The two-dimensional (2D) proximal isovelocity surface area (PISA) method has some technical limitations, mainly the geometric assumptions of PISA shape required to calculate effective regurgitant orifice area (EROA). Recently developed single-beat, real-time three-dimensional (3D) color Doppler imaging allows direct measurement of PISA without geometric assumptions. The aim of this study was to validate this novel method in patients with chronic mitral regurgitation (MR).
Thirty-three patients were included, 25 (75.7%) with degenerative MR and eight (24.2%) with functional MR. EROA and regurgitant volume were assessed using transthoracic 2D and 3D PISA methods. The quantitative Doppler method and 3D transesophageal echocardiographic planimetry of EROA were used as reference methods.
Both EROA and regurgitant volume assessed using the 3D PISA method had better correlations with the reference methods than conventional 2D PISA. A consistent significant underestimation of EROA and regurgitant volume using 2D PISA was observed, particularly in the assessment of eccentric jets. On the basis of 3D transesophageal echocardiographic planimetry of EROA, 14 patients had severe MR (EROA ≥ 0.4 cm 2 ). Of these 14 patients, 42.8% (6 of 14) were underestimated as having nonsevere MR (EROA ≤ 0.4 cm 2 ) by the 2D PISA method. In contrast, the 3D PISA method had 92.9% (13 of 14) agreement with 3D transesophageal planimetry in classifying severe MR. Good intraobserver and interobserver agreement for 3D PISA measurements was observed, with intraclass correlation coefficients of 0.96 and 0.92, respectively.
Direct measurement of PISA without geometric assumptions using single-beat, real-time 3D color Doppler echocardiography is feasible in the clinical setting. MR quantification using this methodology is more accurate than the conventional 2D PISA method.
Quantitative assessment of mitral regurgitation (MR) is an important but still controversial issue. Effective regurgitant orifice area (EROA) is a useful index of the severity of MR. EROA calculation using the proximal isovelocity surface area (PISA) method has been well validated with in vitro and in vivo models. Despite its usefulness, pitfalls and limitations of this technique are well recognized. The conventional two-dimensional (2D) PISA method is based on the assumption of hemispheric symmetry of PISA. However, PISA can be variable depending on the instrument settings and the shape of the regurgitant orifice, leading to a discrepancy between EROA calculated with hemispheric assumption and the actual area. Three-dimensional (3D) echocardiography is an imaging technique that can provide the actual geometry of the flow convergence. Direct measurement of PISA with 3D color Doppler echocardiography does not require the use of geometric assumptions and should reduce the errors in calculating EROA present with the 2D method. The aims of this study were to assess the feasibility and accuracy of direct PISA measurement using single-beat, real-time 3D color transthoracic echocardiographic imaging in routine clinical practice and to compare its derived EROA with that obtained by quantitative Doppler echocardiography and direct planimetry by 3D color Doppler transesophageal echocardiographic (TEE) imaging.
From March to September 2011, we prospectively included 33 patients referred to the echocardiographic laboratory at our hospital for TEE imaging who met the following inclusion criteria: (1) the presence of at least moderate MR in the standard color Doppler evaluation of regurgitant jet size, (2) the presence of a recognizable proximal flow convergence region on the ventricular side of the mitral valve in the four-chamber view, and (3) the absence of concomitant lesions (more than mild aortic stenosis, aortic insufficiency, or mitral stenosis) and more than one flow convergence region. During recruitment, 11 patients were excluded because of the presence of significant concomitant lesions (four with mitral stenosis, four with aortic regurgitation, and three with aortic stenosis) and five because of the presence of more than one flow convergence region. No patient was excluded on the basis of imaging quality. All patients underwent echocardiography because of clinical indications and gave written informed consent before undergoing echocardiography in accordance with a protocol approved by the institutional review board.
Two-dimensional transthoracic echocardiography was performed with the patient in the left lateral decubitus position in expiratory apnea. Conventional evaluation of MR severity with 2D color Doppler echocardiography was performed as previously described. All patients were studied in the apical four-chamber view. Typical scanning depth was 12 cm, with a color Doppler sector angle of 30°. These settings provided a color Doppler frame rate of 14 to 15 frames/sec with a Nyquist limit of 0.9 to 1.0 m/sec. The ventricular surface of the mitral leaflets was carefully scanned to recognize the PISA, and its size was magnified to facilitate analysis. The position of the transducer was modified to minimize the angle between the centerline of the PISA and the ultrasound beam. We optimized the appearance of the PISA by shifting the color Doppler aliasing velocity from 23.0 to 48.0 cm/sec (mean, 32.6 ± 7.6 cm/sec). For each cardiac cycle, the frame with the largest flow convergence region was selected as coinciding with maximal regurgitant flow, excluding transients in the first frame after mitral valve closure and the last before mitral valve opening. A straight line was traced along the centerline of the region from the center of the regurgitant orifice as demarcated by the leaflets to the farthest boundary of the PISA. The maximal velocity of the regurgitant jet was determined by continuous-wave Doppler. According to reported values of PISA radius, EROA was calculated using the following formula: EROA = 2 × π × (PISA radius) 2 × V aliasing / V max , where V aliasing is the aliasing velocity of PISA (cm/sec), and V max is the maximal velocity of the continuous-wave Doppler MR signal (cm/sec). Two-dimensional PISA regurgitant volume (Rvol) was calculated as 2D PISA–derived EROA multiplied by the MR time-velocity integral. Quantitative pulsed Doppler assessment of EROA was performed in all patients as an independent method for comparison of the 2D and 3D PISA approaches. Mitral inflow and aortic outflow were calculated as the time-velocity integral of the mitral or aortic inflow multiplied by the cross-sectional area of the mitral annulus (2 × π × a × b ) or aortic annulus (2 × π × r 2 ), where a is the mitral annular dimension in the four-chamber view, b is the mitral annular dimension in the apical two-chamber view, and r is the left ventricular outflow tract diameter in the parasternal long-axis view (1 cm proximal to the aortic annulus). Maximal velocity and time-velocity integral were averaged over five beats in patients with atrial fibrillation. Mitral Rvol was calculated as the difference between mitral and aortic forward stroke volumes, and EROA was calculated as Rvol divided by the time-velocity integral of the continuous-wave Doppler MR signal. Regurgitant fraction was calculated as Rvol divided by the mitral stroke volume and expressed as a percentage. Regurgitant jets were classified as eccentric if they were in close contact with the mitral leaflet behind the regurgitant orifice and impinged to the medial or lateral wall of the left atrium, whereas central jets were initially directed into the center of the left atrium.
3D PISA Method
Without changing flow conditions, 3D Doppler data were acquired immediately after the 2D transthoracic study and before the transesophageal study. We used custom software specifically developed for 3D PISA determination (Siemens Medical Solutions USA, Inc., Mountain View, CA). Measurements were performed blinded to flow measurements, regurgitant orifice characteristics, and 2D data. A single-beat, real-time 3D transthoracic echocardiographic system (ACUSON SC2000; Siemens Medical Solutions USA, Inc.) with a 2.5-MHz handheld transducer (4Z1c; Siemens Medical Solutions USA, Inc.) was used. Three-dimensional full-volume images of the entire left ventricle and 3D color Doppler images of MR (color four-dimensional mode) were acquired from an apical transthoracic window. We optimized the aspect of the PISA by reducing the color Doppler aliasing velocity to a value between 20 and 40 cm/sec (mean, 34 ± 7 cm/sec). To maximize the volume frame rate of acquisition, depth was optimized. To minimize the potential effect of low temporal resolution of 3D color Doppler imaging, five nonstitched real-time 3D color Doppler volumes from consecutive cardiac cycles were acquired in each patient, looking for the largest convergence zone. The full-volume ultrasound images were displayed in three orthogonal planes, as seen in Figure 1 . We were careful to include the entire PISA of MR in the volume data sets. The average nonstitched 3D color Doppler volume frame rate was 16 Hz.
All image data were digitally stored on a hard disk and transferred to a PC-based workstation for offline analysis using the dedicated SC2000 workplace system (Siemens Medical Solutions USA, Inc.). On 3D color Doppler images of MR, the frame in which PISA appeared the largest during systole was chosen to analyze PISA. The software performs automated quantification of 3D PISA, visualized as green overlay on 3D color Doppler images ( Figure 1 ). After selection of the appropriate volume the software allows the user to select an aliasing velocity and initial seed point for 3D PISA analysis. The software then performs the 3D segmentation in the volume data, applying the random walker algorithm, and computes the actual flow convergence area free of any geometric assumption. The segmented mask is used to generate a mesh in 3D space and flow convergence surface area is computed and displayed. The results are displayed on the reference planes as well as in the volume-rendered image. Three-dimensional PISA was used to derive EROA as (3D PISA × V aliasing )/peak MR velocity. Three-dimensional PISA Rvol was calculated as 3D PISA–derived EROA multiplied by the MR time-velocity integral. To assess the effect of observer variability and the reproducibility of the 3D PISA method, a second independent blinded observer analyzed 15 randomly selected cases. Both experienced investigators had previously used the 2D PISA method for several years. On the same full-volume acquisition of the PISA, each observer measured the PISA with the described method. Intraobserver variability was assessed by comparing the measurements given by the same observer after an interval of >1 week between the two measurements.
3D Transesophageal Planimetry of EROA
TEE imaging was performed immediately after the transthoracic studies using a commercially available echocardiographic system (iE33; Philips Medical Systems, Andover, MA) equipped with the fully sampled matrix-array X7-2t transducer, allowing real-time 3D images. The mitral valve was interrogated by using multiple planes, including short-axis views, four-chamber and five-chamber views, and slight variations of them. Three-dimensional color Doppler data sets of the MR jets were acquired from the views that provided the visualization of the entire vena contracta area. Full-volume data sets were obtained using electrocardiographic gating over six consecutive heartbeats to combine six small real-time subvolumes into a larger pyramidal volume. The images were acquired during a brief suspension of breathing, and special care was taken to stabilize the probe during data acquisition to avoid stitch artifacts. All images were digitally stored for offline analysis (3DQ, QLAB 7.0; Philips Medical Systems). Using multiplanar reconstruction of the 3D TEE volume data set, a cross-sectional plane through the vena contracta perpendicular to the jet direction was selected, and EROA was measured using manual planimetry of the color Doppler flow signal from an en face view ( Figure 2 ). Rvol was calculated as 3D TEE planimetry–derived EROA multiplied by the MR time-velocity integral.
Continuous variables are expressed as mean ± SD. Categorical data are presented as absolute numbers or percentages. Correlations between 2D and 3D PISA measurements and those obtained by reference methods were assessed using simple linear regression analysis. Bland-Altman plots were constructed to demonstrate agreement between methods. Graphed data indicate mean test value ± 2 SDs and measurement bias. Interobserver and intraobserver reproducibility were evaluated using intraclass correlation coefficients. Differences were considered statistically significant at P < .05 (two sided). Statistical analysis was performed using SPSS version 15.0 (SPSS, Inc., Chicago, IL) and MedCalc version 9.3 (MedCalc Software, Mariakerke, Belgium.).
Clinical and echocardiographic characteristics of the 33 patients studied are summarized in Table 1 . The mean age was 68 ± 14 years, and 18 patients (54%) were men. Twenty-seven patients (81.8%) were in sinus rhythm and six in atrial fibrillation when studied. The mean heart rate was 80 ± 16 beats/min during transthoracic echocardiography and 82 ± 17 beats/min during TEE imaging. Neither systolic blood pressure (127 ± 28 vs 125 ± 25 mm Hg) nor diastolic blood pressure (74 ± 6 vs 73 ± 4 mm Hg) differed significantly between transthoracic echocardiography and TEE imaging. Twenty-five patients (75.7%) had degenerative MR and eight (24.2%) had functional MR. The jet was central in 15 patients (45.4%) and eccentric in 18 patients (54.5%). Peak Doppler velocity across the regurgitant orifice averaged 492.9 cm/sec (range, 345–762 cm/sec).
|Age (y)||68 ± 14|
|New York Heart Association functional class|
|Atrial fibrillation||6 (18.1%)|
|End-diastolic volume (mL) (Simpson)||135.7 ± 41.2|
|End-systolic volume (Simpson)||58.7 ± 34.1|
|Ejection fraction (%)||57.5 ± 14.6|
|Four-chamber left atrial area (cm 2 )||29.5 ± 4.2|
|Pulmonary artery systolic pressure (mm Hg)||48.5 ± 15.4|
|Cause of MR|
|Eccentric jet||18 (54.5%)|
|Four-chamber color Doppler jet area (cm 2 )||7.6 ± 3.1|
|Vena contracta (cm)||0.6 ± 0.2|
MR Quantification by the 2D and 3D PISA Methods Compared with Reference Methods
The quality of the PISA zone images was excellent for both 2D and 3D transthoracic echocardiography. The duration of EROA assessment by the 3D PISA method was 4 to 5 min. Three-dimensional PISA measurements were optimal in all patients. PISA geometry was hemielliptic rather than hemispheric in the majority of patients, even in patients with degenerative MR. Patients with functional MR had a more elongated and hemielliptic shape of PISA compared with patients with degenerative MR ( Figure 3 ). EROA, Rvol, and regurgitant fraction determined by the four techniques are reported in Table 2 for comparison. Using the 2D PISA method, the derived EROA was significantly smaller than that obtained by the reference methods (3D TEE planimetry and quantitative Doppler echocardiography). In contrast, using the 3D PISA method, the resultant EROA was very close, although a little smaller than that obtained by the reference methods. Correlation between EROA obtained by the 2D and 3D PISA methods with 3D TEE planimetry and quantitative Doppler echocardiography are shown in Figures 4 and 5 , respectively. Acceptable correlation was observed between 2D PISA–derived EROA and the reference methods (with 3D TEE planimetry, r = 0.93, P < .001; with quantitative Doppler echocardiography, r = 0.89, P < .001). However, the regression equation indicated a consistent significant underestimation of EROA using the 2D PISA method. A better correlation was observed between 3D PISA–derived EROA and that obtained by the reference methods (with 3D TEE planimetry, r = 0.99, P < .001; with quantitative Doppler echocardiography, r = 0.96, P < .001). Linear regression showed an excellent correlation, with uniform clustering of data around the regression line. Bland-Altman analysis showed better agreement when comparing 3D PISA–determined EROA with the reference methods than when comparing the former with 2D PISA–determined EROA. Figure 6 shows the correlation between Rvol derived from 2D and 3D PISA with that obtained by the reference methods. Consistent with previous data, 3D PISA–derived Rvol had better correlation with the reference methods than did the 2D PISA method. The analysis stratified by the type of jet showed that the 3D PISA method was more accurate than the 2D PISA method for both central and eccentric jets ( Figure 7 ). In addition, there was a bias toward increased relative underestimation of actual EROA in eccentric jets with the 2D PISA method. On the basis of 3D TEE planimetry–derived EROA, 15 patients had severe MR by American Society of Echocardiography guidelines (EROA ≥ 0.4 cm 2 ), 11 in the group with degenerative MR and three in the group with functional MR. Of these 14 patients, 42.8% (6 of 14) were underestimated as having nonsevere MR (EROA ≤ 0.4 cm 2 ) by the 2D PISA method. Underestimation of severe MR by the 2D PISA method was more common in the group with functional MR (two of three [66.6%]) than in the group with degenerative MR (four of 11 [36.4%]). In contrast, the 3D PISA method had 92.9% (13 of 14) agreement with 3D TEE planimetry in classifying severe MR. Good intraobserver and interobserver agreement for 3D PISA measures was shown, with intraclass correlation coefficients of 0.96 and 0.92, respectively.