Jun Kwan a, *, Marc A. Gillinov c, James D. Thomas b, Takahiro Shiota b

Eur J Echocardiography (2007) 8, 195e203 Geometric predictor of significant mitral regurgitation in patients with severe ischemic cardiomyopathy, undergoing Dor procedure: A real-time 3D echocardiographic study Jun Kwan a, *, Marc A. Gillinov c, James D. Thomas b, Takahiro Shiota b a Department of Cardiology, Inha University Hospital, 7-206, 3-Ga, Shinheung-Dong, Jung-Gu, Inchon 400-711, Republic of Korea b Cardiovascular Imaging Center, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, OH, USA c Department of Cardiac Surgery, The Cleveland Clinic Foundation, Cleveland, OH, USA Received 24 November 2005; received in revised form 26 February 2006; accepted 2 March 2006 Available online 18 April 2006 KEYWORDS Cardiomyopathy; Mitral valve; Echocardiography Abstract Background and purpose: Significant mitral regurgitation (MR) is frequently associated with coronary artery disease. The precise geometric predictors of significant MR in ischemic cardiomyopathy are not clearly defined. We performed real-time 3D echocardiography (RT3DE) in 48 patients scheduled for infarct exclusion surgery or Dor procedure, 22 of whom had moderate or severe MR (DorMR) and 26 with no or trivial MR (DorNoMR). Methods: Two orthogonal apical volumetric planes of LV, commissureecommissure (CC) and antero-posterior (AP) planes, were generated during mid-systole. Mitral valve tenting height (MVTht) and area (MVTa) were measured. The degree of leaflet tethering was estimated by the angles between the annular plane and each leaflet (anterior leaflet: Aa, posterior leaflet: Pa). Results: MVTht (1.11 0.14 vs 0.78 0.20 cm, P < 0.01) and MVTa (1.30 0.34 vs 0.87 0.27 cm 2, P < 0.01) were significantly larger in DorMR compared with Dor- NoMR. In DorMR, both Aa (38 6vs317, P < 0.01) and Pa (60 7vs418, P < 0.01) significantly increased more than those in DorNoMR. Multiple logistic regression analysis found Pa to be the most important geometric predictor of significant MR. MV tenting area was found to be the strongest determinant of MR severity in ischemic cardiomyopathy patients with significant MR by multivariate linear regression analysis. * Corresponding author. Tel.: þ8232 890 2453; fax: þ8232 890 2447. E-mail address: kuonmd@inha.ac.kr (J. Kwan). 1525-2167/$32 ª 2006 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.euje.2006.03.002

196 J. Kwan et al. Conclusions: Detecting significant posterior leaflet tethering, the most important predictor of significant MR, and measuring MV tenting area, the strongest determinant of MR severity, using RT3DE may be helpful in decision making of additive surgical intervention for MR in patients with severe ischemic cardiomyopathy. ª 2006 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. Ischemic mitral regurgitation (MR) is functional MR caused by coronary artery disease, in particular, right and left circumflex artery disease. 1 The prognostic implication of ischemic MR in the chronic phase is associated with excess mortality independent of baseline characteristics and degree of ventricular function. 2 The precise geometric determinants of ischemic MR have not been clearly understood, although such knowledge is important to improve mitral valve reparative techniques. Advances in three-dimensional (3D) echocardiography have provided much additional information on geometry of the mitral apparatus and allowed us to understand the mechanism for ischemic MR. 3e5 Real-time three-dimensional echocardiography (RT3DE) has been validated for its quantitative accuracy of geometric measurement of cardiac structure as well as volume measurement. 6e8 The purpose of this study was to determine the geometric predictors of significant MR and to investigate determinants of MR severity in the patients with severe ischemic cardiomyopathy using RT3DE. Methods We studied 48 patients with severe ischemic cardiomyopathy scheduled for infarct exclusion surgery, so called Dor procedure, 22 of whom had significant MR (moderate or severe MR from the color flow mapping) (DorMR) and 26 patients with no or trivial MR (DorNoMR). Inclusion criteria were (1) structurally normal mitral valve; (2) available color flow and Doppler image allowing calculating regurgitant orifice area (ROA); (3) available RT3DE image of LV chamber and the mitral apparatus allowing analysis of 3D geometry; and (4) sinus rhythm. Exclusion criteria were (1) clinical and echocardiographic evidences of other cardiac disease, such as organic valvular or infiltrative heart disease; (2) organic abnormality of the mitral apparatus such as chordae rupture, mitral valve prolapse or restricted leaflet due to degenerative calcification; (3) suboptimal 2D or 3D echocardiographic image leading to incomplete quantification of ROA or incomplete analysis of 3D geometry of the LV chamber and the mitral apparatus; and (4) atrial fibrillation. 2D echocardiographic measurements 2D echocardiography was performed with a phased array ultrasound sector scanner of a Sequoia 512 (Acuson) using a multifrequency 3.5e5 MHz probe. Posterior wall motion was estimated by semiquantitative grade as 1 for normal, 2 for mild to moderate hypokinesia, 3 for severe hypokinesia, 4 for akinesia, 5 for dyskinesia on a parasternal short axis view and multiple apical imaging planes. Wall motion with grade >3 was defined as significant wall motion abnormality. LV end diastolic volume (EDV) and end systolic volume (ESV) and ejection fraction (EF) were measured by the biplane Simpson disk method. 9 In DorMR group (significant MR from the color flow mapping), MR severity was quantified by ROA (cm 2 ) using the simple proximal isovelocity surface area (PISA) method. 10 Real-time 3D echocardiography Volumetric image acquisition An RT3DE imaging system with a 2.5 MHz hand held transducer was used to image the mitral apparatus (Volumetric Medical Imaging Inc., Durham, North Carolina). For all patients, transthoracic volumetric images were obtained using the apical view. Care was taken to include the entire mitral apparatus in the volumetric data set during one cardiac cycle. The volumetric frame rate was 17e22 volumes/s with an imaging depth of 12e16 cm. All volumetric images were digitally stored on magneto-optical disk and transferred into a personal computer for off-line analysis. 3D echocardiographic measurements We used a 3D computer software (TomTec, Inc., Munich, Germany), to define exact planes. First, a mid-systole of heart cycle was defined. Then, a cross-sectional plane of the mitral valve that clearly visualized both mitral commissures was used to define the commissureecommissure (CC)

Geometric predictor of ischemic mitral regurgitation 197 Figure 1 Volumetric images showing how to obtain 2 longitudinal apical planes using TomTec 3D software. By rotating the longitudinal plane on cross-sectional volumetric image at MV level (bottom left), CC plane (top right) connecting both commissures and AP plane (top left, bottom right) were obtained. Geometric measurements of the mitral valve were measured on these 2 longitudinal planes. AML, anterior mitral leaflet; PML, posterior mitral leaflet; MVTht, mitral valve tenting height; MVTa, mitral valve tenting area; Aa, tethering angle of the anterior leaflet; and Pa, tethering angle of the posterior leaflet. plane, a plane that passes through both commissures and the LV apex. Finally, antero-posterior (AP) plane perpendicular to the center of CC plane was defined for imaging the tented mitral valve (Fig. 1). 11 The sphericity of LV chamber was calculated by the ratio of the LV chamber width measured at the level of the papillary muscle to the height of the level from the mitral annulus using 3D computer software (TomTec, Co., Munich, Germany) during mid-systole. The degree of circularization of the annulus was calculated by the ratio of the AP dimension to the CC dimension of the annulus (Fig. 1). Mitral annular area (MAA) was then calculated with the simplified equation as MAA ¼ 3.14 CC dimension AP dimension/4. The degree of leaflet tethering was estimated by measuring the angle where each leaflet met the annular plane (anterior leaflet: Aa, posterior leaflet: Pa) in AP plane (Fig. 1). Mitral valve tenting area (MVTa), the area enclosed by the annular plane and two leaflets, and mitral valve tenting height (MVTht), the distance between the leaflet coaptation and the mitral annular plane, were also measured in AP plane (Fig. 1). Statistics Data were expressed as mean SD. Group comparisons were analyzed by Student s t test. To determine the predictor of significant MR, multiple logistic regression analysis of 2D and 3D echocardiographic measurements regarding the presence of significant MR as a dependent variable was done. Receiver operator characteristic (ROC) curve analysis was created from the obtained predictor to determine its discrimination (the ability to distinguish between those with and those without significant MR) with the highest sum of sensitivity and specificity. In DorMR group, all 2D and 3D echocardiographic measurements were stratified by ROA and multivariate analysis of these parameters based on stepwise multiple regression analysis was done for the determination of MR severity. A value of P < 0.05 was considered to be significant.

198 J. Kwan et al. Results 2D echocardiographic measurements Significant posterior wall motion abnormality was observed in 21 (93%) out of 23 patients with significant MR (DorMR), while it was observed in only 3 (11%) out of 27 patients without significant MR (DorNoMR). In DorMR, ROA of MR was 0.35 0.12 cm 2 (0.21e0.66 cm 2 ). There was no significant difference (P > 0.05) of LV chamber volume between 2 patient groups, but global LV systolic function (EF) was more impaired in DorMR (P < 0.01) (Table 1). 3D echocardiographic measurements Geometric measurements of the mitral valve and annulus including the LV chamber are described in Table 1. Sphericity of the LV chamber at the papillary muscle level increased more (P < 0.01) in DorMR as compared with DorNoMR. MAA and the degree of circularization of the annulus expressed as the ratio of AP dimension to CC dimension of the annulus were significantly larger (P < 0.01) in Table 1 Baseline characteristics and geometric parameters of two patient groups DorNoMR (N ¼ 26) DorMR (N ¼ 22) Age (years) 59 11 60 10 Sex (% male) 81 82 BSA (m 2 ) 1.9 0.2 1.9 0.2 LV chamber EDVI (ml/m 2 ) 94 38 107 39 ESVI (ml/m 2 ) 64 37 81 34 EF (%) 34 8 25 7* Sphericity 1.36 0.13 1.64 0.11* Mitral apparatus CC dimension (cm) 2.96 0.13 3.08 0.12* AP dimension (cm) 2.47 0.13 2.80 0.11* Annular circularization 0.84 0.05 0.91 0.02* MAA (cm 2 ) 5.73 0.44 6.78 0.51* MVTht (cm) 0.78 0.20 1.11 0.14* MVTa (cm 2 ) 0.87 0.27 1.30 0.34* Aa ( ) 31 7 38 6* Pa ( ) 41 8 60 7* EDVI, end diastolic volume index; ESVI, end systolic volume index; EF, ejection fraction; CC, commissureecommissure; AP, antero-posterior; MAA, mitral annular area; MVTht, mitral valve tenting height; MVTa, mitral valve tenting area; Aa, tethering angle of the anterior leaflet; and Pa, tethering angle of the posterior leaflet. *P < 0.01 vs DorNoMR. DorMR than in DorNoMR. MVTa and MVTht were larger (P < 0.01) in DorMR than in DorNoMR. In DorMR, both Aa and Pa were also larger (P < 0.01) than in DorNoMR. Predictor of significant MR As we explored the major predictor of significant MR in patients with ischemic cardiomyopathy using multiple logistic regression analysis of all geometric measurements regarding the presence of significant MR as a dependent variable, Pa showing prominent difference between two groups (Fig. 2) was found to be the most important geometric predictor of significant MR. Receiver operator characteristic (ROC) curve analysis defined the posterior leaflet angle >47 as the cut-off value discriminating between those with and those without significant MR (moderate MR) with sensitivity of 96% and specificity of 84% (Fig. 3). Determinant of MR severity in patients with significant MR In DorMR, MVTa (r ¼ 0.70, P < 0.001), MAA (r ¼ 0.62, P < 0.001) and Pa (r ¼ 0.49, P ¼ 0.02) showed significant correlation with MR severity (ROA) (Fig. 4) (Table 2). For local LV remodeling, sphericity of LV chamber at the papillary muscle level was significantly associated with ROA (r ¼ 0.50, P ¼ 0.02), whereas neither of the two LV chamber volume indices (EDVI, ESVI) showed significant association with the degree of MR. Multivariate stepwise linear regression analysis of the geometric measurements showing significant correlation with the MR severity defined the MVTa as the strongest determinant of MR severity expressed as ROA (R 2 ¼ 0.49). Pα (º) 80 70 60 50 40 30 20 10 0 DorNoMR DorMR Figure 2 Tethering angle of the posterior leaflet (Pa), a main predictor of significant mitral regurgitation in severe ischemic cardiomyopathy.

Geometric predictor of ischemic mitral regurgitation 199 scientific approach to appropriate intervention for treating ischemic MR. With the recent advances in 3D imaging techniques, determining the geometric changes of the mitral apparatus that are accompanied by distortion of the regional or global LV chamber have been explored. 3e5,17,18 In these studies, leaflet tethering due to displacement of the papillary muscle has been reported as a main mechanism of functional MR. Figure 3 Receiver operator characteristic (ROC) curve analysis defined the posterior leaflet angle >47 as the cut-off value discriminating between those with and those without significant MR with the highest sum of sensitivity (96%) and specificity (84%). Discussion The presence of significant functional MR that causes pulmonary hypertension 12 and LV volume overload, 13,14 which in turn potentiates the LV remodeling, is a major determinant for the outcome of LV dysfunction, and this is known to be a marker of a poor long-term prognosis in ischemic cardiomyopathy. However, functional MR is a treatable, correctable component of the LV dysfunction. 15 Furthermore, surgical treatment of MR has been suggested to be an important therapeutic option for ischemic cardiomyopathy. 16 Nonetheless, the lack of quantitative data on the geometric determinants of significant MR has hindered the ROA (cm 2 ) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 r = 0.70 Advantages of RT3DE over 2D echocardiography Of course, the geometric parameters measured in the present study, such as MAA, MVTa and MVTht, can also be provided by 2D echocardiography, as was shown in several previous studies. 19,20 However, considering that the geometric measurement of such small cardiac structures as the annulus or valve requires meticulous care, obtaining the same planes that cross identical portions of the annulus, or that cross at a specific angle (perpendicular to the axis in this study), must be guaranteed in every measurement in order to ensure the reliability of the measurements. Fortunately, the MA has two well-known anatomical reference markers; these are its two commissural points, which are easily delineated in the crosssectional plane of the LV at the valvular level. This requirement for the accurate delineation of the landmarks can be satisfied with using RT3DE and its cropping method in the multi-planar reconstructive modes (TomTec, Co., Munich, Germany). With this method, we obtained the same AP plane vertically crossing the CC plane for the measurement of MVTa, MVTht and the tethering angles of both leaflets in every case. However, this process of measurement is not guaranteed with using conventional 2D echocardiography. ROA (cm 2 ) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 r = 0.62 0 0 0.5 1 1.5 2 5.5 6 6.5 7 7.5 8 MVTa (cm 2 ) MAA (cm 2 ) Figure 4 Determinants of ROA. Correlations between ROA (y-axis) and, on the x-axis, valvular tenting area (left) and mitral annular area (right). ROA, regurgitant orifice area; MVTa, mitral valve tenting area; and MAA, mitral annular area.

200 J. Kwan et al. Table 2 Univariate and multivariate regression analyses for determinants of MR severity (ROA) Univariate Multivariate r P P LV sphericity 0.50 0.02 0.31 CC dimension 0.62 0.002 0.12 AP dimension 0.54 0.01 0.64 MAA 0.62 0.002 0.24 MVTht 0.47 0.03 0.41 MVTa 0.70 <0.001 <0.001 Pa 0.49 0.02 0.54 CC, commissureecommissure; AP, antero-posterior; MAA, mitral annular area; MVTht, mitral valve tenting height; MVTa, mitral valve tenting area; Aa, tethering angle of the anterior leaflet; and Pa, tethering angle of the posterior leaflet. Geometric characteristics of the LV chamber In terms of the LV geometry, our population had several distinctive characteristics as compared to the populations in the previous, similarly designed studies. First, the LV chambers of our patients with significant MR were not enlarged as much as those of the patients in the previous studies. 19,20 Second, there was no significant difference of the LV chamber size between the patients with and without significant MR (107 39 vs 94 38 ml/m 2, respectively, P > 0.05) in our study, while the LVEDVs of the patients with significant MR were significantly larger than those of the patients without MR in the previous studies. 19,20 Instead, there were two distinctive differences of the LV geometry between the two groups in the present study: posterior wall motion abnormality and LV sphericity. In the present study, the posterior wall motion was severely impaired in most of the patients (93%) with significant MR, while it was preserved in most of the patients (89%) without significant MR. The contribution of the posterior wall motion abnormality to the infarction of the LAD was the reason why the global LV systolic function was more impaired in the DorMR patients. Our finding supported the previous observations that the posterior wall motion abnormality followed by displacement of the posterior-medial papillary muscle and leaflet tethering might be the fundamental mechanism of ischemic MR. 12,21,22 Another contributing mechanism has been suggested by the previous animal studies. 17,22 Glasson et al. 17 have demonstrated that there was enlargement and circularization of the MA after left circumflex artery occlusion, as compared to left anterior descending artery occlusion. This probably resulted from the annular dilatation being confined to the posterior part of the annulus, i.e., the muscular component, which was affected by the posterior wall infarction caused by the LCX occlusion. Of course, ischemic cardiomyopathy with preserved posterior wall motion may cause significant MR. However, this usually occurs in the patients with chronically remodeled LV chamber (LV dilatation) followed by papillary muscle displacement and leaflet tethering, the same as functional MR does in the patients with severe dilated cardiomyopathy. Therefore, posterior wall motion abnormality is probably a fundamental cause of significant MR, particularly for the patients with ischemic cardiomyopathy without severe LV dilatation, as were the cases of our study population. Previous studies have attributed functional MR not to the degree of LV enlargement, but to the degree of LV sphericalization. 12,23,24 In the present study, we had the consistent finding that the LV sphericity, as measured at the papillary muscle level, was significantly increased in the patients with significant MR, and this is probably due to regional (posterior wall) dilatation, compared with the patients without significant MR despite that there was no significant difference in the LV chamber size between them. Geometric characteristic of the mitral apparatus As demonstrated previously, we observed that circular enlargements of the mitral annulus 17,22, leaflet tethering 3,5 and mitral valve tenting 25,26 were more prominent in the patients suffering with significant MR than in the patients without MR. However, among several geometric measurements, significant posterior leaflet tethering (>47 ) was found to be the most important geometric predictor of significant MR in ischemic cardiomyopathy, and this predictor had both high sensitivity and specificity. So then, what is the contribution of annular dilatation to the presence of significant MR? Considering that the valve tolerance to annular dilatation in the normal papillary muscle position was 1.8e2.0 times the norm 23,25e28, a mild to moderate annular enlargement alone might not be enough to produce incomplete leaflet closure for causing significant MR. Therefore, a mild to moderate annular enlargement alone does not seem to play a primary role in generating enough incomplete leaflet closure to cause substantial MR. Instead, it may play an augmentative role along with the other geometric changes such as leaflet

Geometric predictor of ischemic mitral regurgitation 201 tethering by the displaced papillary muscles, which has been suggested to be a main cause for ischemic MR. 4 With respect to the geometric determinant of the MR severity in the patients with significant MR, all the measurements except A showed significant correlation (P < 0.05) with the MR severity. Among all the geometric measurements that showed good correlation with the MR severity, the MV tenting area (determined by both the annular dimension and the degree of both the leaflets tethering) was defined as the strongest geometric determinant of the MR severity. This result was consistent with that of a previous clinical study performed on patients with systolic LV dysfunction. 11,25 This finding also suggests that even though generating significant ischemic MR is mainly determined by the degree of leaflet tethering by the displaced papillary muscle rather than by the degree of annular enlargement 29,30, the MR severity is most closely associated with the MV tenting area, as determined by both the degree of annular enlargement and the leaflet tethering. Clinical implications Early surgical repair combined with coronary revascularization should be taken into consideration when treating significant ischemic MR since it yields better patient survival and improved LV function. 31 The present study has proposed the likely geometric predictors with using quantitative data (a tethering angle of the posterior leaflet >47 ) for determining significant MR; this provides for the possibility of a new clinical decision making strategy for the early surgical correction of MR in the patients suffering with ischemic cardiomyopathy. In addition, our result may rationalize and justify the necessity of additive reconstructive surgical intervention to minimize leaflet tethering for the complete correction of MR, besides performing a Dor procedure, if a patient has a large tethering angle of the posterior leaflet before surgery. To meet all these challenges in the clinical setting, RT3DE is an appropriate diagnostic and measurement tool as it provides more precise geometric information on the mitral apparatus than does 2D echocardiography. Study limitations In the present study, we estimated the degree of MR by the PISA method, which was previously validated by a animal study that demonstrated that the degree of MR measured by PISA method was well correlated with that estimated by an electromagnetic flow probe. 32 In this study, all the patients were scheduled for a Dor procedure due to apical aneurysm, so there was a high probability of underestimating the LV sphericity in a conventional way (the ratio of the length from the mitral annular plane to the LV apex to the LV width) 33 because of the lengthened LV chamber via the apical aneurysm. That is the reason why we estimated the LV sphericity at the papillary muscle level. The spatial resolution of the volumetric plane image was limited compared to the conventional 2D images due to the low frequency of the transducer and the parallel processing. However, the mitral annular hinge points and the mitral leaflets have strong signal intensities, which made them easy to identify on the images. Finally, the degree of the papillary muscle displacement was not estimated in the present study. For defining the papillary muscle displacement, the distance from a specific anatomic marker to the head of the papillary muscle should be measured. However, the papillary muscle is anatomically known to be composed of 2 (bifid) or 3 (trifid) separated heads with different distributions of chordae to the MV; this makes it is confusing to determine which head is to be measured. Moreover, although once we determine a specific head to be measured, it would not be easy to discriminate the same head with 100% certainty in every measurement without clear visualization of the chordae distribution. Nevertheless, to better understand the relationship between the mitral valvular geometry and the MR severity, this should be explored in the future in conjunction with the degree of the papillary muscle displacement by using the more advanced RT3DE technique with better resolution. In summary, for the patient suffering from ischemic cardiomyopathy, the LV sphericity, the annular enlargement with circularization and the mitral valve tenting were more prominent in the patients with significant MR than that in those patients without MR. Significant tethering of the posterior leaflet (>47 ) was found to be the important predictor of significant MR, whereas the severity of MR was strongly associated with the MV tenting area. These quantitative geometric data, as determined by RT3DE, may provide a new decision making strategy for performing additional surgical intervention for the correction of MR in the patients suffering with severe ischemic cardiomyopathy. Acknowledgement This study was supported by INHA University Research Grant.

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