Vena contracta area for severity grading in functional and degenerative mitral regurgitation: a transoesophageal 3D colour Doppler analysis in 500 patients

Vena contracta area for severity grading in functional and degenerative mitral regurgitation: a... Abstract Aims Vena contracta area (VCA3D), derived by 3D colour Doppler echocardiography, has already been validated against cardiac magnetic resonance imaging, but the number of clinical studies to define cut-off values for grading of mitral regurgitation (MR) is limited. Aim of the study was to assess VCA3D in a large population of patients with functional (FMR) and degenerative MR (DMR). Methods and results Transoesophageal echocardiography was performed in 500 patients with MR. The following 2D parameters were assessed for grading of MR: vena contracta width, effective regurgitant orifice area (EROAPISA), and regurgitation volume (RVPISA). VCA3D and the corresponding regurgitation volume (RVVCA) were quantified using 3D colour Doppler loop and CW Doppler tracing of the regurgitant jet. In 104 patients a 3D dataset of the left ventricle (LV) and the left ventricular outflow tract (LVOT) was acquired. As a reference method, regurgitation volume (RV3D) was calculated as difference between LV overall and LVOT stroke volumes. For prediction of severe MR, VCA3D yielded higher values of area under the ROC curve compared to EROAPISA (overall patient group 0.98 for VCA3D vs. 0.90 for EROAPISA, P < 0.001; FMR group 0.97 for VCA3D vs. 0.92 for EROAPISA, P = 0.002). RVVCA correlated closer with RV3D compared to RVPISA (r = 0.96 for RVPISA, r = 0.79 for RVPISA). Conclusion This study delivers cut-off values for VCA3D in patients with different types of MR. VCA3D is a robust parameter for quantification of MR, showing a good correlation with the reference method using 3D datasets of LV. mitral regurgitation, vena contracta area, 3D colour Doppler echocardiography Introduction In clinical practice, echocardiography is the standard tool for assessing mechanism and severity of mitral regurgitation (MR). According to the guidelines several parameters, including vena contracta width (VC) and effective regurgitation orifice area by proximal isovelocity surface area method (EROAPISA) have to be taken into account for judging MR severity.1 EROA hydrodynamically corresponds to the cross-sectional area of the vena contracta (VCA), which is located at the smallest region between the proximal laminar flow acceleration zone and the distal downstream of the jet into the left atrium.2 As three-dimensional (3D) colour Doppler studies already revealed, in most cases EROA especially in functional MR is non-circular, limiting the ability of two-dimensional (2D) based echocardiographic parameters3 to quantify MR. Khanna et al.4 firstly described direct planimetry of vena contracta area (VCA3D) in a real-time 3D colour Doppler dataset. The concept of 3D echocardiographic derived VCA has already been validated in an in vitro model of MR and against velocity-encoded cardiac magnetic resonance imaging (cMRI),5,6 but the number of clinical studies to define cut-off values for VCA is limited.7 Aim of the study was to assess VCA3D by transoesophageal 3D colour Doppler echocardiography (3D-TEE) in a large population of patients with functional (FMR) and degenerative MR (DMR) and to define cut-off values for quantification of MR severity. Methods Study population Patients with at least moderate MR who underwent 3D-TEE in our department between May 2009 and February 2015 for clinical indications were consecutively considered eligible for this study. The patient population was divided according to the main pathology underlying MR into a group with FMR and a group with DMR. The aetiology of MR was defined as functional if resulting from either a regional myocardial dysfunction or global left ventricular remodelling in the presence of an anatomically normal valve apparatus. DMR comprised the following structural defects of the mitral valve (MV): valve prolapse, flail, and degenerative alterations including valve thickening, immobility, or annular calcification. Echocardiographic measurements Echocardiographic images were acquired using an iE33 ultrasound system (Philips Medical Systems, Andover, Massachusetts) equipped with a matrix-array transducer for transthoracic (X5-1) and transoesophageal echocardiography (X7-2 t). Heart rate (HR) and blood pressure (RR) were monitored during echocardiographic examination. Left atrial (LA), end-diastolic, and end-systolic left ventricular (LV) volume were quantified by transthoracic echocardiography and indexed to body surface area. LV ejection fraction (EF) was calculated using the modified biplane Simpson method from a four and two-chamber view.8 For quantification of VC by TEE multiple views from 0° to 180° including four chamber, intercommissural, and long-axis view were obtained using 2D colour Doppler mode. Nyquist limits were set between 50 and 70 cm/s, with the gain set just below the threshold for noise. In patients with DMR VC was measured in the view with the largest convergence zone, whereas in FMR VC was calculated as mean between four chamber and intercommissural views. EROAPISA and regurgitation volume (RVPISA) were quantified according to proximal isovelocity surface area (PISA) method.1 A continuous wave (CW) Doppler cursor was aligned parallel to MR flow to obtain the peak velocity of the MR jet and the velocity time integral (Figure 1E). In patients with FMR EROAPISA was derived from a colour Doppler recorded in a four chamber view (Figure 1A). In patients with DMR the view with the largest convergence zone was chosen to quantify the radius of PISA. Special care was taken, that PISA radius and flow velocity measurements for calculation of EROAPISA were obtained at similar timepoints throughout systole. Figure 1 View largeDownload slide Example of a 57-year-old, male patient suffering from a functional mitral regurgitation after posterior myocardial infarction. Vena contracta area (VCA3D) derived by multiplanar reconstruction in a 3D colour Doppler data set (A) was 0.28 cm2. Using the velocity time integral (VTIMR) of the regurgitation jet derived by CW Doppler (B) the calculated MR volume (RVVCA) was: 0.28 cm2 × 210 cm = 59 mL. Effective regurgitation orifice area (ERO) quantified in a four-chamber view (B) by PISA method was 0.16 cm2 resulting in a regurgitation volume (MR Volume) of 34 ml. For comparison overall stroke volume (SV) was measured in a 3D dataset of the left ventricle (D), whereas stroke volume over the aortic valve was derived using left ventricular outflow tract area (AreaLVOT 3D, E) and velocity time integral by pulsed wave Doppler (VTILVOT) positioned in the LVOT (F). Using this combined approach MR volume (RV3D) was 52 mL [SV – (AreaLVOT 3D × VTILVOT) = 86.2 mL – (3.76 cm2 × 9.19 cm)] and EROA3D 0.25 cm2 [RV3D/VTIMR = 52 mL/210 cm]. Figure 1 View largeDownload slide Example of a 57-year-old, male patient suffering from a functional mitral regurgitation after posterior myocardial infarction. Vena contracta area (VCA3D) derived by multiplanar reconstruction in a 3D colour Doppler data set (A) was 0.28 cm2. Using the velocity time integral (VTIMR) of the regurgitation jet derived by CW Doppler (B) the calculated MR volume (RVVCA) was: 0.28 cm2 × 210 cm = 59 mL. Effective regurgitation orifice area (ERO) quantified in a four-chamber view (B) by PISA method was 0.16 cm2 resulting in a regurgitation volume (MR Volume) of 34 ml. For comparison overall stroke volume (SV) was measured in a 3D dataset of the left ventricle (D), whereas stroke volume over the aortic valve was derived using left ventricular outflow tract area (AreaLVOT 3D, E) and velocity time integral by pulsed wave Doppler (VTILVOT) positioned in the LVOT (F). Using this combined approach MR volume (RV3D) was 52 mL [SV – (AreaLVOT 3D × VTILVOT) = 86.2 mL – (3.76 cm2 × 9.19 cm)] and EROA3D 0.25 cm2 [RV3D/VTIMR = 52 mL/210 cm]. In each patient 3D colour Doppler datasets were acquired from an intercommissural view using full volume applying the following settings: colour Doppler gain = 50%, smoothing = 2, colour map = 4, flow optimization = medium, line density = medium, and filter = medium. In patients with sinus rhythm (SR) an acquisition with six subvolumes was attempted (mean frame rate 18 ± 3 Hz, range 11–26 Hz). To avoid stitching artefacts in patients with atrial fibrillation (Afib) a lower number of subvolumes was used or a 3D colour Doppler loop with high volume rate was acquired (mean frame rate 15 ± 2 Hz). Quantification of VCA3D was performed by multiplanar reconstruction (Figure 1B) using a dedicated software (Philips QLAB Versions 9.0) as described before.9 With regard to the timing of VCA3D measurements again the occurrence of peak velocity in the corresponding CW-Doppler signal was used as orientation. In FMR patients a mid-systolic frame was chosen whereas in DMR patients especially with leaflet prolapse a more mid- to late-systolic frame was selected. If more than one jet occurred in the frame chosen for analyse, each jet was cropped individually and the VCA was derived as the sum of all cross-sectional areas. VCA3D derived regurgitation volume (RVVCA) was calculated by multiplying VCA3D with the MR velocity time integral of the CW-Doppler signal. VCA3D shape index was calculated as ratio between intercommissural and long axis diameter of VCA3D. In patients with Afib the parameters were calculated as mean of 3–5 measurements. In 104 patients (60 with FMR and 44 with DMR) with SR and without aortic regurgitation a 3D full volume data set of the LV and of the mitral valve including the left ventricular outflow tract (LVOT) were acquired by TEE (median frame rate 28 Hz, range 26–32 Hz). Using dedicated software tools (4D LV-Analysis© and 4D Cardio-View™, TomTec - Imaging Systems, Unterschleissheim, Germany). LV overall stroke volume (SVLV 3D) was derived by subtracting end-systolic (LVVs3D) from end-diastolic (LVVd3D) LV volume (Figure 1D). LVOT area was traced in a 3D dataset as shown in Figure 1C. In a transgastric view the sample volume of a pulsed-wave Doppler was placed into the LVOT (Figure 1F) to measure VTI of outflow velocities (VTILVOT). Using this combined approach MR volume (RV3D) was calculated as following: RV3D = SVLV 3D − (VTILVOT × LVOT area). Statistical analyses The data analysis was performed with the Statistical Package for Social Science software (SPSS for Windows 22.0, Chicago, Il, USA). All values were presented as mean ± standard deviation for continuous variables. Comparison between groups was done by Student’s t-test or one-way ANOVA analysis of variance with Bonferroni and Tamhane post-hoc tests. P < 0.05 was considered significant. Correlations between different parameters were examined using Pearson's test or linear regression analyses. Receiver operating characteristics (ROC) analyses were performed to assess the ability of the parameters to identify patients with severe MR. The value closest to the upper left corner of the ROC curve was defined as the cut off value for optimal sensitivity and specificity. The areas under the ROC were compared using the method described by Hanley and McNeil.10 The agreements between the reference method for regurgitation volume (RV3D) and both RVPISA and RVVCA were evaluated with Bland–Altman analysis.11 Observer variability in VCA3D measurements was determined in 40 randomly selected patients and calculated as the intraclass correlation coefficient. For intraobserver variability measurements were performed twice by a single observer (≥1 week interval), whereas for interobserver variability measurements were repeated by a second blinded observer. To assess re-test reliability of VCA3D measurements, 40 patients were chosen in whom TEE had been performed twice. The same was done in 20 patients for the quantification of LV volumes by 3D-TEE. Results Characteristics of the study population Twenty-one patients with inadequate images quality were excluded from the study. In the remaining 500 patients MR severity was graded semiquantitatively using the integrative approach recommended by the guidelines.1 The clinical characteristics of the patients are summarized in Table 1. In the FMR group 115 patients (44%) suffered from ischaemic cardiomyopathy with a previous myocardial infarction (MI) and 144 patients (56%) had dilated cardiomyopathy. Table 1 Clinical data FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) Values are mean ± SD or n (%). Afib, atrial fibrillation; AR, aortic regurgitation; AS, aortic stenosis; CAD, coronary artery disease; DMR, degenerative mitral regurgitation; FMR, functional mitral regurgitation. Table 1 Clinical data FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) Values are mean ± SD or n (%). Afib, atrial fibrillation; AR, aortic regurgitation; AS, aortic stenosis; CAD, coronary artery disease; DMR, degenerative mitral regurgitation; FMR, functional mitral regurgitation. In the DMR group the aetiology of MR was as following: leaflet prolapse n = 55 (23%), flail leaflet n = 65 (27%), leaflet cleft n = 4 (1.7%), thickening of leaflets and sclerosis of mitral annulus n = 85 (35%), rheumatic MV disease n = 14 (5.8%), endocarditis n = 12 (5%), and hypertrophic obstructive cardiomyopathy n = 6 (2.5%). In the overall patient population 17 cases of MR with mixed aetiology were identified, which were allocated to the DMR group: Two patients with papillary muscle rupture after MI, seven patients with reduced EF <45% had a dominant leaflet pathology (flail n = 4, prolapse n = 2), two patients with rheumatic mitral stenosis had reduced EF, five patients with severe sclerosis had hypertensive and one patient with cleft had ischaemic heart disease. In the overall study population, multiple jets where identified in the 3D colour Doppler dataset in 31% of FMR and 26% of DMR patients. Echocardiographic parameters The echocardiographic measurements are shown in Table 2. As expected, patients in the FMR group had reduced EF and increased LV volumes. In regard to the parameters for quantification of MR degree, EROAPISA was lower in FMR groups with severe MR when compared to patients in the DMR group, whereas VCA3D values were almost similar in both groups. The difference between VCA3D and EROAPISA calculated for the total study population correlated with VCA3D shape index (r = 0.38, P < 0.001) and LV end-diastolic volume (r = 0.22, P < 0.001). Irrespective of MR degree, VCA3D was significantly larger than EROAPISA in both FMR groups (P < 0.001). The distribution of EROAPISA in FMR patients with VCA3D ≥0.4 cm2 were as following: EROAPISA <0.2 cm2 in 2%, 0.2–0.29 cm2 in 34%, 0.3–0.39 cm2 in 36% and ≥0.4 cm2 in 28% of cases. On the contrary, in 46 patients with an EROAPISA ≥0.2 cm2 the VCA3D values were below 0.4 cm2. An EROAPISA cut-off value of ≥0.2 cm2 for prediction of VCA3D ≥0.4 cm2 resulted in a sensitivity of 98% and a specificity of 43%, whereas a value of ≥0.25 cm2 for EROAPISA equalizes sensitivity and specificity to 82% (AUC under ROC curve 0.93, P < 0.001, 95% CI 0.895 to 0.957). Table 2 Echocardiographic data FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 Values are mean ± SD; * P < 0.05 vs. FMR, ° P < 0.05 vs. moderate MR. EF, ejection fraction; EROAPISA, effective regurgitation orifice area according to PISA method; FMR, functional mitral regurgitation; LAVi, left atrial volume index; LVVDi/LVVSi, left ventricular end-diastolic/end-systolic volume; MR, mitral regurgitation; RR, blood pressure; RV3D, regurgitation volume using 3D volumes; RVPISA, regurgitation volume according to EROAPISA; RVVCA, regurgitation volume according to VCA3D; SV3D, stroke volume; VC, vena contracta width; VCA3D, vena contracta area by 3D colour Doppler. Table 2 Echocardiographic data FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 Values are mean ± SD; * P < 0.05 vs. FMR, ° P < 0.05 vs. moderate MR. EF, ejection fraction; EROAPISA, effective regurgitation orifice area according to PISA method; FMR, functional mitral regurgitation; LAVi, left atrial volume index; LVVDi/LVVSi, left ventricular end-diastolic/end-systolic volume; MR, mitral regurgitation; RR, blood pressure; RV3D, regurgitation volume using 3D volumes; RVPISA, regurgitation volume according to EROAPISA; RVVCA, regurgitation volume according to VCA3D; SV3D, stroke volume; VC, vena contracta width; VCA3D, vena contracta area by 3D colour Doppler. In the DMR group EROAPISA values were lower than VCA3D only for moderate MR (0.25 ± 0.09 vs. 0.28 ± 0.08, P < 0.001), whereas with severe DMR EROAPISA yielded higher values compared to VCA (0.69 ± 0.31 vs. 0.62 ± 0.20, P < 0.001). The percentage of patients with DMR caused by sclerosis of leaflets and annulus was higher in the moderate compared to the severe DMR subgroup (62% in the moderate and 18% in the severe DMR subgroup) with a more oval shaped VCA compared to patients with flail or prolapse of leaflets (VCA3D shape index 3.1 ± 1.5 vs. 2.40 ± 1.3, P = 0.003). Figure 2 displays the relation between MR classification according to EROAPISA and VCA3D based MR grading. Overall, 16% of the patients were misclassified when EROAPISA alone was used for MR grading. Figure 2 View largeDownload slide Bar graph showing the relation between mitral regurgitation (MR) classification according to effective regurgitation orifice area by PISA method (EROAPISA) and vena contracta area (VCA3D) based severity grading. Red bars represent percentage of patients in whom MR severity was under- or overestimated by EROAPISA compared to VCA3D. Figure 2 View largeDownload slide Bar graph showing the relation between mitral regurgitation (MR) classification according to effective regurgitation orifice area by PISA method (EROAPISA) and vena contracta area (VCA3D) based severity grading. Red bars represent percentage of patients in whom MR severity was under- or overestimated by EROAPISA compared to VCA3D. ROC curves for prediction of severe MR were drawn for VCA3D and EROAPISA. In the overall patient population and in the FMR group VCA3D yielded higher areas under the ROC curve (AUC) when compared to EROAPISA (overall patient population AUC for VCA3D 0.98 vs. 0.90 for EROAPISA, P < 0.001; FMR group AUC for VCA3D 0.97 vs. 0.92 for EROAPISA, P = 0.002) (Figure 3). As shown in Figure 4, in patients with Afib VCA3D had a lower but statistical not significant area under the ROC curve compared to patients with SR (difference between areas 0.025, P = 0.1). The calculated sensitivity and specificity of both parameters for prediction of severe MR are given in Table 3. Table 3 Receiver operating characteristic curves for prediction of severe MR Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% DMR, functional MR; EROAPISA, effective regurgitant orifice area according to PISA method; FMR, functional MR; MR, mitral regurgitation; VCA3D, vena contracta area by 3D colour Doppler. Table 3 Receiver operating characteristic curves for prediction of severe MR Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% DMR, functional MR; EROAPISA, effective regurgitant orifice area according to PISA method; FMR, functional MR; MR, mitral regurgitation; VCA3D, vena contracta area by 3D colour Doppler. Figure 3 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area by PISA method (EROAPISA) in the overall patient population (left diagram), in the subgroup with degenerative MR (DMR, middle diagram) and functional MR (FMR, right diagram). Figure 3 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area by PISA method (EROAPISA) in the overall patient population (left diagram), in the subgroup with degenerative MR (DMR, middle diagram) and functional MR (FMR, right diagram). Figure 4 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area according to PISA method (EROAPISA) in patients with sinus rhythm (left) and in the subgroup with atrial fibrillation (right). AUC, area under the ROC curve; CI, confidence interval. Figure 4 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area according to PISA method (EROAPISA) in patients with sinus rhythm (left) and in the subgroup with atrial fibrillation (right). AUC, area under the ROC curve; CI, confidence interval. Bland Altman plots were drawn comparing the reference method for calculation of regurgitation volume with RVVCA and RVPISA, respectively (Figure 5). In the overall group RVVCA showed a closer correlation to RV3D than RVPISA (for RVVCAr = 0.96, P < 0.001; for RVPISAr = 0.79, P < 0.001). The results of inter- and intraobserver variability and re-test reliability of VCA3D measurements are displayed in Table 4. Table 4 Analyse of observer variability for VCA3D and 3D LV volumes Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL LV, left ventricle; LVVD3D/LVVS3D, left ventricular end-diastolic/end-systolic volume by 3D TEE; ICC, intraclass correlation coefficient; SD, standard deviation; VCA3D, vena contracta area by 3D colour Doppler. Table 4 Analyse of observer variability for VCA3D and 3D LV volumes Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL LV, left ventricle; LVVD3D/LVVS3D, left ventricular end-diastolic/end-systolic volume by 3D TEE; ICC, intraclass correlation coefficient; SD, standard deviation; VCA3D, vena contracta area by 3D colour Doppler. Figure 5 View largeDownload slide Bland Altman plots comparing regurgitation volume (RV) derived by vena contracta area (RVVCA, black circles) and by PISA method (RVPISA, grey squares) with RV calculated by reference method (RV3D) in patients with functional (FMR group, plot displayed left) and degenerative mitral regurgitation (DMR group, plot displayed right). SD, standard deviation. Figure 5 View largeDownload slide Bland Altman plots comparing regurgitation volume (RV) derived by vena contracta area (RVVCA, black circles) and by PISA method (RVPISA, grey squares) with RV calculated by reference method (RV3D) in patients with functional (FMR group, plot displayed left) and degenerative mitral regurgitation (DMR group, plot displayed right). SD, standard deviation. Discussion Several echocardiographic studies have already described measurement of VCA using3D colour Doppler echocardiography. The large number of patients included in this study allows for the first time to assess the value of VCA quantification in regard to MR aetiology. The major findings in this study are as following: VCA3D is superior to EROAPISA alone for determination of severity grade especially in patients with functional MR. Overall, VCA3D showed a satisfying correlation to the reference method, whereas EROAPISA underestimates RV in FMR patients and overestimates RV in patients with severe DMR. According to intra- and interobserver variability, VCA3D is a robust and reliable parameter for quantification of MR In clinical practice, echocardiography is the standard tool for assessing mechanism and severity of MR. Acknowledging that all conventional echocardiographic parameters for assessing MR severity have known technical limitations, the guidelines recommend a multiparametric approach.1 Although the integrative approach has been shown to predict outcomes in patients with MR, unfortunately the intraobserver variability for these parameters is relatively high.12,13 Quantification of VCA by 3D colour Doppler is a promising technique for a more accurate grading of MR severity, but it has not yet gained wide clinical use.5,6 The only other study comparing VCA3D with the 2D echocardiographic integrative approach proposed a cut-off value of 0.41 cm2 in a mixed patient population with different types of MR.7 For the first time, this study shows that the optimal cut-off value slightly differs according to the main aetiology of MR being higher in the DMR group. In both patient groups VCA3D distinguished between moderate and severe MR with higher sensitivity and specificity than EROAPISA alone. Compared to degenerative MR, quantization of functional MR is even more challenging because of a frequent low-flow state pushing the limits of quantitative techniques and the oval shaped regurgitation orifice.3 Both, the ESC and the current AHA/ACC guidelines propose a lower cut-off value of ≥0.2 cm2 for EROAPISA in patients with secondary MR to define severe regurgitation.14,15 The rationale for this recommendation is based on the results of outcome studies in FMR patients, showing an adverse prognosis when EROA is higher than 0.2 cm2.16 This decision had been criticized especially because multiple trials have demonstrated that surgical intervention in FMR does not improve the 5-year survival rate.17 This lower cut-off value for FMR applied in our study acknowledges whether intentionally or not the systematic underestimation of true regurgitation orifice in a crescent shaped convergence zone. Our study does not deliver patients outcome data yet. Regarding the technical shortcoming of EROAPISA, it was found that in 98% of patients in the FMR group with an EROAPISA ≥0.2 cm2 had a corresponding VCA value of ≥0.4 cm2. However, this comes at the cost of a relatively low specificity for prediction of severe FMR by EROAPISA alone. In this study, a closer correlation was found between VCA3D and the reference method than compared to EROAPISA. The superiority of VCA over EROAPISA in the FMR group is mainly due to the oval shaped cross-sectional area of the vena contracta.3 Calculating the EROA using the hemispheric model for the PISA method in a four chamber view clearly underestimates the vena contracta area in FMR. Quantification of EROA based on a hemielliptic model might compensate for potential asymmetry of non-circular regurgitant orifices, but it requires two planes when using 2D colour Doppler.18 In the group with moderate DMR regurgitation volume derived by PISA method again was significantly lower compared to RVVCA partial due to a high proportion of patients with oval shaped regurgitation orifice. On the contrary, RVPISA values exceeded significantly both RV3D and RVVCA in the group with severe DMR. Pathoanatomical conditions again are an explanation for this finding. The large, 2D colour Doppler convergence zone seen in DMR due to a flail leaflet is wedge-shaped and not completely hemispheric resulting in an overestimation of regurgitation volume by PISA method. To overcome this known limitation an angle correction factor has been proposed in this situation.19 The successful implementation of VCA3D quantification by 3D colour Doppler in clinical routine depends on the feasibility and reliability of the method. Therefore, this study investigated intra- and interobserver variability of VCA3D measurements in a larger number of patients, showing in accordance to previous studies good results for both.7,8,20 In addition, for the first time re-test reliability was tested in patients, who underwent TEE examination twice, mainly before and during mitral valve repair. Especially, functional mitral regurgitation varies dynamically in accordance with changes in afterload and fluid status, negatively effecting re-test reliability of any echocardiographic parameter for severity grading.21,22 Limitations This study neither includes a test population to validate the threshold values of VCA3D for MR severity grading nor a reference method to verify the accuracy VCA3D measurements. The quantification of VCA3D based on 3D colour Doppler has several technically shortcomings. The limited spatial resolution of 3D colour Doppler can be a problem when quantifying small regurgitant orifice areas, but may not be as important in moderate to severe MR. To increase temporal resolution, stitched datasets were acquired in this study, predisposing to artefacts, especially in patients with Afib. The regurgitation jet changes dynamically during systole. Hence choice of the systolic frame affects VCA measurement. Even using multiplanar reconstruction it can be challenging to define the cross-sectional plane for planimetry, especially in DMR with very eccentric jets. Although acquiring a 3D colour Doppler loop with a reasonable quality using TEE is less time-consuming than the 2D integrative approach, the post-processing still requires a significant amount of time. Conclusion This study delivers cut-off values for VCA3D in patients with different types of mitral regurgitation. By eliminating geometric and flow assumptions, the 3D VCA method is reliable in clinical routine and improves accuracy of MR grading compared with conventional 2D parameters. Given the potential strengths of 3D colour Doppler echocardiography, prospective studies are needed to explore the prognostic value of VCA3D in MR patients. Conflict of interest: Björn Goebel, Ali Hamadanchi, and Tudor C. Poerner have received fees for scientific presentations from TomTec-Imaging Systems Unterschleissheim, Germany. All other authors have no conflicts of interests to declare. References 1 Lancellotti P , Tribouilloy C , Hagendorff A , Popescu BA , Edvardsen T , Pierard LA et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 611 – 44 . Google Scholar CrossRef Search ADS PubMed 2 Yoganathan AP , Cape EG , Sung HW , Williams FP , Jimoh A. Review of hydrodynamic principles for the cardiologist: applications to the study of blood flow and jets by imaging techniques . J Am Coll Cardiol 1988 ; 12 : 1344 – 53 . Google Scholar CrossRef Search ADS PubMed 3 Kahlert P , Plicht B , Schenk IM , Janosi RA , Erbel R , Buck T. Direct assessment of size and shape of noncircular vena contracta area in functional versus organic mitral regurgitation using real-time three-dimensional echocardiography . J Am Soc Echocardiogr 2008 ; 2 : 912 – 21 . Google Scholar CrossRef Search ADS 4 Khanna D , Vengala S , Miller AP , Nanda NC , Lloyd SG , Ahmed S et al. Quantification of mitral regurgitation by live three-dimensional transthoracic echocardiographic measurements of vena contracta area . Echocardiography 2004 ; 21 : 737 – 43 . Google Scholar CrossRef Search ADS PubMed 5 Little SH , Pirat B , Kumar R , Igo SR , McCulloch M , Hartley CJ et al. Three-dimensional color Doppler echocardiography for direct measurement of vena contracta area in mitral regurgitation . JACC Cardiovasc Imaging 2008 ; 1 : 695 – 704 . Google Scholar CrossRef Search ADS PubMed 6 Marsan NA , Westenberg JJ , Ypenburg C , Delgado V , van Bommel RJ , Roes SD et al. Quantification of functional mitral regurgitation by real-time 3D echocardiography: comparison with 3D velocity-encoded cardiac magnetic resonance . JACC Cardiovasc Imaging 2009 ; 2 : 1245 – 52 . Google Scholar CrossRef Search ADS PubMed 7 Zeng X , Levine RA , Hua L , Morris EL , Kang Y , Flaherty M et al. Diagnostic value of vena contracta area in the quantification of mitral regurgitation severity by color Doppler 3D echocardiography . Circ Cardiovasc Imaging 2011 ; 4 : 506 – 13 . Google Scholar CrossRef Search ADS PubMed 8 Lang RM , Badano LP , Mor-Avi V , Afilalo J , Armstrong A , Ernande L et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European association of cardiovascular imaging . Eur Heart J Cardiovasc Imaging 2015 ; 16 : 233 – 70 . Google Scholar CrossRef Search ADS PubMed 9 Thavendiranathan P , Phelan D , Collier P , Thomas JD , Flamm SD , Marwick TH. Quantitative assessment of mitral regurgitation: how best to do it . JACC Cardiovasc Imaging 2012 ; 5 : 1161 – 75 . Google Scholar CrossRef Search ADS PubMed 10 Hanley JA , McNeil BJ. The meaning and use of the area under a Receiver Operating Characteristic (ROC) curve . Radiology 1982 ; 143 : 29 – 36 . Google Scholar CrossRef Search ADS PubMed 11 Bland JM , Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement . Lancet 1986 ; 1 : 307 – 10 . Google Scholar CrossRef Search ADS PubMed 12 Enriquez-Sarano M , Avierinos JF , Messika-Zeitoun D , Detaint D , Capps M , Nkomo V et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation . N Engl J Med 2005 ; 352 : 875 – 83 . Google Scholar CrossRef Search ADS PubMed 13 Biner S , Rafique A , Rafii F , Tolstrup K , Noorani O , Shiota T et al. Reproducibility of proximal isovelocity surface area, vena contracta, and regurgitant jet area for assessment of mitral regurgitation severity . J Am Coll Cardiol Imaging 2010 ; 3 : 235 – 43 . Google Scholar CrossRef Search ADS 14 Vahanian A , Alfieri O , Andreotti F , Antunes MJ , Barón-Esquivias G , Baumgartner H et al. Guidelines on the management of valvular heart disease (version 2012) . Eur Heart J 2012 ; 33 : 2451 – 96 . Google Scholar CrossRef Search ADS PubMed 15 Nishimura RA , Otto CM , Bonow RO , Carabello BA , Erwin JP III , Guyton RA et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC Guidelines for the Management of Patients With Valvular Heart Disease; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . J Am Coll Cardiol 2014 ; 63 : e57 – 185 . Google Scholar CrossRef Search ADS PubMed 16 Grigioni F , Enriquez-Sarano M , Zehr KJ , Bailey KR , Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment . Circulation 2001 ; 103 : 1759 – 64 . Google Scholar CrossRef Search ADS PubMed 17 Beigel R , Siegel RJ. Should the guidelines for the assessment of the severity of functional mitral regurgitation be redefined? J Am Coll Cardiol Imaging 2014 ; 7 : 313 – 4 . Google Scholar CrossRef Search ADS 18 Yosefy C , Levine RA , Solis J , Vaturi M , Handschumacher MD , Hung J. Proximal flow convergence region as assessed by real-time 3-dimensional echocardiography: challenging the hemispheric assumption . J Am Soc Echocardiogr 2007 ; 20 : 389 – 96 . Google Scholar CrossRef Search ADS PubMed 19 Pu M , Vandervoort PM , Greenberg NL , Powell KA , Griffin BP , Thomas JD. Impact of wall constraint on velocity distribution in proximal flow convergence zone. Implications for color Doppler quantification of mitral regurgitation . J Am Coll Cardiol 1996 ; 27 : 706 – 13 . Google Scholar CrossRef Search ADS PubMed 20 Hyodo E , Iwata S , Tugcu A , Arai K , Shimada K , Muro T et al. Direct measurement of multiple vena contracta areas for assessing the severity of mitral regurgitation using realtime 3D TEE . JACC Cardiovasc Imaging 2012 ; 5 : 669 – 76 . Google Scholar CrossRef Search ADS PubMed 21 Grewal KS , Malkowski MJ , Piracha AR , Astbury JC , Kramer CM , Dianzumba S et al. Effect of general anesthesia on the severity of mitral regurgitation by transesophageal echocardiography . Am J Cardiol 2000 ; 85 : 199 – 203 . Google Scholar CrossRef Search ADS PubMed 22 Kizilbash AM , Willett DL , Brickner E , Heinle SK , Grayburn PA. Effects of afterload reduction on vena contracta width in mitral regurgitation . J Am Coll Cardiol 1998 ; 32 : 427 – 31 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Vena contracta area for severity grading in functional and degenerative mitral regurgitation: a transoesophageal 3D colour Doppler analysis in 500 patients

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Aims Vena contracta area (VCA3D), derived by 3D colour Doppler echocardiography, has already been validated against cardiac magnetic resonance imaging, but the number of clinical studies to define cut-off values for grading of mitral regurgitation (MR) is limited. Aim of the study was to assess VCA3D in a large population of patients with functional (FMR) and degenerative MR (DMR). Methods and results Transoesophageal echocardiography was performed in 500 patients with MR. The following 2D parameters were assessed for grading of MR: vena contracta width, effective regurgitant orifice area (EROAPISA), and regurgitation volume (RVPISA). VCA3D and the corresponding regurgitation volume (RVVCA) were quantified using 3D colour Doppler loop and CW Doppler tracing of the regurgitant jet. In 104 patients a 3D dataset of the left ventricle (LV) and the left ventricular outflow tract (LVOT) was acquired. As a reference method, regurgitation volume (RV3D) was calculated as difference between LV overall and LVOT stroke volumes. For prediction of severe MR, VCA3D yielded higher values of area under the ROC curve compared to EROAPISA (overall patient group 0.98 for VCA3D vs. 0.90 for EROAPISA, P < 0.001; FMR group 0.97 for VCA3D vs. 0.92 for EROAPISA, P = 0.002). RVVCA correlated closer with RV3D compared to RVPISA (r = 0.96 for RVPISA, r = 0.79 for RVPISA). Conclusion This study delivers cut-off values for VCA3D in patients with different types of MR. VCA3D is a robust parameter for quantification of MR, showing a good correlation with the reference method using 3D datasets of LV. mitral regurgitation, vena contracta area, 3D colour Doppler echocardiography Introduction In clinical practice, echocardiography is the standard tool for assessing mechanism and severity of mitral regurgitation (MR). According to the guidelines several parameters, including vena contracta width (VC) and effective regurgitation orifice area by proximal isovelocity surface area method (EROAPISA) have to be taken into account for judging MR severity.1 EROA hydrodynamically corresponds to the cross-sectional area of the vena contracta (VCA), which is located at the smallest region between the proximal laminar flow acceleration zone and the distal downstream of the jet into the left atrium.2 As three-dimensional (3D) colour Doppler studies already revealed, in most cases EROA especially in functional MR is non-circular, limiting the ability of two-dimensional (2D) based echocardiographic parameters3 to quantify MR. Khanna et al.4 firstly described direct planimetry of vena contracta area (VCA3D) in a real-time 3D colour Doppler dataset. The concept of 3D echocardiographic derived VCA has already been validated in an in vitro model of MR and against velocity-encoded cardiac magnetic resonance imaging (cMRI),5,6 but the number of clinical studies to define cut-off values for VCA is limited.7 Aim of the study was to assess VCA3D by transoesophageal 3D colour Doppler echocardiography (3D-TEE) in a large population of patients with functional (FMR) and degenerative MR (DMR) and to define cut-off values for quantification of MR severity. Methods Study population Patients with at least moderate MR who underwent 3D-TEE in our department between May 2009 and February 2015 for clinical indications were consecutively considered eligible for this study. The patient population was divided according to the main pathology underlying MR into a group with FMR and a group with DMR. The aetiology of MR was defined as functional if resulting from either a regional myocardial dysfunction or global left ventricular remodelling in the presence of an anatomically normal valve apparatus. DMR comprised the following structural defects of the mitral valve (MV): valve prolapse, flail, and degenerative alterations including valve thickening, immobility, or annular calcification. Echocardiographic measurements Echocardiographic images were acquired using an iE33 ultrasound system (Philips Medical Systems, Andover, Massachusetts) equipped with a matrix-array transducer for transthoracic (X5-1) and transoesophageal echocardiography (X7-2 t). Heart rate (HR) and blood pressure (RR) were monitored during echocardiographic examination. Left atrial (LA), end-diastolic, and end-systolic left ventricular (LV) volume were quantified by transthoracic echocardiography and indexed to body surface area. LV ejection fraction (EF) was calculated using the modified biplane Simpson method from a four and two-chamber view.8 For quantification of VC by TEE multiple views from 0° to 180° including four chamber, intercommissural, and long-axis view were obtained using 2D colour Doppler mode. Nyquist limits were set between 50 and 70 cm/s, with the gain set just below the threshold for noise. In patients with DMR VC was measured in the view with the largest convergence zone, whereas in FMR VC was calculated as mean between four chamber and intercommissural views. EROAPISA and regurgitation volume (RVPISA) were quantified according to proximal isovelocity surface area (PISA) method.1 A continuous wave (CW) Doppler cursor was aligned parallel to MR flow to obtain the peak velocity of the MR jet and the velocity time integral (Figure 1E). In patients with FMR EROAPISA was derived from a colour Doppler recorded in a four chamber view (Figure 1A). In patients with DMR the view with the largest convergence zone was chosen to quantify the radius of PISA. Special care was taken, that PISA radius and flow velocity measurements for calculation of EROAPISA were obtained at similar timepoints throughout systole. Figure 1 View largeDownload slide Example of a 57-year-old, male patient suffering from a functional mitral regurgitation after posterior myocardial infarction. Vena contracta area (VCA3D) derived by multiplanar reconstruction in a 3D colour Doppler data set (A) was 0.28 cm2. Using the velocity time integral (VTIMR) of the regurgitation jet derived by CW Doppler (B) the calculated MR volume (RVVCA) was: 0.28 cm2 × 210 cm = 59 mL. Effective regurgitation orifice area (ERO) quantified in a four-chamber view (B) by PISA method was 0.16 cm2 resulting in a regurgitation volume (MR Volume) of 34 ml. For comparison overall stroke volume (SV) was measured in a 3D dataset of the left ventricle (D), whereas stroke volume over the aortic valve was derived using left ventricular outflow tract area (AreaLVOT 3D, E) and velocity time integral by pulsed wave Doppler (VTILVOT) positioned in the LVOT (F). Using this combined approach MR volume (RV3D) was 52 mL [SV – (AreaLVOT 3D × VTILVOT) = 86.2 mL – (3.76 cm2 × 9.19 cm)] and EROA3D 0.25 cm2 [RV3D/VTIMR = 52 mL/210 cm]. Figure 1 View largeDownload slide Example of a 57-year-old, male patient suffering from a functional mitral regurgitation after posterior myocardial infarction. Vena contracta area (VCA3D) derived by multiplanar reconstruction in a 3D colour Doppler data set (A) was 0.28 cm2. Using the velocity time integral (VTIMR) of the regurgitation jet derived by CW Doppler (B) the calculated MR volume (RVVCA) was: 0.28 cm2 × 210 cm = 59 mL. Effective regurgitation orifice area (ERO) quantified in a four-chamber view (B) by PISA method was 0.16 cm2 resulting in a regurgitation volume (MR Volume) of 34 ml. For comparison overall stroke volume (SV) was measured in a 3D dataset of the left ventricle (D), whereas stroke volume over the aortic valve was derived using left ventricular outflow tract area (AreaLVOT 3D, E) and velocity time integral by pulsed wave Doppler (VTILVOT) positioned in the LVOT (F). Using this combined approach MR volume (RV3D) was 52 mL [SV – (AreaLVOT 3D × VTILVOT) = 86.2 mL – (3.76 cm2 × 9.19 cm)] and EROA3D 0.25 cm2 [RV3D/VTIMR = 52 mL/210 cm]. In each patient 3D colour Doppler datasets were acquired from an intercommissural view using full volume applying the following settings: colour Doppler gain = 50%, smoothing = 2, colour map = 4, flow optimization = medium, line density = medium, and filter = medium. In patients with sinus rhythm (SR) an acquisition with six subvolumes was attempted (mean frame rate 18 ± 3 Hz, range 11–26 Hz). To avoid stitching artefacts in patients with atrial fibrillation (Afib) a lower number of subvolumes was used or a 3D colour Doppler loop with high volume rate was acquired (mean frame rate 15 ± 2 Hz). Quantification of VCA3D was performed by multiplanar reconstruction (Figure 1B) using a dedicated software (Philips QLAB Versions 9.0) as described before.9 With regard to the timing of VCA3D measurements again the occurrence of peak velocity in the corresponding CW-Doppler signal was used as orientation. In FMR patients a mid-systolic frame was chosen whereas in DMR patients especially with leaflet prolapse a more mid- to late-systolic frame was selected. If more than one jet occurred in the frame chosen for analyse, each jet was cropped individually and the VCA was derived as the sum of all cross-sectional areas. VCA3D derived regurgitation volume (RVVCA) was calculated by multiplying VCA3D with the MR velocity time integral of the CW-Doppler signal. VCA3D shape index was calculated as ratio between intercommissural and long axis diameter of VCA3D. In patients with Afib the parameters were calculated as mean of 3–5 measurements. In 104 patients (60 with FMR and 44 with DMR) with SR and without aortic regurgitation a 3D full volume data set of the LV and of the mitral valve including the left ventricular outflow tract (LVOT) were acquired by TEE (median frame rate 28 Hz, range 26–32 Hz). Using dedicated software tools (4D LV-Analysis© and 4D Cardio-View™, TomTec - Imaging Systems, Unterschleissheim, Germany). LV overall stroke volume (SVLV 3D) was derived by subtracting end-systolic (LVVs3D) from end-diastolic (LVVd3D) LV volume (Figure 1D). LVOT area was traced in a 3D dataset as shown in Figure 1C. In a transgastric view the sample volume of a pulsed-wave Doppler was placed into the LVOT (Figure 1F) to measure VTI of outflow velocities (VTILVOT). Using this combined approach MR volume (RV3D) was calculated as following: RV3D = SVLV 3D − (VTILVOT × LVOT area). Statistical analyses The data analysis was performed with the Statistical Package for Social Science software (SPSS for Windows 22.0, Chicago, Il, USA). All values were presented as mean ± standard deviation for continuous variables. Comparison between groups was done by Student’s t-test or one-way ANOVA analysis of variance with Bonferroni and Tamhane post-hoc tests. P < 0.05 was considered significant. Correlations between different parameters were examined using Pearson's test or linear regression analyses. Receiver operating characteristics (ROC) analyses were performed to assess the ability of the parameters to identify patients with severe MR. The value closest to the upper left corner of the ROC curve was defined as the cut off value for optimal sensitivity and specificity. The areas under the ROC were compared using the method described by Hanley and McNeil.10 The agreements between the reference method for regurgitation volume (RV3D) and both RVPISA and RVVCA were evaluated with Bland–Altman analysis.11 Observer variability in VCA3D measurements was determined in 40 randomly selected patients and calculated as the intraclass correlation coefficient. For intraobserver variability measurements were performed twice by a single observer (≥1 week interval), whereas for interobserver variability measurements were repeated by a second blinded observer. To assess re-test reliability of VCA3D measurements, 40 patients were chosen in whom TEE had been performed twice. The same was done in 20 patients for the quantification of LV volumes by 3D-TEE. Results Characteristics of the study population Twenty-one patients with inadequate images quality were excluded from the study. In the remaining 500 patients MR severity was graded semiquantitatively using the integrative approach recommended by the guidelines.1 The clinical characteristics of the patients are summarized in Table 1. In the FMR group 115 patients (44%) suffered from ischaemic cardiomyopathy with a previous myocardial infarction (MI) and 144 patients (56%) had dilated cardiomyopathy. Table 1 Clinical data FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) Values are mean ± SD or n (%). Afib, atrial fibrillation; AR, aortic regurgitation; AS, aortic stenosis; CAD, coronary artery disease; DMR, degenerative mitral regurgitation; FMR, functional mitral regurgitation. Table 1 Clinical data FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) FMR group DMR group (n = 259) (n = 241) Age (years) 72 ± 11 75 ± 14 Gender (male/female) 185 (71%)/74 (29%) 120 (50%)/121 (50%) Afib (n) 86 (33%) 76 (32%) CAD (1-,2-,3-vessel) 30 (12%)/18 (7%)/68 (26%) 20 (8%)/10 (4%)/24 (10%) myocardial infarction (anterior/inferoposterior/both) 59 (23%)/53 (21%)/3 (1%) 4 (2%)/6 (3%) Dilated cardiomyopathy 144 (56%) Valvular disease (AS/AR) 13 (5%)/6 (2%) 38 (16%)/8 (3%) Values are mean ± SD or n (%). Afib, atrial fibrillation; AR, aortic regurgitation; AS, aortic stenosis; CAD, coronary artery disease; DMR, degenerative mitral regurgitation; FMR, functional mitral regurgitation. In the DMR group the aetiology of MR was as following: leaflet prolapse n = 55 (23%), flail leaflet n = 65 (27%), leaflet cleft n = 4 (1.7%), thickening of leaflets and sclerosis of mitral annulus n = 85 (35%), rheumatic MV disease n = 14 (5.8%), endocarditis n = 12 (5%), and hypertrophic obstructive cardiomyopathy n = 6 (2.5%). In the overall patient population 17 cases of MR with mixed aetiology were identified, which were allocated to the DMR group: Two patients with papillary muscle rupture after MI, seven patients with reduced EF <45% had a dominant leaflet pathology (flail n = 4, prolapse n = 2), two patients with rheumatic mitral stenosis had reduced EF, five patients with severe sclerosis had hypertensive and one patient with cleft had ischaemic heart disease. In the overall study population, multiple jets where identified in the 3D colour Doppler dataset in 31% of FMR and 26% of DMR patients. Echocardiographic parameters The echocardiographic measurements are shown in Table 2. As expected, patients in the FMR group had reduced EF and increased LV volumes. In regard to the parameters for quantification of MR degree, EROAPISA was lower in FMR groups with severe MR when compared to patients in the DMR group, whereas VCA3D values were almost similar in both groups. The difference between VCA3D and EROAPISA calculated for the total study population correlated with VCA3D shape index (r = 0.38, P < 0.001) and LV end-diastolic volume (r = 0.22, P < 0.001). Irrespective of MR degree, VCA3D was significantly larger than EROAPISA in both FMR groups (P < 0.001). The distribution of EROAPISA in FMR patients with VCA3D ≥0.4 cm2 were as following: EROAPISA <0.2 cm2 in 2%, 0.2–0.29 cm2 in 34%, 0.3–0.39 cm2 in 36% and ≥0.4 cm2 in 28% of cases. On the contrary, in 46 patients with an EROAPISA ≥0.2 cm2 the VCA3D values were below 0.4 cm2. An EROAPISA cut-off value of ≥0.2 cm2 for prediction of VCA3D ≥0.4 cm2 resulted in a sensitivity of 98% and a specificity of 43%, whereas a value of ≥0.25 cm2 for EROAPISA equalizes sensitivity and specificity to 82% (AUC under ROC curve 0.93, P < 0.001, 95% CI 0.895 to 0.957). Table 2 Echocardiographic data FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 Values are mean ± SD; * P < 0.05 vs. FMR, ° P < 0.05 vs. moderate MR. EF, ejection fraction; EROAPISA, effective regurgitation orifice area according to PISA method; FMR, functional mitral regurgitation; LAVi, left atrial volume index; LVVDi/LVVSi, left ventricular end-diastolic/end-systolic volume; MR, mitral regurgitation; RR, blood pressure; RV3D, regurgitation volume using 3D volumes; RVPISA, regurgitation volume according to EROAPISA; RVVCA, regurgitation volume according to VCA3D; SV3D, stroke volume; VC, vena contracta width; VCA3D, vena contracta area by 3D colour Doppler. Table 2 Echocardiographic data FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 FMR group DMR group P-value (ANOVA) Moderate MR Severe MR Moderate MR Severe MR (n = 113) (n = 146) (n = 125) (n = 116) Heart rate (1/min) 71 ± 10 73 ± 15 79 ± 19 77 ± 14 0.456 RR systolic (mmHg) 127 ± 23 119 ± 23 136 ± 29 132 ± 25* <0.001 RR diastolic (mmHg) 69 ± 13 66 ± 15 66 ± 16 70 ± 15 0.170 EF (%) 35 ± 10 31 ± 8 60 ± 10* 62 ± 11* <0.001 LVVDi (mL/m2) 90 ± 33 110 ± 39° 62 ± 18* 75 ± 23*° <0.001 LVVSi (mL/m2) 60 ± 27 78 ± 33° 26 ± 12* 31 ± 14* <0.001 LAVi (mL/m2) 56 ± 17 65 ± 26° 58 ± 26 61 ± 31 0.015 VC (mm) 6.0 ± 1.5 8.0 ± 1.8° 5.4 ± 1.6 7.4 ± 2.2° <0.001 EROAPISA (cm2) 0.19 ± 0.05 0.34 ± 0.11° 0.25 ± 0.09 0.69 ± 0.32*° <0.001 RVPISA (mL) 27 ± 8 46 ± 18° 40 ± 15* 92 ± 40*° <0.001 VCA3D (cm2) 0.30 ± 0.07 0.52 ± 0.11° 0.29 ± 0.08 0.62 ± 0.21*° <0.001 RVVCA (mL) 46 ± 13 74 ± 23° 50 ± 18 88 ± 26*° <0.001 VCA shape index 3.4 ± 1.6 3.5 ± 1.2 2.9 ± 1.6 2.4 ± 1.2* <0.001 Reference method for calculation of MR volumes (n = 104) LVVDi3D (mL/m2) 121 ± 36 142 ± 34 77 ± 16* 98 ± 24* <0.001 LVVSi3D (mL/m2) 80 ± 34 99 ± 34 30 ± 12* 34 ± 18* <0.001 EF3D (%) 36 ± 10 33 ± 8 63 ± 9* 67 ± 12* <0.001 Overall SV3D (mL) 80 ± 17 88 ± 13 89 ± 18 124 ± 31* <0.001 RV3D (mL) 36 ± 7 51 ± 8° 34 ± 8* 71 ± 21*° <0.001 Values are mean ± SD; * P < 0.05 vs. FMR, ° P < 0.05 vs. moderate MR. EF, ejection fraction; EROAPISA, effective regurgitation orifice area according to PISA method; FMR, functional mitral regurgitation; LAVi, left atrial volume index; LVVDi/LVVSi, left ventricular end-diastolic/end-systolic volume; MR, mitral regurgitation; RR, blood pressure; RV3D, regurgitation volume using 3D volumes; RVPISA, regurgitation volume according to EROAPISA; RVVCA, regurgitation volume according to VCA3D; SV3D, stroke volume; VC, vena contracta width; VCA3D, vena contracta area by 3D colour Doppler. In the DMR group EROAPISA values were lower than VCA3D only for moderate MR (0.25 ± 0.09 vs. 0.28 ± 0.08, P < 0.001), whereas with severe DMR EROAPISA yielded higher values compared to VCA (0.69 ± 0.31 vs. 0.62 ± 0.20, P < 0.001). The percentage of patients with DMR caused by sclerosis of leaflets and annulus was higher in the moderate compared to the severe DMR subgroup (62% in the moderate and 18% in the severe DMR subgroup) with a more oval shaped VCA compared to patients with flail or prolapse of leaflets (VCA3D shape index 3.1 ± 1.5 vs. 2.40 ± 1.3, P = 0.003). Figure 2 displays the relation between MR classification according to EROAPISA and VCA3D based MR grading. Overall, 16% of the patients were misclassified when EROAPISA alone was used for MR grading. Figure 2 View largeDownload slide Bar graph showing the relation between mitral regurgitation (MR) classification according to effective regurgitation orifice area by PISA method (EROAPISA) and vena contracta area (VCA3D) based severity grading. Red bars represent percentage of patients in whom MR severity was under- or overestimated by EROAPISA compared to VCA3D. Figure 2 View largeDownload slide Bar graph showing the relation between mitral regurgitation (MR) classification according to effective regurgitation orifice area by PISA method (EROAPISA) and vena contracta area (VCA3D) based severity grading. Red bars represent percentage of patients in whom MR severity was under- or overestimated by EROAPISA compared to VCA3D. ROC curves for prediction of severe MR were drawn for VCA3D and EROAPISA. In the overall patient population and in the FMR group VCA3D yielded higher areas under the ROC curve (AUC) when compared to EROAPISA (overall patient population AUC for VCA3D 0.98 vs. 0.90 for EROAPISA, P < 0.001; FMR group AUC for VCA3D 0.97 vs. 0.92 for EROAPISA, P = 0.002) (Figure 3). As shown in Figure 4, in patients with Afib VCA3D had a lower but statistical not significant area under the ROC curve compared to patients with SR (difference between areas 0.025, P = 0.1). The calculated sensitivity and specificity of both parameters for prediction of severe MR are given in Table 3. Table 3 Receiver operating characteristic curves for prediction of severe MR Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% DMR, functional MR; EROAPISA, effective regurgitant orifice area according to PISA method; FMR, functional MR; MR, mitral regurgitation; VCA3D, vena contracta area by 3D colour Doppler. Table 3 Receiver operating characteristic curves for prediction of severe MR Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% Parameter Area under curve 95% confidence interval P Cut-off values Sensitivity Specificity EROAPISA in all patients 0.90 0.87 to 0.92 <0.001 >0.29 cm2 81% 81% EROAPISA in FMR group 0.92 0.88 to 0.95 <0.001 >0.24 cm2 83% 74% EROAPISA in DMR group 0.96 0.93 to 0.98 <0.001 >0.38 cm2 88% 90% VCA3D in all patients 0.98 0.96 to 0.99 <0.001 >0.40 cm2 94% 93% VCA3D in FMR group 0.97 0.95 to 0.99 <0.001 >0.39 cm2 92% 90% VCA3D in DMR group 0.98 0.96 to 1.00 <0.001 >0.41 cm2 95% 97% DMR, functional MR; EROAPISA, effective regurgitant orifice area according to PISA method; FMR, functional MR; MR, mitral regurgitation; VCA3D, vena contracta area by 3D colour Doppler. Figure 3 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area by PISA method (EROAPISA) in the overall patient population (left diagram), in the subgroup with degenerative MR (DMR, middle diagram) and functional MR (FMR, right diagram). Figure 3 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area by PISA method (EROAPISA) in the overall patient population (left diagram), in the subgroup with degenerative MR (DMR, middle diagram) and functional MR (FMR, right diagram). Figure 4 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area according to PISA method (EROAPISA) in patients with sinus rhythm (left) and in the subgroup with atrial fibrillation (right). AUC, area under the ROC curve; CI, confidence interval. Figure 4 View largeDownload slide Receiver-operating characteristic (ROC) curves for the prediction of severe mitral regurgitation (MR) using vena contracta area (VCA3D) or effective regurgitation orifice area according to PISA method (EROAPISA) in patients with sinus rhythm (left) and in the subgroup with atrial fibrillation (right). AUC, area under the ROC curve; CI, confidence interval. Bland Altman plots were drawn comparing the reference method for calculation of regurgitation volume with RVVCA and RVPISA, respectively (Figure 5). In the overall group RVVCA showed a closer correlation to RV3D than RVPISA (for RVVCAr = 0.96, P < 0.001; for RVPISAr = 0.79, P < 0.001). The results of inter- and intraobserver variability and re-test reliability of VCA3D measurements are displayed in Table 4. Table 4 Analyse of observer variability for VCA3D and 3D LV volumes Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL LV, left ventricle; LVVD3D/LVVS3D, left ventricular end-diastolic/end-systolic volume by 3D TEE; ICC, intraclass correlation coefficient; SD, standard deviation; VCA3D, vena contracta area by 3D colour Doppler. Table 4 Analyse of observer variability for VCA3D and 3D LV volumes Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL Parameter Variability ICC 95% confidence interval SD of differences VCA3D Intraobserver 0.971 0.936 to 0.978 0.076 cm2 Interobserver 0.912 0.815 to 0.939 0.083 cm2 Re-test 0.869 0.755 to 0.877 0.101 cm2 LVVD3D Intraobserver 0.997 0.997 to 0.999 9 mL Interobserver 0.990 0.971 to 0.996 16 mL Re-test 0.985 0.962 to 0.994 20 mL LVVS3D Intraobserver 0.993 0.983 to 0.997 14 mL Interobserver 0.986 0.965 to 0.994 20 mL Re-test 0.978 0.944 to 0.991 27 mL LV, left ventricle; LVVD3D/LVVS3D, left ventricular end-diastolic/end-systolic volume by 3D TEE; ICC, intraclass correlation coefficient; SD, standard deviation; VCA3D, vena contracta area by 3D colour Doppler. Figure 5 View largeDownload slide Bland Altman plots comparing regurgitation volume (RV) derived by vena contracta area (RVVCA, black circles) and by PISA method (RVPISA, grey squares) with RV calculated by reference method (RV3D) in patients with functional (FMR group, plot displayed left) and degenerative mitral regurgitation (DMR group, plot displayed right). SD, standard deviation. Figure 5 View largeDownload slide Bland Altman plots comparing regurgitation volume (RV) derived by vena contracta area (RVVCA, black circles) and by PISA method (RVPISA, grey squares) with RV calculated by reference method (RV3D) in patients with functional (FMR group, plot displayed left) and degenerative mitral regurgitation (DMR group, plot displayed right). SD, standard deviation. Discussion Several echocardiographic studies have already described measurement of VCA using3D colour Doppler echocardiography. The large number of patients included in this study allows for the first time to assess the value of VCA quantification in regard to MR aetiology. The major findings in this study are as following: VCA3D is superior to EROAPISA alone for determination of severity grade especially in patients with functional MR. Overall, VCA3D showed a satisfying correlation to the reference method, whereas EROAPISA underestimates RV in FMR patients and overestimates RV in patients with severe DMR. According to intra- and interobserver variability, VCA3D is a robust and reliable parameter for quantification of MR In clinical practice, echocardiography is the standard tool for assessing mechanism and severity of MR. Acknowledging that all conventional echocardiographic parameters for assessing MR severity have known technical limitations, the guidelines recommend a multiparametric approach.1 Although the integrative approach has been shown to predict outcomes in patients with MR, unfortunately the intraobserver variability for these parameters is relatively high.12,13 Quantification of VCA by 3D colour Doppler is a promising technique for a more accurate grading of MR severity, but it has not yet gained wide clinical use.5,6 The only other study comparing VCA3D with the 2D echocardiographic integrative approach proposed a cut-off value of 0.41 cm2 in a mixed patient population with different types of MR.7 For the first time, this study shows that the optimal cut-off value slightly differs according to the main aetiology of MR being higher in the DMR group. In both patient groups VCA3D distinguished between moderate and severe MR with higher sensitivity and specificity than EROAPISA alone. Compared to degenerative MR, quantization of functional MR is even more challenging because of a frequent low-flow state pushing the limits of quantitative techniques and the oval shaped regurgitation orifice.3 Both, the ESC and the current AHA/ACC guidelines propose a lower cut-off value of ≥0.2 cm2 for EROAPISA in patients with secondary MR to define severe regurgitation.14,15 The rationale for this recommendation is based on the results of outcome studies in FMR patients, showing an adverse prognosis when EROA is higher than 0.2 cm2.16 This decision had been criticized especially because multiple trials have demonstrated that surgical intervention in FMR does not improve the 5-year survival rate.17 This lower cut-off value for FMR applied in our study acknowledges whether intentionally or not the systematic underestimation of true regurgitation orifice in a crescent shaped convergence zone. Our study does not deliver patients outcome data yet. Regarding the technical shortcoming of EROAPISA, it was found that in 98% of patients in the FMR group with an EROAPISA ≥0.2 cm2 had a corresponding VCA value of ≥0.4 cm2. However, this comes at the cost of a relatively low specificity for prediction of severe FMR by EROAPISA alone. In this study, a closer correlation was found between VCA3D and the reference method than compared to EROAPISA. The superiority of VCA over EROAPISA in the FMR group is mainly due to the oval shaped cross-sectional area of the vena contracta.3 Calculating the EROA using the hemispheric model for the PISA method in a four chamber view clearly underestimates the vena contracta area in FMR. Quantification of EROA based on a hemielliptic model might compensate for potential asymmetry of non-circular regurgitant orifices, but it requires two planes when using 2D colour Doppler.18 In the group with moderate DMR regurgitation volume derived by PISA method again was significantly lower compared to RVVCA partial due to a high proportion of patients with oval shaped regurgitation orifice. On the contrary, RVPISA values exceeded significantly both RV3D and RVVCA in the group with severe DMR. Pathoanatomical conditions again are an explanation for this finding. The large, 2D colour Doppler convergence zone seen in DMR due to a flail leaflet is wedge-shaped and not completely hemispheric resulting in an overestimation of regurgitation volume by PISA method. To overcome this known limitation an angle correction factor has been proposed in this situation.19 The successful implementation of VCA3D quantification by 3D colour Doppler in clinical routine depends on the feasibility and reliability of the method. Therefore, this study investigated intra- and interobserver variability of VCA3D measurements in a larger number of patients, showing in accordance to previous studies good results for both.7,8,20 In addition, for the first time re-test reliability was tested in patients, who underwent TEE examination twice, mainly before and during mitral valve repair. Especially, functional mitral regurgitation varies dynamically in accordance with changes in afterload and fluid status, negatively effecting re-test reliability of any echocardiographic parameter for severity grading.21,22 Limitations This study neither includes a test population to validate the threshold values of VCA3D for MR severity grading nor a reference method to verify the accuracy VCA3D measurements. The quantification of VCA3D based on 3D colour Doppler has several technically shortcomings. The limited spatial resolution of 3D colour Doppler can be a problem when quantifying small regurgitant orifice areas, but may not be as important in moderate to severe MR. To increase temporal resolution, stitched datasets were acquired in this study, predisposing to artefacts, especially in patients with Afib. The regurgitation jet changes dynamically during systole. Hence choice of the systolic frame affects VCA measurement. Even using multiplanar reconstruction it can be challenging to define the cross-sectional plane for planimetry, especially in DMR with very eccentric jets. Although acquiring a 3D colour Doppler loop with a reasonable quality using TEE is less time-consuming than the 2D integrative approach, the post-processing still requires a significant amount of time. Conclusion This study delivers cut-off values for VCA3D in patients with different types of mitral regurgitation. By eliminating geometric and flow assumptions, the 3D VCA method is reliable in clinical routine and improves accuracy of MR grading compared with conventional 2D parameters. Given the potential strengths of 3D colour Doppler echocardiography, prospective studies are needed to explore the prognostic value of VCA3D in MR patients. Conflict of interest: Björn Goebel, Ali Hamadanchi, and Tudor C. Poerner have received fees for scientific presentations from TomTec-Imaging Systems Unterschleissheim, Germany. All other authors have no conflicts of interests to declare. References 1 Lancellotti P , Tribouilloy C , Hagendorff A , Popescu BA , Edvardsen T , Pierard LA et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 611 – 44 . Google Scholar CrossRef Search ADS PubMed 2 Yoganathan AP , Cape EG , Sung HW , Williams FP , Jimoh A. Review of hydrodynamic principles for the cardiologist: applications to the study of blood flow and jets by imaging techniques . J Am Coll Cardiol 1988 ; 12 : 1344 – 53 . Google Scholar CrossRef Search ADS PubMed 3 Kahlert P , Plicht B , Schenk IM , Janosi RA , Erbel R , Buck T. Direct assessment of size and shape of noncircular vena contracta area in functional versus organic mitral regurgitation using real-time three-dimensional echocardiography . J Am Soc Echocardiogr 2008 ; 2 : 912 – 21 . 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The meaning and use of the area under a Receiver Operating Characteristic (ROC) curve . Radiology 1982 ; 143 : 29 – 36 . Google Scholar CrossRef Search ADS PubMed 11 Bland JM , Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement . Lancet 1986 ; 1 : 307 – 10 . Google Scholar CrossRef Search ADS PubMed 12 Enriquez-Sarano M , Avierinos JF , Messika-Zeitoun D , Detaint D , Capps M , Nkomo V et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation . N Engl J Med 2005 ; 352 : 875 – 83 . Google Scholar CrossRef Search ADS PubMed 13 Biner S , Rafique A , Rafii F , Tolstrup K , Noorani O , Shiota T et al. Reproducibility of proximal isovelocity surface area, vena contracta, and regurgitant jet area for assessment of mitral regurgitation severity . J Am Coll Cardiol Imaging 2010 ; 3 : 235 – 43 . 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Direct measurement of multiple vena contracta areas for assessing the severity of mitral regurgitation using realtime 3D TEE . JACC Cardiovasc Imaging 2012 ; 5 : 669 – 76 . Google Scholar CrossRef Search ADS PubMed 21 Grewal KS , Malkowski MJ , Piracha AR , Astbury JC , Kramer CM , Dianzumba S et al. Effect of general anesthesia on the severity of mitral regurgitation by transesophageal echocardiography . Am J Cardiol 2000 ; 85 : 199 – 203 . Google Scholar CrossRef Search ADS PubMed 22 Kizilbash AM , Willett DL , Brickner E , Heinle SK , Grayburn PA. Effects of afterload reduction on vena contracta width in mitral regurgitation . J Am Coll Cardiol 1998 ; 32 : 427 – 31 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Apr 21, 2017

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