2 and 3, respectively) and the corresponding percentage variabilities (columns 4 and 5) in measured parameters noted in a subgroup of 30 study subjects selected to assess measurement reproducibility

	Interobserver difference	Intraobserver difference	Interobserver % variability	Intraobserver % variability
MA size
AP diameter, cm	0.3 ± 0.2	0.2 ± 0.2	9 ± 7	8 ± 6
AL-PM diameter, cm	0.3 ± 0.2	0.2 ± 0.2	8 ± 6	6 ± 5
Circumference, cm	0.9 ± 0.8	0.7 ± 0.6	8 ± 7	6 ± 6
2D area, cm2	1.5 ± 1.1	1.1 ± 0.8	16 ± 12	13 ± 10
3D area, cm3	1.9 ± 2.0	1.4 ± 1.5	18 ± 16	14 ± 12
MA shape
NPA, °	11 ± 6	12 ± 14	7 ± 4	8 ± 9
Annular height, cm	0.19 ± 0.15	0.15 ± 0.13	25 ± 22	19 ± 17
Tenting volume, cm3	1.4 ± 0.9	0.5 ± 0.4	36 ± 20	18 ± 17
Tenting area, cm2	0.7 ± 0.4	0.4 ± 0.3	31 ± 15	20 ± 16
Tenting height, mm	2.7 ± 1.4	2.0 ± 1.4	27 ± 15	22 ± 16
Sphericity index (AP/AL-PM)	0.06 ± 0.04	0.08 ± 0.05	7 ± 5	9 ± 6
Mitral leaflets
Anterior leaflet area, cm2	1.1 ± 1.0	0.8 ± 0.6	17 ± 14	14 ± 10
Posterior leaflet area, cm2	1.4 ± 0.8	1.0 ± 0.7	23 ± 13	18 ± 14
Anterior leaflet length, cm	0.3 ± 0.2	0.4 ± 0.2	12 ± 9	14 ± 9
Posterior leaflet length, cm	0.4 ± 0.2s	0.3 ± 0.3	24 ± 14	24 ± 23

Dynamic Measurements

Changes in MV parameters during systole are shown in Figure 2. In the entire cohort, both MA 2D area and circumference showed small variations throughout the ventricular systolic contraction (Figure 2, left). Minimal values were noted at 20% systole time (9.69 ± 2.30 cm² and 11.77 ± 1.39 cm, respectively) and maximum values at end-systole (9.93 ± 2.30 cm² and 11.89 ± 1.39 cm, respectively). The changes in AL-PM and AP diameters occurred at different timings and in opposite directions: AP diameter initially decreased minimally, reaching its lowest value at 10% of systole (3.23 ± 0.40 cm) and then increasing to its highest value at end-systole (3.37 ± 0.40 cm), while AL-PM diameter showed its highest value at the beginning of systole (3.69 ± 0.45 cm) and then decreased to its lowest value (3.64 ± 0.40 cm) at end-systole. Of note, the peak-to-peak amplitude of the variation in AP diameter was 1.6 mm (5% change from its initial value), whereas that of AL-PM diameter was only 0.5 mm (~1% change from its initial value). Sphericity index increased through the whole of systole, reaching its highest mean value (0.92 ± 0.07) at the end of systole. This behavior in MV dynamics was noted in both men and women. Sex-related dynamic data are shown in Figure 2 (right), with notable differences in the magnitude of the parameters that followed the same patterns of changes throughout systole in both sexes. There were no differences in MV dynamic patterns between age groups.

Figure 2.

Dynamic measurements of MV parameters throughout systole for the entire study cohort (left) and separately for men (blue) and women (pink; right panels).

DISCUSSION

Previous studies reported echocardiographic normal values in specific countries or regions or performed meta-analyses to establish global normal reference ranges. Although reference values from MV quantitative analysis using data from 3D TTE and TEE have been reported,^16,22–24 to the best of our knowledge, this is the first report of normative values from a large group of multiethnic healthy individuals, derived from images obtained using a uniform acquisition protocol and analyzed in a core laboratory using vendor-independent software.

The main findings of this study are summarized as follows: (1) MA size, MA shape, and leaflet parameters are larger in men than in women, with sex-related differences being mitigated by BSA or height indexing; (2) MA size and shape parameters were not age dependent, but anterior leaflet area was significantly smaller in older subjects, irrespective of indexing; (3) Asian populations showed significantly smaller MA size and larger NPA compared with the other races; (4) AL-PM and AP diameters changed in opposite directions throughout systole, with the mitral annulus enlarging and adopting a more circular shape toward the end of systole; and (5) all these differences should be interpreted with caution because of the associated measurement variability.

Feasibility of 3D TTE for MV Assessment

Although TEE provides additional and often more accurate information than TTE in specific patients and clinical scenarios, the semi-invasive nature of the former procedure limits the ability to establish normal values for cardiac structures in a healthy population.²² Recent advances in computer and transducer technologies resulted in significant improvements in the quality of 3D transthoracic echocardiographic images, and the advantages over 2D measurements have been described in several settings.¹⁶ Specifically for MV assessment, 3D TTE enables real-time volumetric imaging and multiplane reconstruction,²⁵ allowing an en face visualization from both LV and left atrial (LA) perspectives.¹¹ In addition, MA assessment using 3D TTE has shown good accuracy compared with other tomographic imaging modalities such as cardiac magnetic resonance imaging.²⁶ Mihăilă et al.²² reported 94% feasibility of quantitative analysis of the MV in healthy subjects using 3D transthoracic echocardiographic data sets, including measurements of the MV annulus throughout systole, resulting in normal reference values for both static and dynamic MV anatomy. Furthermore, they demonstrated that MA measurements derived from 3D transthoracic data sets correlated closely with 3D TEE–derived measurements. Therefore, 3D TTE appears to be a reliable, accurate method for assessing MA anatomy and function that can overcome many of the intrinsic limitations of 2D echocardiographic measurements.

MA Parameters

The software used in this study provides static and dynamic information from multiple mitral apparatus parameters. Currently, there are no recommendations or guidelines stating which of these measurements should be used routinely. In this paper, we report only those parameters that were considered the most relevant for clinical practice.

MA size, shape, and leaflet measurements were all significantly larger in men, irrespective of age group and race. Effects of BSA and height indexing could be summarized as a reduction, or sometimes even an inversion, of these sex-related differences. Parameters that would be unlikely to be affected by BSA indexing, such as NPA and sphericity index, were indeed not different between men and women, further suggesting that sex differences in other parameters that were different between the sex groups, were indeed driven by body size.

Meaningful differences in LA size related to aging have been recently described.²⁰ However, for MA parameters, we found that there was no consistent trend with age. Anterior leaflet area was the only parameter that was smaller in the oldest age group, even after indexing. Although statistically significant, clinical relevance of this finding is uncertain.

It has been reported that the coaptation zone of the anterior leaflet is longer than that of the posterior leaflet, suggesting that this redundant tissue allows the valve to compensate for small increments in annular dilation without significant changes in coaptation surface and thus, avoiding regurgitation.²⁷ Also, it has been described that alterations in the proportion of coapting zones between leaflets could be the initial anatomic alteration, eventually leading to mitral incompetence, even though the valve appears normal and measurements falling within the normal range.²⁸ Interestingly, in our study, we found a reduction in the anterior leaflet area, with a parallel increase in annular height, and decreases in NPA and tenting in the oldest age group compared with the middle-aged group. We postulate that these findings may stem from the primary reduction in leaflet area encountered in the elderly group, which may lead to a compensatory change in MA shape, increasing the nonplanarity of the annulus to prevent early systolic mitral regurgitation (MR). Compensatory mechanisms characterized by endothelial-mesenchymal leaflet transformation have been described in pathological settings, such as atrial functional MR and ischemic MR.²⁹ Similar mechanisms probably also affect the tricuspid valve.³⁰

Differences between our data and previous studies using 3D TTE for MA assessment should be noted. Compared with the measurements reported in a cohort of 211 healthy white patients using 3D TTE,²² our study showed larger early systolic measurements of AP diameter (3.3 ± 0.04 vs 2.3 ± 0.3 cm), AL-PM diameter (3.7 ± 0.5 vs 3.4 ± 0.4 cm), MA circumference (11.8 ± 1.4 vs 9.8 ± 1.1 cm), and 3D area (10.3 ± 5.2 vs 6.9 ± 1.5 cm²). Values of both anterior leaflet area (6.9 ± 1.7 vs 5.7 ± 1.2 cm²) and posterior leaflet area (5.9 ± 1.8 vs 3.7 ± 1.0 cm²) were also larger in our study. We postulate that these differences probably stem from the differences in the populations of the two studies, with our sample of the normal population being considerably larger and more diverse.

Sonne et al.^16,24 assessed MV and papillary apparatus using real-time 3D TTE. Compared with the findings of the present study, measurements of MA size and shape were smaller, although it is important to consider that in these smaller measurements were obtained in mid-systole, whereas the present values were obtained in early systole.

Kovalova and Necas³¹ used 3D TEE to evaluate MA characteristics in patients with significant mitral regurgitant lesions using quantitative MV analysis, including a control group of 28 healthy subjects. Our MA circumference and area values were larger than those described in their control group (11.28 ± 2.15 cm and 8.72 ± 3.22 cm², respectively), but smaller than those reported in in patients with ischemic regurgitation, MV prolapse and Barlow disease.

Interestingly, MA size measurements reported in our study were similar to those described by Maffessanti et al.¹⁰ in a small cohort of normal individuals, using cardiac magnetic resonance. Although 3D echocardiography provides detailed views of the complex structure of the MV apparatus, it has been shown that values can vary widely among normal subjects.²⁴ It is also important to interpret our findings, when comparing them with cardiac magnetic resonance values in the literature, in the context of intermodality differences in spatial resolution.

Dynamic Analysis

Distinctive features related to impairment in MV dynamics have been described in several disease states. For instance, patients with MA calcification showed decreased early systolic annular contraction.³² Patients with ischemic MV disease showed significant loss in motility of the mitral annulus, associated with a delayed increase in the anterior leaflet area³³ and markedly enlarged mitral annulus. Redundant leaflets and augmented dynamic changes were previously described in patients with degenerative MV disease and prolapse.³⁴

Nevertheless, some aspects of normal MV dynamics still remain uncertain, and accurate measurement of MA area and motion continues to be challenging. The normal mitral annulus presents its characteristic nonplanar, saddle-shaped structure,^22,34 relying not only on MA dimensions but also on normal annular contraction. Although variations of MA size throughout diastole have been described to be minimal,³⁵ changes during systole are complex. During early systole, the mitral annulus contracts and folds predominantly in the AP direction and not in the relatively fixed AL-PM diameter, leading to leaflet approximation and coaptation. These changes were noted even during the isovolumetric contraction, before aortic valve opening.³⁶ During mid- and late systole, the papillary muscles contract symmetrically, pulling apically to close both leaflets and keep them under tension. As systole progresses, changes in the mitral annulus have little potential for inducing MR because of the firm apposition of the leaflets.³⁶

These changes in MA shape have been also assessed using cardiac computed tomography, demonstrating that the saddle shape is present in most phases of the cardiac cycle, gradually turning into a more rounded and flatter shape during the 0% and 90% phase.³⁵ Mihăilă et al.²² reaffirmed the presence of early systolic contraction of the mitral annulus, noticing that the smallest annular size is reached in early systole and that MA contraction occurs mainly along the AP diameter, in agreement with our findings.

We noticed that there was a minimal decrease in AP diameter during LV contraction, reaching its minimum value at the 20% of systole, in agreement with Tang et al.,³⁷ who described an abrupt reduction of AP diameter reaching its minimum in early systole. Topilsky et al.³⁶ described similar findings, noticing that despite AP contraction and annular height increase during systole, AL-PM diameter remained unchanged, contributing to early systolic annular area contraction and approximation of anterior and posterior leaflets.

As multiple studies have already shown,^22,38–40 we noticed progressive increases in MV area and circumference after initial decreases in these parameters in early systole, although it is important to consider that changes in a single annular diameter may not necessarily predict changes in annular area or circumference, highlighting the role of 3D echocardiography in avoiding geometric assumptions and erroneous conclusions.¹¹

The MA plays a structural and functional role in the interplay between the left ventricle and the left atrium. Muscle cells are present in both leaflets in the proximity of the mitral annulus.⁴¹ Interestingly, these cells resemble atrial cells and are excitable from the atrial side even before LV contraction, highlighting the influence of LA function on the mechanisms of MV closure.⁴¹ Although LA remodeling is a crucial factor in the initiation and maintenance of functional MR and atrial fibrillation, to what extent impaired LA function affects MA dynamics remains to be defined.⁴² This suggests that early changes in normal MA mechanics may be a surrogate of LA myopathy, before the onset of severe MR or LA enlargement. Further research is necessary to corroborate these hypotheses.

Indexing of MV Measurements

Important associations of MV area with BSA and sex have been reported.^22–24 The previously described differences persisted irrespective of sex and race. BSA in white men was similar between both studies, but white women in our group had larger BSAs than in the 2014 study.

Probably predominantly attributable to BSA and height differences, all MV measurements were smaller in the Asian population compared with white and black individuals. In contrast, the differences between white and black cohorts were not significant. Although normal reference ranges for the MV and their BSA dependency have been reported,^22–24 our findings are unique, as no other studies, to our knowledge, have described race differences in MV anatomy.

Indexing plays an important role to reduce differences in “normal values” among groups of subjects with different body sizes. Nevertheless, to the best of our knowledge, height indexing has not been used in clinical practice. In this study, BSA indexing mitigated the differences in 2D and 3D area measurements, while an effect of height indexing was noticed for one-dimensional parameters (diameters and circumference), particularly when analyzing sex differences. This might raise the question of whether all parameters should be indexed exclusively to BSA or, alternatively, whether indexing technique should depend on the dimensionality of each parameter. The results of this study seem to provide evidence in support of the latter approach.

Implications of MV Normal Values

MR is the most common valvular pathology in the general population.⁴³ Availability of reliable 3D-derived normative values of the mitral apparatus is imperative to better detect and understand MV pathology and factors that are important for surgical and procedural planning, especially as these interventions become more universal. For MV pathology identification, 3D-derived MV parameters such as annular area, AL-PM diameter, and intercommissural diameter were shown to differentiate normal MV anatomy from fibroelastic deficiency and Barlow disease. Also, functional MR is another MV pathology for which the availability of well-established normal values is critically important.⁴⁴

Additionally, transcatheter MV repair and replacement rely on imaging-based parameters to determine procedure candidacy, procedure planning, and device selection. For example, in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, evaluating efficacy of the MitraClip system for the treatment of severe secondary MR, a MV orifice area < 4.0 cm² was used as an exclusion criterion because of risk for resultant mitral stenosis.⁴⁵ Additional mobile posterior leaflet length >10 mm was considered necessary to successfully place the MitraClip device.⁴⁶ An important consideration that arises from the present study is how alterations in normal MV dynamics in pathologic states can affect planning, success of MR reduction, and avoidance of mitral stenosis in various interventions, namely, transcatheter edge-to-edge repair.

In surgical realms, MV parameters of annular diameter and tethering area were predictors of failure following surgical MV repair.⁴⁷ It is likely that the normal values reported in this study may have implications for procedural planning and device design aiming at restoration of normal MV geometry. This is with the understanding that it is likely that the majority of patients scheduled for structural heart disease procedures would in most circumstances undergo 3D TEE rather than TTE. However, for understandable reasons that importantly include the semi-invasive nature of TEE, it would be impossible to obtain normal values of cardiac parameters specifically for this imaging modality.

Limitations

The 3D software used in this study tracks the mitral annulus throughout systole only, thus lacking data on MA dynamics during diastole. Additionally, the semiautomated software requires manual identification of structures such as the highest point of the MA on the aortomitral curtain, as well as commissural points, which can be challenging and introduces measurement variability when creating a 3D model. Errors in defining these points can significantly affect the accuracy of the model data. Lack of uniform criteria in choosing the reference frames may be the answer to some differences noted in MA dimensions compared with previous studies, although this should not affect systolic dynamics, which seem to be consistent with previous, smaller reports. The lack of LV and LA data to correlate our findings with (especially dynamic analysis) may be seen as a limitation as well. The fact that 3D echocardiography is not fully incorporated into daily clinical practice may limit the applicability of the findings of this study, although most centers with structural heart programs nowa-days use 3D technologies routinely. Wide intersubject variability in normal 3D echocardiography–derived MV annular geometry, leaflet tenting, and papillary muscle position has been described elsewhere.²⁴ Although statistically significant, our findings related to population differences in MV parameters should be interpreted with caution in view of this associated measurement variability, and further prospective research is necessary to ascertain the clinical relevance of these differences.

CONCLUSION

The heterogeneity of imaging acquisition protocols and populations limiting previous studies may restrict the applicability of normal values of MV parameters reported in the literature. As a part of the WASE Normal Values Study, this report provides important information with a potential to overcome these obstacles and helps in reassessing normative values of static and dynamic parameters of the MV across sex, age, and racial groups. This information may contribute to building the foundation for future investigation into MV pathology and therapeutics.

HIGHLIGHTS.

• A total of 748 healthy adult subjects were studied.

• Normal values of 3D static and dynamic MV parameters were established.

• Age, sex, and race affect 3D MV measurements.

Abbreviations

2D

Two-dimensional

3D

Three-dimensional

AL

Anterolateral

AP

Anteroposterior

BSA

Body surface area

LA

Left atrial

LV

Left ventricular

MA

Mitral annular

MR

Mitral regurgitation

MV

Mitral valve

NPA

Nonplanar angle

PM

Posteromedial

TEE

Transesophageal echocardiography

TTE

Transthoracic echocardiography

WASE

World Alliance Societies of Echocardiography

ADDITIONAL WASE INVESTIGATORS

Argentina: Aldo D. Prado, Centro Privado de Cardiologia, Tucumán, Argentina; Eduardo Filipini, Universidad Nacional de la Plata, Buenos Aires, Argentina.

Australia: Agatha Kwon and Samantha Hoschke-Edwards, Heart Care Partners, Queensland, Australia.

Brazil: Tania Regina Afonso, Albert Einstein Hospital, Sao Paulo, Brazil.

Canada: Babitha Thampinathan and Maala Sooriyakanthan, Toronto General Hospital, University of Toronto, Canada.

China: Mei Zhang, Yingbin Wang and Yu Zhang, Qilu Hospital of Shandong University, Jinan, China; Tiangang Zhu and Zhilong Wang, Peking University People’s Hospital, Beijing, China; Lixue Yin and Shuang Li, Sichuan Provincial People’s Hospital, Sichuan, China.

India: R. Alagesan, Madras Medical College, Chennai, India; S. Balasubramanian, Madurai Medical College, Madurai, India; R.V.A. Ananth, Jeyalakshmi Heart Center, Madurai, India; Manish Bansal, Medanta Heart Institute, Medanta, Haryana, India.

Iran: Azin Alizadehasl, Rajaie Cardiovascular Medical Center, IUMS, Tehran, Iran.

Italy: Luigi Badano, University of Milano-Bicocca, and Istituto Auxologico Italiano, IRCCS, Milan, Italy; Eduardo Bossone, Davide Di Vece and Michele Bellino, University of Salerno, Salerno, Italy.

Japan: Tomoko Nakao, Takayuki Kawata, Megumi Hirokawa and Naoko Sawada MD, The University of Tokyo, Tokyo, Japan; Yousuke Nabeshima MD, University of Occupational and Environmental Health, Kitakyushu, Japan.

Republic of Korea: Hye Rim Yun and Ji-won Hwang, Samsung Medical Center, Seoul, Republic of Korea.