The mitral annulus displays complex conformational changes during the cardiac cycle that can now be quantified by three-dimensional echocardiography. Mitral annular calcification (MAC) is increasingly encountered, but its structural and dynamic consequences are largely unexplored. The objective of this study was to describe alterations in mitral annular dimensions and dynamics in patients with MAC.
Transthoracic three-dimensional echocardiography was performed in 43 subjects with MAC and 36 age- and sex-matched normal control subjects. Mitral annular dimensions were quantified, using dedicated software, at six time points (three diastolic, three systolic) during the cardiac cycle.
In diastole, the calcified annulus was larger and flatter than normal, with increased anteroposterior diameter (29.4 ± 0.6 vs 27.8 ± 0.6 mm, P = .046), reduced height (2.8 ± 0.2 vs 3.6 ± 0.2 mm, P = .006), and decreased saddle shape (8.9 ± 0.6% vs 11.4 ± 0.6%, P = .005). In systole, patients with MAC had greater annular area at all time points ( P < .05 for each) compared with control subjects, because of reduced contraction along the anteroposterior diameter ( P < .001). Saddle shape increased in early systole (from 10.5% to 13.5%, P = .04) in control subjects but not in those with MAC ( P = NS). Valvular alterations were also noted; although mitral valve tent length decreased during systole in both groups, decreases were less in patients with MAC ( P < .05 for mid- and late systole). For certain parameters (e.g., annular area), changes were confined largely to those patients with moderate to severe MAC ( P = .006 vs control subjects, but nonsignificant for patients with mild MAC).
Quantitative three-dimensional echocardiography provides new insights into the dynamic consequences of MAC. This imaging technique demonstrates that the mitral annulus is not made smaller by calcification. However, there is loss of annular contraction, particularly along the anteroposterior diameter, and loss of early systolic folding along the intercommissural diameter. Associated valvular alterations include smaller than usual declines in tenting during systole. These quantitative three-dimensional echocardiographic data provide new insights into the dynamic physiology of the calcified mitral annulus.
The calcified mitral annulus is larger and flatter than normal.
There is decreased annular contraction and systolic saddle deepening.
There is increased systolic tenting of the met with the aortic root and iflets.
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.
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.
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.
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.
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.
Demographic and clinical characteristics of the two groups are shown in Table 1 . Comparing patients with MAC with control subjects, there were no significant differences in age or sex. Patients with MAC had significantly more diabetes, hypertension, and hyperlipidemia. The mean ejection fraction for the MAC group was somewhat lower than in normal control subjects. Comparing mild MAC with moderate to severe MAC, there were more male subjects in the mild MAC group, but numbers were small. Otherwise, no significant differences were seen.
|Variable||Control subjects ( n = 36)||MAC ( n = 43)||P||Mild MAC ( n = 12)||Moderate to severe MAC ( n = 31)||P|
|Age (y)||62 ± 12||65 ± 12||.20||62 ± 12||67 ± 12||.28|
|Men||17 (47%)||22 (51%)||.82||10 (83%)||12 (39%)||.007|
|BMI (kg/m 2 )||26.2 ± 5.0||27.7 ± 8.2||.33||27.7 ± 6.4||27.7 ± 8.9||.98|
|DM||4 (13%)||28 (65%)||<.0001||9 (75%)||19 (61%)||.39|
|HTN||17 (47%)||40 (93%)||<.0001||11 (92%)||29 (94%)||.83|
|Hyperlipidemia||10 (28%)||29 (67%)||.0006||9 (75%)||20 (65%)||.50|
|Ejection fraction||65 ± 5||61 ± 8||.01||58 ± 7||62 ± 8||.21|
Values for all echocardiographic parameters, comparing subjects with MAC with control subjects, are displayed in Tables 2, 3, and 4 .
|Measurement||Control subjects||MAC||P||Mild MAC||Moderate to severe MAC||P|
|Annular area (cm 2 )||7.18 ± 1.58||7.79 ± 1.80||.11||7.28 ± 1.71||7.99 ± 1.82||.14|
|Circumference (mm)||96.62 ± 10.43||100.17 ± 11.92||.17||96.89 ± 11.10||101.43 ± 12.16||.19|
|AP diameter (mm)||27.76 ± 3.15||29.44 ± 4.05||.046||29.26 ± 4.31||29.51 ± 4.02||.14|
|IC diameter (mm)||31.87 ± 3.88||33.02 ± 4.40||.23||31.04 ± 3.67||33.78 ± 4.46||.07|
|Annular height (mm)||3.56 ± 1.00||2.85 ± 1.23||.006||3.14 ± 1.24||2.73 ± 1.22||.01|
|Saddle shape (%)||11.45 ± 3.66||8.91 ± 4.03||.005||10.46 ± 4.37||8.30 ± 3.80||.005|
|Measurement||Early diastole||Mid-diastole||Late diastole||Early systole||Midsystole||Late systole||Group||Phase||Group × phase interaction|
|Annular area (cm 2 )|
|Control subjects||7.28 ± 1.84||7.40 ± 1.86||6.95 ± 1.57||6.40 ± 1.57||6.50 ± 1.77||6.50 ± 1.77||.03||<.001||.02|
|MAC||7.63 ± 1.98||7.93 ± 1.74||7.81 ± 2.12||7.68 ± 2.01||7.54 ± 1.97||7.58 ± 2.04|
|Control subjects||97.09 ± 12.08||98.22 ± 12.43||95.05 ± 10.48||91.61 ± 10.88||91.89 ± 12.05||88.66 ± 17.81||.02||<.001||.01|
|MAC||99.04 ± 13.14||101.22 ± 11.00||100.24 ± 14.03||99.87 ± 13.45||98.43 ± 13.59||98.73 ± 14.30|
|AP diameter (mm)|
|Control subjects||28.15 ± 3.64||28.27 ± 3.62||27.05 ± 3.54||24.86 ± 3.56||25.57 ± 3.74||25.93 ± 3.71||.004||<.001||.001|
|MAC||28.92 ± 4.59||30.11 ± 4.12||29.29 ± 4.58||28.46 ± 4.51||28.60 ± 4.09||28.61 ± 4.45|
|IC diameter (mm)|
|Control subjects||31.54 ± 4.42||32.16 ± 4.77||32.00 ± 3.80||31.30 ± 4.18||31.20 ± 4.33||30.58 ± 3.86||.12||.18||.78|
|MAC||32.71 ± 5.00||33.21 ± 4.12||33.14 ± 5.25||33.37 ± 5.18||32.61 ± 5.19||32.66 ± 5.25|
|Annular height (mm)|
|Control subjects||3.79 ± 1.33||3.64 ± 1.48||3.27 ± 1.06||4.19 ± 1.33||3.45 ± 1.27||3.45 ± 1.62||.007||.02||.08|
|MAC||3.20 ± 2.17||2.35 ± 1.68||2.99 ± 1.54||3.17 ± 1.76||3.18 ± 1.56||3.07 ± 1.45|
|Saddle shape (%)|
|Control subjects||12.35 ± 4.77||11.52 ± 5.09||10.45 ± 3.89||13.57 ± 4.24||11.21 ± 4.16||11.27 ± 4.66||.004||.02||.09|
|MAC||10.04 ± 6.70||7.31 ± 5.79||9.37 ± 5.16||9.86 ± 6.04||10.05 ± 5.44||9.75 ± 5.01|