Normal mitral valve function depends on a sequence of motions involving multiple cardiac structures. There is an aortic-mitral interaction, mitral leaflet motion, and coordinated contraction of the papillary muscles and underlying myocardium. In the healthy state, these structures act in concert to prevent systolic regurgitation, minimize leaflet stress, and allow laminar flow across the valve in diastole. A hallmark of disease is loss of one or more of these interconnected motions.

The mitral annulus has a complex three-dimensional (3D) shape similar to a saddle ( Figure 1 , Video 1 ; available at www.onlinejase.com ). The anterior (aortic) and posterior aspects are elevated compared with the medial and lateral (or commissural) portions. With the advent of real-time 3D echocardiography (3DE), it has become possible to describe not only annular dimensions but also the dynamics of the mitral annulus throughout the cardiac cycle. For the first time, it is possible to image the mitral annulus in its entirety within a single data set. Normal mitral annular function involves contraction in early systole, particularly along the anteroposterior (AP) diameter of the annulus, resulting in reduced annular area and early approximation of the mitral leaflets. In early systole, there is also accentuation of the saddle shape due to descent of the commissural portions of the annulus and folding along the intercommissural (IC) diameter ( Figure 2 ). These motions bring the leaflets together in early systole, contributing to sealing of the valve while leaflet apposition is not yet complete, at the same time minimizing leaflet stress.

Schematic of the mitral annulus, looking down obliquely from the left atrium, illustrating its saddle shape. The high points of the mitral annulus occur anteriorly where it abuts the aortic annulus (marked “annular height”) and posteriorly. The crescent-shaped line in the middle of the figure indicates the line of leaflet coaptation with the posterior leaflet toward the top right of the figure and the anterior leaflet toward the bottom left. See also Video 1 .

Schematic of the mitral annulus in diastole and systole. Note that in systole, the saddle shape is accentuated and there is folding along the intercommissural diameter.

Application of 3D echocardiographic technology, along with quantitative software, has provided insights into annular shape and motion in various mitral diseases, with characteristic alterations emerging for each disease state. For instance, the annulus is typically enlarged and adynamic in patients with functional mitral regurgitation. In those with myxomatous mitral valve disease, annular dilatation in all directions is observed, along with ventricular-annular decoupling, decreased annular contraction, and decreased saddle deepening despite preserved ventricular function. However, little attention has been paid to effects of mitral annular calcification (MAC) on annular function, and this disease state has not yet been studied by 3D echocardiographic technology.

Calcification of cardiac structures is common with aging and various disease states, particularly chronic kidney disease. Calcific deposits in the mitral leaflets limit their mobility and affect valve function. MAC ( Figure 3 , Videos 2 and 3 ; available at www.onlinejase.com ) is widely prevalent, found in approximately 40% of those >65 years of age. We hypothesized that MAC affects annular size and dynamics, particularly early systolic AP contraction and annular saddle shape accentuation. We prospectively collected 3D echocardiograms, from the transthoracic approach, in patients with MAC and matched control subjects. The specific aims of this study were to evaluate the 3D geometry and motion of the calcified annulus in real time.

Schematic of the mitral annulus as seen in the parasternal long-axis and short-axis views. The areas in white illustrate calcific deposits in the annulus (see Videos 2 and 3 ).

Methods

Population

Forty-three subjects with varying degrees of MAC were prospectively enrolled from a group of inpatients and outpatients referred for echocardiography. MAC was defined as an intense echogenic structure located at the juncture of the atrioventricular groove and the mitral valve. Aside from MAC, these subjects were free of valvular abnormalities (including calcific aortic stenosis) and were free of significant aortic root calcification. None had a focal wall motion abnormality. They were compared with 36 age- and sex-matched control subjects, free of all heart disease. The control group was created from a larger group of normal subjects using frequency matching. This process ensures that the two groups have similar frequencies of the predefined characteristics of interest, in this case age and sex, though not necessarily equal numbers. Analyses were done considering subjects with MAC as a single group, and divided into subgroups (mild MAC and moderate to severe MAC) on the basis of the extent of calcification on two-dimensional echocardiography.

Definition of MAC

To define the MAC subgroups, we used a previously published global cardiac calcification score, focusing on the portion assessing the mitral annulus. This score divides the annulus into anterior and posterior parts. The anterior annulus is visualized in the parasternal and apical long-axis views as the point of attachment of the anterior mitral leaflet with the aortic root and in the apical four- and two-chamber views as the point of attachment of the anterior leaflet with the atrial wall. The posterior annulus is visualized in the parasternal short-axis view, where it is divided into three segments of equal size (corresponding to P1, P2, and P3). For this study, mild MAC was defined as (1) isolated calcium deposits limited to the anterior annulus or (2) calcium deposits limited to the posterior annulus and involving one or two, but not all three, of its segments. Greater degrees of calcification were classed as moderate to severe MAC. Twelve subjects (28%) had mild MAC, and 31 (72%) had moderate to severe MAC.

Echocardiographic Measurements

Echocardiograms were acquired with a Philips iE33 system (Philips Medical Systems, Andover, MA) and an X3-1 or X5-1 transducer. After a standard two-dimensional echocardiographic examination was performed, transthoracic 3D volumetric images were acquired from the apex using the full-volume mode. The volumetric frame rate was 15 to 20 frames/sec (average, 18 frames/sec) with imaging depth at or near 15 cm. Three-dimensional data sets were digitally stored, transformed into Cartesian coordinates, and transferred to a workstation equipped with a custom software package (REAL VIEW; YD Ltd, Nara, Japan). Steps in quantitation were (1) defining, in cross-sectional planes, the left ventricular long axis through the mitral annular center and the mitral annular AP and IC axes, (2) automated cropping of 3D data into 18 radial planes spaced 10° apart, and (3) automated placement of annular marks and leaflet tracings, which were then manually adjusted in each radial plane ( Figure 4 ). All spatial positioning and measurements were performed in early, mid-, and late diastole and early, mid-, and late systole. Early diastole was identified just after mitral valve opening, late diastole as the time point just preceding mitral closure, and mid-diastole as midway between those frames. Early systole was identified as the time point immediately following onset of mitral closure, late systole as the time point at or immediately preceding aortic valve closure, and midsystole as midway between these two frames. Measurements were made of mitral annular area, annular circumference, AP diameter, IC diameter, mean and maximal tenting length, and maximal tenting volume. Annular height was defined as the maximal vertical distance between the highest (anterior or posterior) and lowest (lateral or medial) annular points and was used to compute the ratio of annular height to IC diameter, a measure of annular saddle shape ( Figure 1 ). A deeper saddle shape is characterized by a more apical position of the medial and lateral aspects of the annulus, with the anterior and posterior aspects remaining basal in position (a higher ratio of annular height to IC diameter). Because no systematic changes were noted in diastole, separate analyses using an average of the three diastolic time points were performed to assess differences in diastole between the calcified annulus and the normal annulus.

Example of 3D analysis. At the top of the figure are orthogonal two-dimensional slices (apex up) derived from the 3D data set. The vertical line marks the long axis of the left ventricle. Annular points are marked in black (the yellow dot marks the mid-point of the anterior annulus). At the bottom of the figure are depictions of the annulus and leaflets (in systole) displayed in topographical format. The middle image on the right-hand side demonstrates the saddle shape of the annulus (note that the ventricular apex is at the top of the image). The software also generates specific annular measurements as seen at bottom left. A , Anterior; L , lateral; M , medial; P , posterior.

Statistical Analysis

Results are expressed as mean ± SD or percentages. Continuous variables were tested for normality by the Shapiro-Wilk test. Differences between patient groups were analyzed with the use of two-sided Student’s t tests for continuous variables, Wilcoxon rank sum tests for ordinal variables and χ ² or Fisher exact tests for categorical variables as appropriate. Changes in Doppler echocardiographic variables were analyzed with the use of a two-way analysis of variance for repeated measures with one factor analyzed as a repeated-measures factor followed by a Tukey post hoc test to evaluate the effect of group (MAC vs no MAC or moderate to severe MAC vs mild MAC vs no MAC) and the effect of cardiac cycle point.

Interobserver and Intraobserver Variability for 3D Measurements

Inter- and intraobserver variability were previously determined in a study comparing patients with functional mitral regurgitation with normal control subjects. Those results are summarized here. Interobserver variability was determined by a second independent blinded observer who measured the echocardiographic variables in 10 randomly selected patients (five in each group). The records measured by the observers were predetermined and provided by the principal investigator. Intraobserver variability was determined by having the first observer remeasure the parameters ≥1 month after the first set of measurements. Interobserver and intraobserver variability was assessed using the Bland-Altman method and the within-subject coefficient of variation. The within-subject coefficient of variation (calculated as the ratio of the SD of the measurement difference to the mean value of all measurements) provides a scale-free, unitless estimate of variation expressed as a percentage. Mean difference was determined as the average of signed differences without regard to sign. We measured intraobserver and interobserver reproducibility for annular area, tenting volume, and annular height.

P values < .05 were considered to indicate statistical significance. The statistical analyses were performed with SigmaPlot version 11.0 (Systat Software, San Jose, CA).

This study was approved by the Einstein Healthcare Network Institutional Review Board.