TY - JOUR
AU - Shiota,, Takahiro
AB - Abstract Aims Percutaneous edge-to-edge repair alters mitral valve (MV) geometry in functional mitral regurgitation (FMR). We sought to characterize MV morphology in patients with central and eccentric FMR, compare the geometrical effect of MitraClip therapy, and elucidate different mechanisms of MR improvement according to FMR subtypes. Methods and results Seventy-six symptomatic patients with Grade 3 to 4+ FMR (central, n = 39; eccentric, n = 37) underwent three-dimensional transoesophageal echocardiography during MitraClip implantation. We defined procedural success as a reduction of MR by ≥1 grade with having a residual mitral regurgitation (MR) of ≤ grade 2+. Procedural success rate was similar between central and eccentric FMR (77% vs. 78%, P = 0.55). After MitraClip, the reduction in anterior-posterior diameter did not differ between FMR subtypes, but patients with eccentric FMR had a greater reduction in the averaged tethering angle difference (P < 0.001) with less reduction in tenting volume and height (both P < 0.001) than did patients with central FMR. On multivariable analysis, in central FMR, MR reduction post-clip was associated with shortening in anterior-posterior diameter [coefficient 0.388, 95% confidence interval (CI) 0.216–0.561; P < 0.001] and an increase in coaptation area (coefficient 0.117, 95% CI 0.039–0.194; P = 0.004), whereas in eccentric FMR MR reduction was mainly associated with a decrease in the averaged tethering angle difference (coefficient 0.050, 95% CI 0.021–0.078; P = 0.001). Conclusion MV geometrical effect and its association with MR improvement after MitraClip therapy differ according to FMR subtypes. Our results indicate the MR jet direction and the leaflet tethering pattern may be considered in the strategy for percutaneous treatment for FMR. functional mitral regurgitation , percutaneous mitral valve repair , 3D transoesophageal echocardiography Introduction Percutaneous edge-to-edge repair using the MitraClip system has emerged as an alternative to surgery in patients with a high operative risk. To date, worldwide multicentre registries of high-risk or inoperable mitral regurgitation (MR) patients demonstrate a high success rate, safety, and functional improvement after MitraClip therapy in patients with functional MR (FMR).1–3 Despite the long-term durability of MR reduction observed in EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) trial,4 significant residual MR occurs in up to 20% at 1 year after MitraClip.5 Furthermore, recent publications demonstrated that both residual MR and mitral stenosis post-clip result in a poor prognosis.6,7 An eccentric regurgitant jet has generally been described in the context of degenerative MR caused by a flail leaflet or single leaflet prolapse; however, its presence in patients with FMR has also been reported, particularly when there is an asymmetric leaflet tethering pattern with a pseudo-prolapse of the anterior leaflet.8,9 This heterogeneity in mitral valve (MV) morphology among the FMR patients may result in differential geometrical effect and MR reduction after MitraClip therapy. Recent studies suggested that the MitraClip device affects MV geometry in FMR patients by decreasing mitral annular diameter along antero-posterior direction and increasing coaptation area.10–13 However, there is little data on its impact on MR reduction according to FMR subtypes. The aims of this study were to compare the geometrical effect of MitraClip therapy in patients with central and eccentric FMR using an intraprocedural three-dimensional (3D) transoesophageal echocardiography (TOE), and to elucidate the different mechanisms of MR improvement between FMR subtypes. Methods Patient population A total of 76 consecutive patients with FMR who underwent MitraClip placement at Cedars-Sinai Medical Center between January 2011 and September 2015 were retrospectively reviewed. All patients were symptomatic with Grade 3 to 4+ MR with an effective regurgitant orifice area of ≥20 mm2, New York Heart Association functional Class III to IV, and concomitant atrial fibrillation (n = 25) despite optimized medical and device therapy.14 All patients underwent the MitraClip procedure under the EVEREST II trial (n = 20), the COAPT (the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial (n = 37), or the compassionate-use programme (n = 19). Patients who underwent the MitraClip procedure under the compassionate-use programme met ≥1 exclusion criterion of the EVEREST II: left ventricular (LV) ejection fraction <25% in nine patients, pre-procedural mitral valve area <4.0 cm2 in six patients, and inoperative candidate for MV surgery in four patients. The protocol of this study was approved by the Cedars-Sinai Institutional Review Board and in concordance with the Declaration of Helsinki. FMR subgroup determination FMR was defined as MR jet with global or regional LV dilatation and reduced LV ejection fraction, despite structurally normal MV leaflets.11,15 The factors related to developing FMR may be multifactorial, which is also caused by pathological changes in annular geometry and pathological tension on the leaflets due to left atrial dilatation causing asymmetrical MV tethering.16 After an in-depth echocardiography review, the primary direction of the MR jets was classified as central or eccentric. The direction of the MR jets was assessed on apical long-axis and intercommisural views at midsystole using colour Doppler 3D echocardiography. Eccentric FMR is defined as eccentric mitral jet coursing along the opposite leaflet, striking it throughout its full length and in close contact with MV leaflets, and rebounding to the back of the left atrium. Symmetric tethering pattern was defined as the followings: (i) symmetric coaptation, which means symmetric and predominant apical tethering of both leaflets into the left ventricle and (ii) a central MR jet observed in all the echocardiography views (Figure 1A).8 Meanwhile, asymmetric tethering pattern was defined as the followings: (i) a pseudo-prolapse of the anterior leaflet, which is identified when this leaflet overrode the posterior one beyond the coaptation line without crossing the annulus plane and (ii) an eccentric, posteriorly directed MR jet (Figure 1B).9 Figure 1 View largeDownload slide FMR subgroup determination. The 3D TOE demonstrates representative cases of a central regurgitant jet with a symmetric tethering pattern (A) and that of an eccentric regurgitant jet with an asymmetric tethering pattern, shaping a ‘pseudo-prolapse’ appearance (B). Eccentric FMR was associated with a higher ratio of anterior-to-posterior mitral leaflet closure area, indicating a posterior movement of coaptation line (yellow dotted lines). 3D, three-dimensional; FMR, functional mitral regurgitation; TOE, transoesophageal echocardiography. Figure 1 View largeDownload slide FMR subgroup determination. The 3D TOE demonstrates representative cases of a central regurgitant jet with a symmetric tethering pattern (A) and that of an eccentric regurgitant jet with an asymmetric tethering pattern, shaping a ‘pseudo-prolapse’ appearance (B). Eccentric FMR was associated with a higher ratio of anterior-to-posterior mitral leaflet closure area, indicating a posterior movement of coaptation line (yellow dotted lines). 3D, three-dimensional; FMR, functional mitral regurgitation; TOE, transoesophageal echocardiography. Procedures The MitraClip procedure was performed as previously described.5,7 Briefly, the delivery system was advanced through the 24 Fr steerable guide catheter from femoral vein following a TOE-guided trans-septal approach into the left atrium and across the MV to the left ventricle. The arms of the clip were placed above the origin of the MR jet and oriented perpendicular to the leaflet coaptation line. With the two arms of the clip extended, the device was retracted to capture both leaflets effectively, and subsequently, closed to coapt the MV leaflets, thereby emulating the surgical double-orifice technique. Before the clip was released, reduction of MR severity was assessed by colour Doppler imaging.17 If further MR reduction was needed, a second MitraClip device was deployed. Transthoracic echocardiography Transthoracic echocardiography was performed using commercially available ultrasound system (S5-1 probe, IE33; Philips, Andover, MA, USA). All measurements were performed according to the current guidelines.18 Initial MR was graded comprehensively with an integrative approach using semiquantitative and at least one of quantitative parameters including proximal isovelocity surface area, effective regurgitation orifice area, as well as vena contracta (VC) width and regurgitant volume according to the recommendations of the European Society of Cardiology and the American Society of Echocardiography using 4 MR grades: mild (1+), moderate (2+), moderate to severe (3+), and severe (4+).14,19 After intervention, post-clip MR severity was determined 1 or 2 day after the procedure before discharge by transthoracic echocardiography with the technique previously reported.20 Procedural success was defined as a reduction of MR by ≥1 grade with having a residual MR of ≤ grade 2+.7,11 Intraprocedural TOE Intraprocedural TOE was performed under sedation using intravenous injection of midazolam equipped with a fully sampled matrix-array transducer which can display both 2D and 3D images (X7-2t Live 3D transducer; Philips). The probe was positioned at the midoesophageal level to acquire volume datasets focused on the entire MV before and immediately after MitraClip implantation using the live 3D zoom mode (n = 35; median frame rate, 15 Hz) or 4-beat full-volume mode (n = 41; median frame rate, 55 Hz). The acquisition was electrocardiographically gated, with sector settings optimized for resolution. In patients with atrial fibrillation, we have chosen the live 3D zoom mode and performed 1-beat volume acquisition to avoid stitch artefacts. In addition, 6-beat colour Doppler full volumes were acquired before MitraClip placement with the narrowest possible depth to obtain a higher frame rate. All 3D TOE data were digitally stored for off-line analysis. 3D MV quantitative analysis MVN analysis For 3D MV measurements before and immediately after MitraClip implantation, the acquired datasets were analysed off-line using the commercial software MVN (Mitral Valve Navigation, QLAB version 10.5; Philips). The 3D measurements of MV annulus and leaflets by MVN were determined at midsystole as follows (Figure 2A)8,21: (i) four reference points of the annulus, such as anterior (A), posterior (P), anterolateral (AL), and posteromedial (PM) points, were marked on two cut planes representing the long-axis view and an orthogonal plane; (ii) the annulus was outlined by marking a total of 20 annular points on eight equiangular image planes intersecting at the centre of the mitral annulus; (iii) the closed MV leaflets were traced at midsystole on successive 17 long-axis planes equidistant parallel to the A–P direction; (iv) the tips of anterior and posterior papillary muscle (Pap) were then identified by comparing the adjacent A–P planes; (v) the MV apparatus was then reconstructed by QLAB, generating 3D geometrical parameters including MV annular A–P diameter, AL-PM diameter, height, 3D annular area, aortic-mitral angle, tenting volume, leaflet closure areas of anterior mitral leaflet (AML) and posterior mitral leaflet (PML), and anterior and posterior Pap-leaflet distances (Figure 2A). Figure 2 View largeDownload slide 3D MV quantitative analysis. (A) Mitral Valve Navigation analysis. The 3D measurements of MV annulus and leaflets were determined at midsystole. Four reference points of the annulus (A, P, AL, and PM) were marked on two cut planes representing the long-axis view and an orthogonal plane, following outlined annulus and traced MV leaflets to obtain 3D reconstruction model (left lower panel) and MV geometrical parameters including A-P diameter, AL-PM diameter, annular height, annular area, aortic-mitral angle, tenting volume, leaflet closure areas of anterior mitral leaflet (AML) and posterior mitral leaflet (PML), and papillary muscle (Pap)-leaflet distances. (B) Cardiac 3D Quantification analysis. The 3D measurements of MV leaflet coaptation were determined in three A–P planes (lateral, central, and medial) perpendicular to the AL-PM plane. On each of the three A–P planes, tenting height and tethering angles were measured at midsystole. (C) Colour 3D analysis. The two-orthogonal long-axis planes were aligned parallel with the direction of the proximal regurgitation jet (upper panels), and then the short-axis plane was aligned perpendicular to the narrowest neck of the regurgitation jet just above the left atrial side of the flow convergence zone. The resultant short-axis image of the vena contracta was traced to obtain the 3D vena contracta area (right lower panel). Ao, ascending aorta; MV, mitral valve. Other abbreviations as Figure 1. Figure 2 View largeDownload slide 3D MV quantitative analysis. (A) Mitral Valve Navigation analysis. The 3D measurements of MV annulus and leaflets were determined at midsystole. Four reference points of the annulus (A, P, AL, and PM) were marked on two cut planes representing the long-axis view and an orthogonal plane, following outlined annulus and traced MV leaflets to obtain 3D reconstruction model (left lower panel) and MV geometrical parameters including A-P diameter, AL-PM diameter, annular height, annular area, aortic-mitral angle, tenting volume, leaflet closure areas of anterior mitral leaflet (AML) and posterior mitral leaflet (PML), and papillary muscle (Pap)-leaflet distances. (B) Cardiac 3D Quantification analysis. The 3D measurements of MV leaflet coaptation were determined in three A–P planes (lateral, central, and medial) perpendicular to the AL-PM plane. On each of the three A–P planes, tenting height and tethering angles were measured at midsystole. (C) Colour 3D analysis. The two-orthogonal long-axis planes were aligned parallel with the direction of the proximal regurgitation jet (upper panels), and then the short-axis plane was aligned perpendicular to the narrowest neck of the regurgitation jet just above the left atrial side of the flow convergence zone. The resultant short-axis image of the vena contracta was traced to obtain the 3D vena contracta area (right lower panel). Ao, ascending aorta; MV, mitral valve. Other abbreviations as Figure 1. Total leaflet closure area was measured as the summation of AML closure area and PML closure area at midsystole, which represents the minimal area that needs to be covered by the leaflets to occlude the mitral orifice.16 Furthermore, the increase in MV coaptation area during MitraClip was assessed by the following: 100 × Δ (total leaflet closure area)/pre-clip total leaflet closure area (%). Additionally, the following calculations were performed to compare MV morphology between central and eccentric FMR8: (i) ratio of annular height: AL-PM diameter, representing the degree of saddle shape; (ii) difference in averaged tethering angle between AML and PML, representing a measure of the tethering pattern; (iii) ratio of AML closure area: PML closure area, representing the position of the coaptation line; and (iv) ratio of 3D VC area: tenting volume, representing MR severity relative to leaflet tethering. 3DQ analysis Using the commercial software 3DQ (Cardiac 3D Quantification; Philips), the 3D measurements of mitral leaflet coaptation were determined in 3 A-P planes (lateral, central, and medial) perpendicular to the AL-PM plane.22 On each of the 3 A-P planes, tenting height and tethering angles between the annulus line and each leaflet were measured on a midsystole frame (Figure 2B). Colour 3D analysis Off-line cropping of the 3D colour Doppler full-volume dataset was performed at midsystole using three multiplanar reconstruction planes. The Nyquist limit was controlled within 45–65 cm/s for optimal visualization of the MR jet. After the two-orthogonal long-axis planes were aligned parallel with the direction of the proximal MR jet, the short-axis plane was aligned perpendicular to the narrowest neck of the MR jet just above the left atrial side of the flow convergence zone. The resultant short-axis image of the VC was traced to obtain the 3D VC area (Figure 2C).21 Statistical analysis Continuous data are presented as mean ± standard deviation and are compared with unpaired Student t test. Categorical data were presented as frequencies and compared with the Pearson χ2 test. The paired t test was used to compare pre- and post-procedural MV geometry. Comparison of MV geometrical effect of MitraClip implantation between FMR subgroups were done using two-way ANOVA for repeated measures. To identify contributing factors related to MR reduction in the central and eccentric FMR groups, multivariable stepwise linear regression analysis was performed. The following potential univariable predictors were initially considered for the analysis: reduction in A-P diameter, increase in AL-PM diameter, reduction in 3D annular area, decrease in tenting volume, decrease in tenting heights (lateral, central, and medial), changes in averaged tethering angles (AML and PML), reduction in averaged tethering angle difference between AML and PML, changes in leaflet closure areas (AML and PML), increase in coaptation area, and decreases in Pap-leaflet distances (anterior and posterior). Because of multicollinearity, only the reduction in A-P diameter (not increase in AL-PM diameter and reduction in 3D annular area), decrease in tenting volume (not tenting heights), reduction in averaged tethering angle difference between AML and PML (not changes in averaged tethering angles), increase in coaptation area (not changes in leaflet closure areas), and decrease in posterior Pap-leaflet distance (not decrease in anterior Pap-leaflet distance) were entered into the model. Because the reduction in averaged tethering angle difference between AML and PML was entered in the multivariable analysis, its individual components were not entered into the model. Correlations of these contributing factors and MR improvement were determined using Spearman rank correlation. Receiver-operating characteristics analysis was performed to assess the predictive value of selected contributing factors for procedural success. Repeatability of 3D MV measurements was evaluated in a dataset by a single trained echocardiologist and intrasession within-subject standard deviation, coefficient of variation, and intraclass correlations were calculated. Reproducibility of 3D MV measurements, as described by absolute difference ± standard deviation and intraclass correlations, was evaluated in 10 datasets a month after the initial measurement (in a blinded fashion) for intraobserver variability and by a second trained echocardiologist blinded to the initial measurements for interobserver variability using the same dataset. All two-sided P-values <0.05 were considered statistically significant. All analyses were performed using SPSS version 21.0 (IBM, Armonk, NY, USA). Results Total FMR cohort The total FMR cohort comprised 56 men and 20 women with a median age of 76 years (interquartile range 68–83 years). The severity of MR was 3+ in 5 (7%) patients and 4+ in 71 (93%) patients with a median VC area of 0.53 cm2 (interquartile range, 0.41–0.72 cm2). Twenty-five (33%) had chronic atrial fibrillation. Abnormal LV systolic function consisted of reduced ejection fraction of ≤60% in 70 (92%) patients and increased end-systolic dimension of ≥40 mm in 57 (75%). The number of MitraClips implanted was 1 in 28 patients (37%) and 2 in 48 (63%). 3D MV parameters according to FMR subtypes Patients with eccentric FMR (n = 37) was associated with a higher ratio of annular height: AL-PM diameter indicative of preserved saddle-back shape of the annulus (P = 0.022; Table 1). As for MV leaflets parameters, central FMR (n = 39) was associated with a larger tenting volume (P = 0.044) and greater tenting height in three parallel A-P planes (all P < 0.02; Table 1), while eccentric FMR was associated with a greater difference in averaged tethering angle with a prominent PML tethering and relatively less AML tethering (all P < 0.001; Table 1). In addition, eccentric FMR was associated with a higher ratio of AML closure area: PML closure area (P < 0.001), suggesting posterior movement of the coaptation line as shown in Figure 1. Notably, longer distances from the tip of papillary muscles to the leaflet were also observed in patients with eccentric FMR than those with central FMR (both P < 0.001; Table 1). Table 1 Baseline clinical and echocardiographic characteristics Total cohort (n = 76) Central FMR (n = 39) Eccentric FMR (n = 37) P-value Age (years) 76 (68–83) 76 (72–82) 76 (62–84) 0.27 Male gender 56 (74) 30 (77) 26 (70) 0.51 Ischaemic cardiomyopathy 47 (62) 25 (64) 22 (60) 0.68 Chronic atrial fibrillation 25 (33) 8 (21) 17 (46) 0.017 LV end-diastolic diameter (mm) 60.2 (53.1–68.8) 59.8 (53.2–65.0) 61.1 (52.5–70.0) 0.96 LV end-systolic diameter (mm) 47.3 (39.5–57.1) 48.0 (42.0–57.0) 46.5 (38.9–57.0) 0.60 LV ejection fraction (%) 33.9 (25.4–44.6) 31.3 (23.2–41.4) 37.9 (26.9–49.4) 0.11 MV area (cm2) 4.7 (3.9–6.3) 4.6 (3.7–5.8) 4.9 (3.9–6.6) 0.38 MR severity  Grade 4+ 71 (93) 38 (97) 33 (89) 0.16  3D VC area (cm2) 0.53 (0.41–0.72) 0.53 (0.41–0.71) 0.53 (0.42–0.74) 0.7 MV annulus  AL-PM diameter (mm) 38.9 (35.3–41.8) 38.3 (35.5–42.0) 39.1 (34.6–41.4) 0.96  A-P diameter (mm) 32.5 (28.6–35.9) 31.4 (28.1–34.4) 33.6 (29.3–38.6) 0.07  Annular height (mm) 4.5 (3.3–5.7) 4.1 (3.2–5.0) 5.3 (3.8–6.2) 0.009  Ratio of annular height: AL-PM diameter 0.12 (0.09–0.15) 0.11 (0.09–0.13) 0.13 (0.10–0.16) 0.022  3D annular area (mm2) 1077 (891–1222) 1049 (898–1180) 1106 (876–1366) 0.38 MV leaflets  Tenting volume (mL) 2.9 (2.3–4.5) 3.2 (2.7–4.7) 2.7 (1.9–4.1) 0.044  AML averaged tethering angle (°) 19.3 (14.3–25.9) 24.1 (19.6–30.2) 14.4 (11.4–18.8) <0.001  PML averaged tethering angle (°) 33.6 (25.3–38.9) 27.2 (22.2–33.6) 37.5 (33.7–46.0) <0.001  Difference in averaged tethering angle (°) 9.5 (1.9–22.3) 2.2 (0.6–4.3) 22.3 (18.9–28.7) <0.001  AML closure area (mm2) 739 (635–910) 681 (598–808) 844 (676–1055) 0.002  PML closure area (mm2) 530 (386–647) 581 (477–682) 473 (317–586) 0.001  Total leaflet closure area (mm2) 1260 (1059–1543) 1255 (1075–1483) 1278 (1050–1628) 0.78  Ratio of AML closure area: PML closure area 1.54 (1.16–1.89) 1.20 (1.08–1.43) 1.87 (1.71–2.17) <0.001  Tenting height (lateral) (mm) 6.5 (4.8–8.3) 7.3 (5.5–8.5) 5.2 (4.0–6.9) 0.001  Tenting height (central) (mm) 8.3 (6.3–9.6) 9.1 (7.0–10.4) 7.5 (5.9–8.8) 0.005  Tenting height (medial) (mm) 7.1 (5.4–8.9) 7.8 (6.0–9.2) 6.6 (4.4–8.5) 0.012 Leaflet to annular ratio 1.20 (1.15–1.27) 1.20 (1.15–1.29) 1.19 (1.15–1.26) 0.32 Ratio of 3D VC area: tenting volume (cm2/mL) 0.17 (0.13–0.25) 0.15 (0.12–0.20) 0.19 (0.14–0.26) 0.023 Aortic-mitral angle (°) 136 (125–149) 135 (125–148) 136 (125–151) 0.74 Anterior Pap-leaflet distance (mm) 23.4 (20.2–26.0) 20.7 (18.0–22.3) 25.6 (23.6–28.5) <0.001 Posterior Pap-leaflet distance (mm) 23.0 (20.4–25.9) 21.2 (18.5–22.7) 25.7 (24.5–29.2) <0.001 Total cohort (n = 76) Central FMR (n = 39) Eccentric FMR (n = 37) P-value Age (years) 76 (68–83) 76 (72–82) 76 (62–84) 0.27 Male gender 56 (74) 30 (77) 26 (70) 0.51 Ischaemic cardiomyopathy 47 (62) 25 (64) 22 (60) 0.68 Chronic atrial fibrillation 25 (33) 8 (21) 17 (46) 0.017 LV end-diastolic diameter (mm) 60.2 (53.1–68.8) 59.8 (53.2–65.0) 61.1 (52.5–70.0) 0.96 LV end-systolic diameter (mm) 47.3 (39.5–57.1) 48.0 (42.0–57.0) 46.5 (38.9–57.0) 0.60 LV ejection fraction (%) 33.9 (25.4–44.6) 31.3 (23.2–41.4) 37.9 (26.9–49.4) 0.11 MV area (cm2) 4.7 (3.9–6.3) 4.6 (3.7–5.8) 4.9 (3.9–6.6) 0.38 MR severity  Grade 4+ 71 (93) 38 (97) 33 (89) 0.16  3D VC area (cm2) 0.53 (0.41–0.72) 0.53 (0.41–0.71) 0.53 (0.42–0.74) 0.7 MV annulus  AL-PM diameter (mm) 38.9 (35.3–41.8) 38.3 (35.5–42.0) 39.1 (34.6–41.4) 0.96  A-P diameter (mm) 32.5 (28.6–35.9) 31.4 (28.1–34.4) 33.6 (29.3–38.6) 0.07  Annular height (mm) 4.5 (3.3–5.7) 4.1 (3.2–5.0) 5.3 (3.8–6.2) 0.009  Ratio of annular height: AL-PM diameter 0.12 (0.09–0.15) 0.11 (0.09–0.13) 0.13 (0.10–0.16) 0.022  3D annular area (mm2) 1077 (891–1222) 1049 (898–1180) 1106 (876–1366) 0.38 MV leaflets  Tenting volume (mL) 2.9 (2.3–4.5) 3.2 (2.7–4.7) 2.7 (1.9–4.1) 0.044  AML averaged tethering angle (°) 19.3 (14.3–25.9) 24.1 (19.6–30.2) 14.4 (11.4–18.8) <0.001  PML averaged tethering angle (°) 33.6 (25.3–38.9) 27.2 (22.2–33.6) 37.5 (33.7–46.0) <0.001  Difference in averaged tethering angle (°) 9.5 (1.9–22.3) 2.2 (0.6–4.3) 22.3 (18.9–28.7) <0.001  AML closure area (mm2) 739 (635–910) 681 (598–808) 844 (676–1055) 0.002  PML closure area (mm2) 530 (386–647) 581 (477–682) 473 (317–586) 0.001  Total leaflet closure area (mm2) 1260 (1059–1543) 1255 (1075–1483) 1278 (1050–1628) 0.78  Ratio of AML closure area: PML closure area 1.54 (1.16–1.89) 1.20 (1.08–1.43) 1.87 (1.71–2.17) <0.001  Tenting height (lateral) (mm) 6.5 (4.8–8.3) 7.3 (5.5–8.5) 5.2 (4.0–6.9) 0.001  Tenting height (central) (mm) 8.3 (6.3–9.6) 9.1 (7.0–10.4) 7.5 (5.9–8.8) 0.005  Tenting height (medial) (mm) 7.1 (5.4–8.9) 7.8 (6.0–9.2) 6.6 (4.4–8.5) 0.012 Leaflet to annular ratio 1.20 (1.15–1.27) 1.20 (1.15–1.29) 1.19 (1.15–1.26) 0.32 Ratio of 3D VC area: tenting volume (cm2/mL) 0.17 (0.13–0.25) 0.15 (0.12–0.20) 0.19 (0.14–0.26) 0.023 Aortic-mitral angle (°) 136 (125–149) 135 (125–148) 136 (125–151) 0.74 Anterior Pap-leaflet distance (mm) 23.4 (20.2–26.0) 20.7 (18.0–22.3) 25.6 (23.6–28.5) <0.001 Posterior Pap-leaflet distance (mm) 23.0 (20.4–25.9) 21.2 (18.5–22.7) 25.7 (24.5–29.2) <0.001 Values are expressed as median (25th–75th percentile) or n (percentage). 3D, three-dimensional; AL-PM, anterolateral-posteromedial; AML, anterior mitral leaflet; A-P, antero-posterior; FMR, functional mitral regurgitation; LV, left ventricular; MV, mitral valve; Pap, papillary muscle; PML, posterior mitral leaflet; VC, vena contracta. Table 1 Baseline clinical and echocardiographic characteristics Total cohort (n = 76) Central FMR (n = 39) Eccentric FMR (n = 37) P-value Age (years) 76 (68–83) 76 (72–82) 76 (62–84) 0.27 Male gender 56 (74) 30 (77) 26 (70) 0.51 Ischaemic cardiomyopathy 47 (62) 25 (64) 22 (60) 0.68 Chronic atrial fibrillation 25 (33) 8 (21) 17 (46) 0.017 LV end-diastolic diameter (mm) 60.2 (53.1–68.8) 59.8 (53.2–65.0) 61.1 (52.5–70.0) 0.96 LV end-systolic diameter (mm) 47.3 (39.5–57.1) 48.0 (42.0–57.0) 46.5 (38.9–57.0) 0.60 LV ejection fraction (%) 33.9 (25.4–44.6) 31.3 (23.2–41.4) 37.9 (26.9–49.4) 0.11 MV area (cm2) 4.7 (3.9–6.3) 4.6 (3.7–5.8) 4.9 (3.9–6.6) 0.38 MR severity  Grade 4+ 71 (93) 38 (97) 33 (89) 0.16  3D VC area (cm2) 0.53 (0.41–0.72) 0.53 (0.41–0.71) 0.53 (0.42–0.74) 0.7 MV annulus  AL-PM diameter (mm) 38.9 (35.3–41.8) 38.3 (35.5–42.0) 39.1 (34.6–41.4) 0.96  A-P diameter (mm) 32.5 (28.6–35.9) 31.4 (28.1–34.4) 33.6 (29.3–38.6) 0.07  Annular height (mm) 4.5 (3.3–5.7) 4.1 (3.2–5.0) 5.3 (3.8–6.2) 0.009  Ratio of annular height: AL-PM diameter 0.12 (0.09–0.15) 0.11 (0.09–0.13) 0.13 (0.10–0.16) 0.022  3D annular area (mm2) 1077 (891–1222) 1049 (898–1180) 1106 (876–1366) 0.38 MV leaflets  Tenting volume (mL) 2.9 (2.3–4.5) 3.2 (2.7–4.7) 2.7 (1.9–4.1) 0.044  AML averaged tethering angle (°) 19.3 (14.3–25.9) 24.1 (19.6–30.2) 14.4 (11.4–18.8) <0.001  PML averaged tethering angle (°) 33.6 (25.3–38.9) 27.2 (22.2–33.6) 37.5 (33.7–46.0) <0.001  Difference in averaged tethering angle (°) 9.5 (1.9–22.3) 2.2 (0.6–4.3) 22.3 (18.9–28.7) <0.001  AML closure area (mm2) 739 (635–910) 681 (598–808) 844 (676–1055) 0.002  PML closure area (mm2) 530 (386–647) 581 (477–682) 473 (317–586) 0.001  Total leaflet closure area (mm2) 1260 (1059–1543) 1255 (1075–1483) 1278 (1050–1628) 0.78  Ratio of AML closure area: PML closure area 1.54 (1.16–1.89) 1.20 (1.08–1.43) 1.87 (1.71–2.17) <0.001  Tenting height (lateral) (mm) 6.5 (4.8–8.3) 7.3 (5.5–8.5) 5.2 (4.0–6.9) 0.001  Tenting height (central) (mm) 8.3 (6.3–9.6) 9.1 (7.0–10.4) 7.5 (5.9–8.8) 0.005  Tenting height (medial) (mm) 7.1 (5.4–8.9) 7.8 (6.0–9.2) 6.6 (4.4–8.5) 0.012 Leaflet to annular ratio 1.20 (1.15–1.27) 1.20 (1.15–1.29) 1.19 (1.15–1.26) 0.32 Ratio of 3D VC area: tenting volume (cm2/mL) 0.17 (0.13–0.25) 0.15 (0.12–0.20) 0.19 (0.14–0.26) 0.023 Aortic-mitral angle (°) 136 (125–149) 135 (125–148) 136 (125–151) 0.74 Anterior Pap-leaflet distance (mm) 23.4 (20.2–26.0) 20.7 (18.0–22.3) 25.6 (23.6–28.5) <0.001 Posterior Pap-leaflet distance (mm) 23.0 (20.4–25.9) 21.2 (18.5–22.7) 25.7 (24.5–29.2) <0.001 Total cohort (n = 76) Central FMR (n = 39) Eccentric FMR (n = 37) P-value Age (years) 76 (68–83) 76 (72–82) 76 (62–84) 0.27 Male gender 56 (74) 30 (77) 26 (70) 0.51 Ischaemic cardiomyopathy 47 (62) 25 (64) 22 (60) 0.68 Chronic atrial fibrillation 25 (33) 8 (21) 17 (46) 0.017 LV end-diastolic diameter (mm) 60.2 (53.1–68.8) 59.8 (53.2–65.0) 61.1 (52.5–70.0) 0.96 LV end-systolic diameter (mm) 47.3 (39.5–57.1) 48.0 (42.0–57.0) 46.5 (38.9–57.0) 0.60 LV ejection fraction (%) 33.9 (25.4–44.6) 31.3 (23.2–41.4) 37.9 (26.9–49.4) 0.11 MV area (cm2) 4.7 (3.9–6.3) 4.6 (3.7–5.8) 4.9 (3.9–6.6) 0.38 MR severity  Grade 4+ 71 (93) 38 (97) 33 (89) 0.16  3D VC area (cm2) 0.53 (0.41–0.72) 0.53 (0.41–0.71) 0.53 (0.42–0.74) 0.7 MV annulus  AL-PM diameter (mm) 38.9 (35.3–41.8) 38.3 (35.5–42.0) 39.1 (34.6–41.4) 0.96  A-P diameter (mm) 32.5 (28.6–35.9) 31.4 (28.1–34.4) 33.6 (29.3–38.6) 0.07  Annular height (mm) 4.5 (3.3–5.7) 4.1 (3.2–5.0) 5.3 (3.8–6.2) 0.009  Ratio of annular height: AL-PM diameter 0.12 (0.09–0.15) 0.11 (0.09–0.13) 0.13 (0.10–0.16) 0.022  3D annular area (mm2) 1077 (891–1222) 1049 (898–1180) 1106 (876–1366) 0.38 MV leaflets  Tenting volume (mL) 2.9 (2.3–4.5) 3.2 (2.7–4.7) 2.7 (1.9–4.1) 0.044  AML averaged tethering angle (°) 19.3 (14.3–25.9) 24.1 (19.6–30.2) 14.4 (11.4–18.8) <0.001  PML averaged tethering angle (°) 33.6 (25.3–38.9) 27.2 (22.2–33.6) 37.5 (33.7–46.0) <0.001  Difference in averaged tethering angle (°) 9.5 (1.9–22.3) 2.2 (0.6–4.3) 22.3 (18.9–28.7) <0.001  AML closure area (mm2) 739 (635–910) 681 (598–808) 844 (676–1055) 0.002  PML closure area (mm2) 530 (386–647) 581 (477–682) 473 (317–586) 0.001  Total leaflet closure area (mm2) 1260 (1059–1543) 1255 (1075–1483) 1278 (1050–1628) 0.78  Ratio of AML closure area: PML closure area 1.54 (1.16–1.89) 1.20 (1.08–1.43) 1.87 (1.71–2.17) <0.001  Tenting height (lateral) (mm) 6.5 (4.8–8.3) 7.3 (5.5–8.5) 5.2 (4.0–6.9) 0.001  Tenting height (central) (mm) 8.3 (6.3–9.6) 9.1 (7.0–10.4) 7.5 (5.9–8.8) 0.005  Tenting height (medial) (mm) 7.1 (5.4–8.9) 7.8 (6.0–9.2) 6.6 (4.4–8.5) 0.012 Leaflet to annular ratio 1.20 (1.15–1.27) 1.20 (1.15–1.29) 1.19 (1.15–1.26) 0.32 Ratio of 3D VC area: tenting volume (cm2/mL) 0.17 (0.13–0.25) 0.15 (0.12–0.20) 0.19 (0.14–0.26) 0.023 Aortic-mitral angle (°) 136 (125–149) 135 (125–148) 136 (125–151) 0.74 Anterior Pap-leaflet distance (mm) 23.4 (20.2–26.0) 20.7 (18.0–22.3) 25.6 (23.6–28.5) <0.001 Posterior Pap-leaflet distance (mm) 23.0 (20.4–25.9) 21.2 (18.5–22.7) 25.7 (24.5–29.2) <0.001 Values are expressed as median (25th–75th percentile) or n (percentage). 3D, three-dimensional; AL-PM, anterolateral-posteromedial; AML, anterior mitral leaflet; A-P, antero-posterior; FMR, functional mitral regurgitation; LV, left ventricular; MV, mitral valve; Pap, papillary muscle; PML, posterior mitral leaflet; VC, vena contracta. Data on the univariable and multivariable linear regression analysis for the log-transformed 3D VC area are shown in Supplementary data online, Tables. Tenting volume in central FMR (P < 0.001) and averaged tethering angle difference (P < 0.001) and posterior Pap-leaflet distance (P = 0.005) in eccentric FMR were selected as independent predictors of the log-transformed 3D VC area. Comparisons of geometrical changes during MitraClip between central and eccentric FMR MV geometrical changes during MitraClip implantation in central and eccentric FMR are shown in Table 2. After MitraClip implantation, patients with central FMR had a greater increase in AL-PM diameter (P = 0.003), while the reduction in A-P diameter and 3D annular area did not differ between FMR subtypes (P = 0.32 and P = 0.17, respectively; Figure 3A). As for leaflet tethering, central FMR group had a greater reduction in tenting volume and height (P < 0.001 and P = 0.001, respectively; Figure 3B). On the other hand, eccentric FMR group had a greater reduction in the averaged tethering angle difference between AML and PML, indicating an improvement of asymmetrical tethering pattern (P < 0.001; Figure 3B). Total leaflet closure area decreased after MitraClip placement in both groups (P < 0.001; Table 2). Notably, the reduction in total leaflet closure area did not differ significantly between patients with central and eccentric FMR (P = 0.81; Figure 3C), indicating an increase in MV coaptation area to the same extent. Additionally, patients with eccentric FMR had a greater decrease in Pap-leaflet distances than did those with central FMR (both, P < 0.001; Figure 3C). 3D MV images and analyses pre- and post-clip in patients with central and eccentric FMR were shown in Figure 4. Table 2 MV geometrical changes during MitraClip between central and eccentric FMR Pre-clip Post-clip P-value P-value for time group interaction AL-PM diameter (mm)  Central FMR 38.3 (35.5–42.0) 39.5 (36.8–42.6) <0.001 0.003  Eccentric FMR 39.1 (34.6–41.4) 39.2 (34.9–41.8) 0.60 A-P diameter (mm)  Central FMR 31.4 (28.1–34.4) 29.4 (26.4–32.1) <0.001 0.32  Eccentric FMR 33.6 (29.3–38.6) 31.9 (27.9–37.0) <0.001 Height (mm)  Central FMR 4.1 (3.2–5.0) 3.9 (3.4–5.1) 0.31 0.63  Eccentric FMR 5.3 (3.8–6.2) 5.1 (4.3–6.1) 0.66 3D annular area (mm2)  Central FMR 1041 (898–1180) 952 (823–1099) <0.001 0.17  Eccentric FMR 1029 (876–1366) 994 (853–1321) <0.001 Tenting volume (mL)  Central FMR 3.2 (2.7–4.7) 2.2 (1.7–4.4) <0.001 <0.001  Eccentric FMR 2.7 (1.9–4.1) 2.4 (1.8–3.9) <0.001 AML averaged tethering angle (°)  Central FMR 24.1 (19.6–30.2) 24.5 (20.4–30.8) 0.44 <0.001  Eccentric FMR 14.4 (11.4–18.8) 16.5 (13.0–21.7) <0.001 PML averaged tethering angle (°)  Central FMR 27.2 (22.2–33.6) 27.6 (22.3–32.7) 0.57 <0.001  Eccentric FMR 37.5 (33.7–46.0) 28.0 (22.2–33.6) <0.001 Difference in averaged tethering angle (°)  Central FMR 2.2 (0.6–4.3) 1.4 (0.2–4.0) 0.12 <0.001  Eccentric FMR 22.3 (18.9–28.7) 9.4 (6.8–14.1) <0.001 AML closure area (mm2)  Central FMR 681 (598–808) 623 (518–766) <0.001 0.38  Eccentric FMR 844 (676–1055) 795 (644–1013) <0.001 PML closure area (mm2)  Central FMR 581 (477–682) 520 (435–656) <0.001 0.37  Eccentric FMR 473 (317–586) 445 (309–543) <0.001 Total leaflet closure area (mm2)  Central FMR 1255 (1075–1483) 1169 (1005–1386) <0.001 0.81  Eccentric FMR 1278 (1050–1628) 1177 (969–1535) <0.001 Ratio of AML closure area: PML closure area  Central FMR 1.20 (1.08–1.43) 1.18 (1.05–1.44) 0.78 0.70  Eccentric FMR 1.87 (1.71–2.17) 1.97 (1.60–2.25) 0.58 Tenting height (lateral) (mm)  Central FMR 7.3 (5.5–8.5) 7.0 (5.1–8.1) 0.003 0.014  Eccentric FMR 5.2 (4.0–6.9) 5.6 (4.1–7.0) 0.90 Tenting height (central) (mm)  Central FMR 9.1 (7.0–10.4) 7.5 (6.0–9.2) <0.001 0.001  Eccentric FMR 7.5 (5.9–8.8) 7.1 (5.6–8.1) 0.002 Tenting height (medial) (mm)  Central FMR 7.8 (6.0–9.2) 7.1 (5.5–8.6) <0.001 <0.001  Eccentric FMR 6.6 (4.4–8.5) 6.5 (4.4–8.0) 0.22 Leaflet to annular ratio  Central FMR 1.20 (1.15–1.29) 1.17 (1.14–1.28) 0.022 0.15  Eccentric FMR 1.19 (1.15–1.26) 1.17 (1.11–1.25) <0.001 Aortic-mitral angle (°)  Central FMR 135 (125–148) 135 (126–145) 0.87 0.45  Eccentric FMR 136 (125–151) 140 (130–148) 0.36 Anterior Pap-leaflet distance (mm)  Central FMR 20.7 (18.0–22.3) 20.6 (18.5–23.0) 0.10 <0.001  Eccentric FMR 25.6 (23.6–28.5) 24.5 (22.1–27.1) <0.001 Posterior Pap-leaflet distance (mm)  Central FMR 21.2 (18.5–22.7) 21.5 (18.6–22.7) 0.42 <0.001  Eccentric FMR 25.7 (24.5–29.2) 24.6 (22.3–27.1) <0.001 Pre-clip Post-clip P-value P-value for time group interaction AL-PM diameter (mm)  Central FMR 38.3 (35.5–42.0) 39.5 (36.8–42.6) <0.001 0.003  Eccentric FMR 39.1 (34.6–41.4) 39.2 (34.9–41.8) 0.60 A-P diameter (mm)  Central FMR 31.4 (28.1–34.4) 29.4 (26.4–32.1) <0.001 0.32  Eccentric FMR 33.6 (29.3–38.6) 31.9 (27.9–37.0) <0.001 Height (mm)  Central FMR 4.1 (3.2–5.0) 3.9 (3.4–5.1) 0.31 0.63  Eccentric FMR 5.3 (3.8–6.2) 5.1 (4.3–6.1) 0.66 3D annular area (mm2)  Central FMR 1041 (898–1180) 952 (823–1099) <0.001 0.17  Eccentric FMR 1029 (876–1366) 994 (853–1321) <0.001 Tenting volume (mL)  Central FMR 3.2 (2.7–4.7) 2.2 (1.7–4.4) <0.001 <0.001  Eccentric FMR 2.7 (1.9–4.1) 2.4 (1.8–3.9) <0.001 AML averaged tethering angle (°)  Central FMR 24.1 (19.6–30.2) 24.5 (20.4–30.8) 0.44 <0.001  Eccentric FMR 14.4 (11.4–18.8) 16.5 (13.0–21.7) <0.001 PML averaged tethering angle (°)  Central FMR 27.2 (22.2–33.6) 27.6 (22.3–32.7) 0.57 <0.001  Eccentric FMR 37.5 (33.7–46.0) 28.0 (22.2–33.6) <0.001 Difference in averaged tethering angle (°)  Central FMR 2.2 (0.6–4.3) 1.4 (0.2–4.0) 0.12 <0.001  Eccentric FMR 22.3 (18.9–28.7) 9.4 (6.8–14.1) <0.001 AML closure area (mm2)  Central FMR 681 (598–808) 623 (518–766) <0.001 0.38  Eccentric FMR 844 (676–1055) 795 (644–1013) <0.001 PML closure area (mm2)  Central FMR 581 (477–682) 520 (435–656) <0.001 0.37  Eccentric FMR 473 (317–586) 445 (309–543) <0.001 Total leaflet closure area (mm2)  Central FMR 1255 (1075–1483) 1169 (1005–1386) <0.001 0.81  Eccentric FMR 1278 (1050–1628) 1177 (969–1535) <0.001 Ratio of AML closure area: PML closure area  Central FMR 1.20 (1.08–1.43) 1.18 (1.05–1.44) 0.78 0.70  Eccentric FMR 1.87 (1.71–2.17) 1.97 (1.60–2.25) 0.58 Tenting height (lateral) (mm)  Central FMR 7.3 (5.5–8.5) 7.0 (5.1–8.1) 0.003 0.014  Eccentric FMR 5.2 (4.0–6.9) 5.6 (4.1–7.0) 0.90 Tenting height (central) (mm)  Central FMR 9.1 (7.0–10.4) 7.5 (6.0–9.2) <0.001 0.001  Eccentric FMR 7.5 (5.9–8.8) 7.1 (5.6–8.1) 0.002 Tenting height (medial) (mm)  Central FMR 7.8 (6.0–9.2) 7.1 (5.5–8.6) <0.001 <0.001  Eccentric FMR 6.6 (4.4–8.5) 6.5 (4.4–8.0) 0.22 Leaflet to annular ratio  Central FMR 1.20 (1.15–1.29) 1.17 (1.14–1.28) 0.022 0.15  Eccentric FMR 1.19 (1.15–1.26) 1.17 (1.11–1.25) <0.001 Aortic-mitral angle (°)  Central FMR 135 (125–148) 135 (126–145) 0.87 0.45  Eccentric FMR 136 (125–151) 140 (130–148) 0.36 Anterior Pap-leaflet distance (mm)  Central FMR 20.7 (18.0–22.3) 20.6 (18.5–23.0) 0.10 <0.001  Eccentric FMR 25.6 (23.6–28.5) 24.5 (22.1–27.1) <0.001 Posterior Pap-leaflet distance (mm)  Central FMR 21.2 (18.5–22.7) 21.5 (18.6–22.7) 0.42 <0.001  Eccentric FMR 25.7 (24.5–29.2) 24.6 (22.3–27.1) <0.001 3D, three-dimensional; AL-PM, anterolateral-posteromedial; AML, anterior mitral leaflet; A-P, antero-posterior; FMR, functional mitral regurgitation; Pap, papillary muscle; PML, posterior mitral leaflet. Table 2 MV geometrical changes during MitraClip between central and eccentric FMR Pre-clip Post-clip P-value P-value for time group interaction AL-PM diameter (mm)  Central FMR 38.3 (35.5–42.0) 39.5 (36.8–42.6) <0.001 0.003  Eccentric FMR 39.1 (34.6–41.4) 39.2 (34.9–41.8) 0.60 A-P diameter (mm)  Central FMR 31.4 (28.1–34.4) 29.4 (26.4–32.1) <0.001 0.32  Eccentric FMR 33.6 (29.3–38.6) 31.9 (27.9–37.0) <0.001 Height (mm)  Central FMR 4.1 (3.2–5.0) 3.9 (3.4–5.1) 0.31 0.63  Eccentric FMR 5.3 (3.8–6.2) 5.1 (4.3–6.1) 0.66 3D annular area (mm2)  Central FMR 1041 (898–1180) 952 (823–1099) <0.001 0.17  Eccentric FMR 1029 (876–1366) 994 (853–1321) <0.001 Tenting volume (mL)  Central FMR 3.2 (2.7–4.7) 2.2 (1.7–4.4) <0.001 <0.001  Eccentric FMR 2.7 (1.9–4.1) 2.4 (1.8–3.9) <0.001 AML averaged tethering angle (°)  Central FMR 24.1 (19.6–30.2) 24.5 (20.4–30.8) 0.44 <0.001  Eccentric FMR 14.4 (11.4–18.8) 16.5 (13.0–21.7) <0.001 PML averaged tethering angle (°)  Central FMR 27.2 (22.2–33.6) 27.6 (22.3–32.7) 0.57 <0.001  Eccentric FMR 37.5 (33.7–46.0) 28.0 (22.2–33.6) <0.001 Difference in averaged tethering angle (°)  Central FMR 2.2 (0.6–4.3) 1.4 (0.2–4.0) 0.12 <0.001  Eccentric FMR 22.3 (18.9–28.7) 9.4 (6.8–14.1) <0.001 AML closure area (mm2)  Central FMR 681 (598–808) 623 (518–766) <0.001 0.38  Eccentric FMR 844 (676–1055) 795 (644–1013) <0.001 PML closure area (mm2)  Central FMR 581 (477–682) 520 (435–656) <0.001 0.37  Eccentric FMR 473 (317–586) 445 (309–543) <0.001 Total leaflet closure area (mm2)  Central FMR 1255 (1075–1483) 1169 (1005–1386) <0.001 0.81  Eccentric FMR 1278 (1050–1628) 1177 (969–1535) <0.001 Ratio of AML closure area: PML closure area  Central FMR 1.20 (1.08–1.43) 1.18 (1.05–1.44) 0.78 0.70  Eccentric FMR 1.87 (1.71–2.17) 1.97 (1.60–2.25) 0.58 Tenting height (lateral) (mm)  Central FMR 7.3 (5.5–8.5) 7.0 (5.1–8.1) 0.003 0.014  Eccentric FMR 5.2 (4.0–6.9) 5.6 (4.1–7.0) 0.90 Tenting height (central) (mm)  Central FMR 9.1 (7.0–10.4) 7.5 (6.0–9.2) <0.001 0.001  Eccentric FMR 7.5 (5.9–8.8) 7.1 (5.6–8.1) 0.002 Tenting height (medial) (mm)  Central FMR 7.8 (6.0–9.2) 7.1 (5.5–8.6) <0.001 <0.001  Eccentric FMR 6.6 (4.4–8.5) 6.5 (4.4–8.0) 0.22 Leaflet to annular ratio  Central FMR 1.20 (1.15–1.29) 1.17 (1.14–1.28) 0.022 0.15  Eccentric FMR 1.19 (1.15–1.26) 1.17 (1.11–1.25) <0.001 Aortic-mitral angle (°)  Central FMR 135 (125–148) 135 (126–145) 0.87 0.45  Eccentric FMR 136 (125–151) 140 (130–148) 0.36 Anterior Pap-leaflet distance (mm)  Central FMR 20.7 (18.0–22.3) 20.6 (18.5–23.0) 0.10 <0.001  Eccentric FMR 25.6 (23.6–28.5) 24.5 (22.1–27.1) <0.001 Posterior Pap-leaflet distance (mm)  Central FMR 21.2 (18.5–22.7) 21.5 (18.6–22.7) 0.42 <0.001  Eccentric FMR 25.7 (24.5–29.2) 24.6 (22.3–27.1) <0.001 Pre-clip Post-clip P-value P-value for time group interaction AL-PM diameter (mm)  Central FMR 38.3 (35.5–42.0) 39.5 (36.8–42.6) <0.001 0.003  Eccentric FMR 39.1 (34.6–41.4) 39.2 (34.9–41.8) 0.60 A-P diameter (mm)  Central FMR 31.4 (28.1–34.4) 29.4 (26.4–32.1) <0.001 0.32  Eccentric FMR 33.6 (29.3–38.6) 31.9 (27.9–37.0) <0.001 Height (mm)  Central FMR 4.1 (3.2–5.0) 3.9 (3.4–5.1) 0.31 0.63  Eccentric FMR 5.3 (3.8–6.2) 5.1 (4.3–6.1) 0.66 3D annular area (mm2)  Central FMR 1041 (898–1180) 952 (823–1099) <0.001 0.17  Eccentric FMR 1029 (876–1366) 994 (853–1321) <0.001 Tenting volume (mL)  Central FMR 3.2 (2.7–4.7) 2.2 (1.7–4.4) <0.001 <0.001  Eccentric FMR 2.7 (1.9–4.1) 2.4 (1.8–3.9) <0.001 AML averaged tethering angle (°)  Central FMR 24.1 (19.6–30.2) 24.5 (20.4–30.8) 0.44 <0.001  Eccentric FMR 14.4 (11.4–18.8) 16.5 (13.0–21.7) <0.001 PML averaged tethering angle (°)  Central FMR 27.2 (22.2–33.6) 27.6 (22.3–32.7) 0.57 <0.001  Eccentric FMR 37.5 (33.7–46.0) 28.0 (22.2–33.6) <0.001 Difference in averaged tethering angle (°)  Central FMR 2.2 (0.6–4.3) 1.4 (0.2–4.0) 0.12 <0.001  Eccentric FMR 22.3 (18.9–28.7) 9.4 (6.8–14.1) <0.001 AML closure area (mm2)  Central FMR 681 (598–808) 623 (518–766) <0.001 0.38  Eccentric FMR 844 (676–1055) 795 (644–1013) <0.001 PML closure area (mm2)  Central FMR 581 (477–682) 520 (435–656) <0.001 0.37  Eccentric FMR 473 (317–586) 445 (309–543) <0.001 Total leaflet closure area (mm2)  Central FMR 1255 (1075–1483) 1169 (1005–1386) <0.001 0.81  Eccentric FMR 1278 (1050–1628) 1177 (969–1535) <0.001 Ratio of AML closure area: PML closure area  Central FMR 1.20 (1.08–1.43) 1.18 (1.05–1.44) 0.78 0.70  Eccentric FMR 1.87 (1.71–2.17) 1.97 (1.60–2.25) 0.58 Tenting height (lateral) (mm)  Central FMR 7.3 (5.5–8.5) 7.0 (5.1–8.1) 0.003 0.014  Eccentric FMR 5.2 (4.0–6.9) 5.6 (4.1–7.0) 0.90 Tenting height (central) (mm)  Central FMR 9.1 (7.0–10.4) 7.5 (6.0–9.2) <0.001 0.001  Eccentric FMR 7.5 (5.9–8.8) 7.1 (5.6–8.1) 0.002 Tenting height (medial) (mm)  Central FMR 7.8 (6.0–9.2) 7.1 (5.5–8.6) <0.001 <0.001  Eccentric FMR 6.6 (4.4–8.5) 6.5 (4.4–8.0) 0.22 Leaflet to annular ratio  Central FMR 1.20 (1.15–1.29) 1.17 (1.14–1.28) 0.022 0.15  Eccentric FMR 1.19 (1.15–1.26) 1.17 (1.11–1.25) <0.001 Aortic-mitral angle (°)  Central FMR 135 (125–148) 135 (126–145) 0.87 0.45  Eccentric FMR 136 (125–151) 140 (130–148) 0.36 Anterior Pap-leaflet distance (mm)  Central FMR 20.7 (18.0–22.3) 20.6 (18.5–23.0) 0.10 <0.001  Eccentric FMR 25.6 (23.6–28.5) 24.5 (22.1–27.1) <0.001 Posterior Pap-leaflet distance (mm)  Central FMR 21.2 (18.5–22.7) 21.5 (18.6–22.7) 0.42 <0.001  Eccentric FMR 25.7 (24.5–29.2) 24.6 (22.3–27.1) <0.001 3D, three-dimensional; AL-PM, anterolateral-posteromedial; AML, anterior mitral leaflet; A-P, antero-posterior; FMR, functional mitral regurgitation; Pap, papillary muscle; PML, posterior mitral leaflet. Figure 3 View largeDownload slide MV geometrical changes during MitraClip implantation. Pre- and post-clip MV geometrical changes in (A) annulus, (B) leaflet tethering, and (C) leaflet coaptation status and papillary muscle (Pap) parameters in FMR subgroup (central: C and eccentric: E). Compared with patients with eccentric FMR, those with central FMR had a greater reduction in A-P diameter and increase in AL-PM diameter and a greater reduction in tenting volume and height. On the other hand, patients with eccentric FMR had a greater reduction in the averaged tethering angle difference between AML and PML and a greater decrease in posterior Pap-leaflet distance but a comparable decrease in total leaflet closure area, this is, an increase in coaptation area. Figure 3 View largeDownload slide MV geometrical changes during MitraClip implantation. Pre- and post-clip MV geometrical changes in (A) annulus, (B) leaflet tethering, and (C) leaflet coaptation status and papillary muscle (Pap) parameters in FMR subgroup (central: C and eccentric: E). Compared with patients with eccentric FMR, those with central FMR had a greater reduction in A-P diameter and increase in AL-PM diameter and a greater reduction in tenting volume and height. On the other hand, patients with eccentric FMR had a greater reduction in the averaged tethering angle difference between AML and PML and a greater decrease in posterior Pap-leaflet distance but a comparable decrease in total leaflet closure area, this is, an increase in coaptation area. Figure 4 View largeDownload slide 3D MV images and analyses pre- and post-clip. Compared with central FMR, eccentric FMR showed a greater improvement of asymmetrical tethering pattern but less prominent reduction of tenting volume. A, anterior; Aα, averaged tethering angle of anterior mitral leaflet; AL, anterolateral; IAS, interatrial septum; P, posterior; Pα, averaged tethering angle of posterior mitral leaflet; Pap, papillary muscle; PM, posteromedial. Pα-Aα means the difference in averaged tethering angle between AML and PML. Figure 4 View largeDownload slide 3D MV images and analyses pre- and post-clip. Compared with central FMR, eccentric FMR showed a greater improvement of asymmetrical tethering pattern but less prominent reduction of tenting volume. A, anterior; Aα, averaged tethering angle of anterior mitral leaflet; AL, anterolateral; IAS, interatrial septum; P, posterior; Pα, averaged tethering angle of posterior mitral leaflet; Pap, papillary muscle; PM, posteromedial. Pα-Aα means the difference in averaged tethering angle between AML and PML. Factors related to MR reduction following MitraClip Procedural success rate was similar between central and eccentric FMR [77% (30/39) vs. 78% (29/37), P = 0.55]. There was no significant difference in the prevalence of two MitraClips implanted between the groups [67% (26/39) in central FMR vs. 60% (22/37) in eccentric FMR; P = 0.52]. We performed multivariable stepwise linear regression analysis to investigate the association of geometrical effect with MR reduction post-clip. In central FMR, the reduction in A-P diameter (P < 0.001) and increase in coaptation area (P = 0.004) were selected as contributing factors associated with MR improvement (Table 3). On the other hand, in eccentric FMR, the reduction in averaged tethering angle difference and decrease in posterior Pap-leaflet distance were selected (both P = 0.001; Table 3). Table 3 Associations of MV geometrical effect with MR improvement following MitraClip Central FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in A-P diameter (per 1 mL) <0.001 0.388 0.216–0.561 4.565 <0.001 1.972 Increase in coaptation area (per 1%) <0.001 0.117 0.039–0.194 3.064 0.004 1.972 Eccentric FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in averaged tethering angle difference (per 1°) <0.001 0.050 0.021–0.078 3.579 0.001 1.244 Decrease in posterior Pap-leaflet distance (per 1 mm) <0.001 0.181 0.083–0.280 3.731 0.001 1.244 Central FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in A-P diameter (per 1 mL) <0.001 0.388 0.216–0.561 4.565 <0.001 1.972 Increase in coaptation area (per 1%) <0.001 0.117 0.039–0.194 3.064 0.004 1.972 Eccentric FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in averaged tethering angle difference (per 1°) <0.001 0.050 0.021–0.078 3.579 0.001 1.244 Decrease in posterior Pap-leaflet distance (per 1 mm) <0.001 0.181 0.083–0.280 3.731 0.001 1.244 A-P, antero-posterior; β, standardized regression coefficient; CI, confidence interval; FMR, functional mitral regurgitation; MR, mitral regurgitation; MV, mitral valve; Pap, papillary muscle; VIF, variance inflation factor. a The following potential univariable predictors were initially considered for the analysis: reduction in A-P diameter, increase in AL-PM diameter, reduction in 3D annular area, decrease in tenting volume, decrease in tenting heights (lateral, central, and medial), changes in averaged tethering angles (AML and PML), reduction in averaged tethering angle difference between AML and PML, changes in leaflet closure areas (AML and PML), increase in coaptation area, and decreases in Pap-leaflet distances (anterior and posterior). Because of multicollinearity, only the reduction in A-P diameter (not increase in AL-PM diameter and reduction in 3D annular area), decrease in tenting volume (not tenting heights), reduction in averaged tethering angle difference between AML and PML (not changes in averaged tethering angles), increase in coaptation area (not changes in leaflet closure areas), and decrease in posterior Pap-leaflet distance (not decrease in anterior Pap-leaflet distance) were entered into the model. Because the reduction in averaged tethering angle difference between AML and PML was entered in the multivariable analysis, its individual components were not entered into the model. Table 3 Associations of MV geometrical effect with MR improvement following MitraClip Central FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in A-P diameter (per 1 mL) <0.001 0.388 0.216–0.561 4.565 <0.001 1.972 Increase in coaptation area (per 1%) <0.001 0.117 0.039–0.194 3.064 0.004 1.972 Eccentric FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in averaged tethering angle difference (per 1°) <0.001 0.050 0.021–0.078 3.579 0.001 1.244 Decrease in posterior Pap-leaflet distance (per 1 mm) <0.001 0.181 0.083–0.280 3.731 0.001 1.244 Central FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in A-P diameter (per 1 mL) <0.001 0.388 0.216–0.561 4.565 <0.001 1.972 Increase in coaptation area (per 1%) <0.001 0.117 0.039–0.194 3.064 0.004 1.972 Eccentric FMR Univariable Multivariablea P-value β 95% CI t P-value VIF Reduction in averaged tethering angle difference (per 1°) <0.001 0.050 0.021–0.078 3.579 0.001 1.244 Decrease in posterior Pap-leaflet distance (per 1 mm) <0.001 0.181 0.083–0.280 3.731 0.001 1.244 A-P, antero-posterior; β, standardized regression coefficient; CI, confidence interval; FMR, functional mitral regurgitation; MR, mitral regurgitation; MV, mitral valve; Pap, papillary muscle; VIF, variance inflation factor. a The following potential univariable predictors were initially considered for the analysis: reduction in A-P diameter, increase in AL-PM diameter, reduction in 3D annular area, decrease in tenting volume, decrease in tenting heights (lateral, central, and medial), changes in averaged tethering angles (AML and PML), reduction in averaged tethering angle difference between AML and PML, changes in leaflet closure areas (AML and PML), increase in coaptation area, and decreases in Pap-leaflet distances (anterior and posterior). Because of multicollinearity, only the reduction in A-P diameter (not increase in AL-PM diameter and reduction in 3D annular area), decrease in tenting volume (not tenting heights), reduction in averaged tethering angle difference between AML and PML (not changes in averaged tethering angles), increase in coaptation area (not changes in leaflet closure areas), and decrease in posterior Pap-leaflet distance (not decrease in anterior Pap-leaflet distance) were entered into the model. Because the reduction in averaged tethering angle difference between AML and PML was entered in the multivariable analysis, its individual components were not entered into the model. Correlations of these contributing factors and MR improvement were demonstrated in Figure 5. The reduction in A-P diameter and increase in MV coaptation area were strongly correlated with MR downgrading post-clip in patients with central FMR (both, r > 0.8; Figure 5A). In contrast, the reduction in averaged tethering angle difference and decrease in posterior Pap-leaflet distance were moderately correlated with MR downgrading post-clip in patients with eccentric FMR (both, r > 0.6; Figure 5B). Figure 5 View largeDownload slide Spearman rank correlation of MV geometrical effect with MR improvement after MitraClip. (A) Central FMR. (B) Eccentric FMR. Figure 5 View largeDownload slide Spearman rank correlation of MV geometrical effect with MR improvement after MitraClip. (A) Central FMR. (B) Eccentric FMR. Receiver-operating characteristics analysis Using a receiver-operating characteristics analysis, the reduction in A-P diameter ≥1.3 mm and increase in leaflet coaptation area ≥5.4% were good predictors for procedural success in central FMR (sensitivity, 80% and 77%; specificity, 100% and 89%, respectively). The reduction in averaged tethering angle difference ≥7° and decrease in posterior Pap-leaflet distance ≥1.3 mm were good predictors for procedural success in eccentric FMR (sensitivity, 90% and 83%; specificity, 100% and 100%, respectively). Repeatability and reproducibility For repeatability, the intrasession within-subject standard deviation and coefficient of variation of A-P diameter/averaged tethering angle difference were 0.5 mm/2° and 1.9%/8.5%. Intraclass correlations [95% confidence interval (CI)] for each of the measurements were A-P diameter: 0.97 (0.95–0.98) and averaged tethering angle difference: 0.96 (0.94–0.98), respectively. For reproducibility, the intraobserver and interobserver variability of 3D measurements were A-P diameter: 1.0 ± 0.4 mm and 1.2 ± 0.5 mm, and averaged tethering angle difference: 6 ± 7° and 8 ± 9°, respectively. Intraclass correlations (95% CI) for each of the measurements were A-P diameter: 0.93 (0.91–0.95) and 0.90 (0.86–0.94), and averaged tethering angle difference: 0.90 (0.86–0.93) and 0.85 (0.82–0.88), respectively. Discussion In this cohort of patients with FMR who underwent percutaneous MV repair with the MitraClip system, we observed that with the use of a 3D TOE-based MV analysis: (i) the morphological features of eccentric FMR included asymmetrical leaflet tethering with prominent posterior leaflet tethering and less anterior leaflet tethering, preserved saddle-back shape of the annulus, posterior movement of the coaptation line, and smaller tenting volume for the same extent of MR severity; (ii) after MitraClip implantation, patients with eccentric FMR had a greater reduction in the averaged tethering angle difference between AML and PML and greater decrease in posterior Pap-leaflet distance with less reduction in tenting volume and height than did patients with central FMR; and (iii) procedural success rate was about 80% irrespective of FMR subtypes, but its contributing factor was different: in central FMR MR reduction post-clip was strongly correlated with the reduction in A-P diameter and increase in coaptation area, whereas in eccentric FMR MR reduction was mainly associated with the improvement of asymmetrical tethering pattern. Characterization of MV morphology in central and eccentric FMR An eccentric regurgitant jet is sometimes encountered in FMR caused by LV dilatation and dysfunction both in patients with non-ischaemic9 and ischemic cardiomyopathy.15 Agricola et al.15 reported in 92 patients with ischaemic MR that the direction of the jet was central in all patients of the symmetric tethering group whereas it was posterior in most patients (83%) of the asymmetric tethering group. Zeng et al.8 analysed 62 patients with ischemic MR and found that greater ratio of posterior to anterior leaflet tethering angle and more posterior displacement of the coaptation line despite smaller tenting volume for the same degree of MR severity were characteristic of eccentric FMR, which is consistent with the present study. Kim et al.16 recently demonstrated that the asymmetrical (posterior greater than anterior) annular dilatation caused by longstanding atrial fibrillation and posterior leaflet tethering by the dilated annulus result in a loss of concavity of the leaflets toward the left ventricle. When the leaflets fail to lengthen sufficiently to accommodate the annular dilatation, posteriorly directed jet from the point at which a pseudo-prolapse of the anterior leaflet is seen can occur.16 Also in our study, the eccentric FMR group has a higher prevalence of chronic atrial fibrillation and greater annular dilatation along the posterior border (Table 1). The major new finding of our study is identification of patients with eccentric FMR caused by regional LV dysfunction and/or chronic atrial fibrillation and the characterization of their structural abnormalities. Using 3D echocardiography, we demonstrate fundamental differences in MV morphology and possible mechanisms between eccentric and central FMR. Our regression model shows that the difference in averaged tethering angle between AML and PML and the posterior Pap-leaflet distance are strongly associated with MR severity in eccentric FMR, whereas the total degree of tenting (tenting volume) is the only independent predictor of MR severity in central MR. Considering that FMR from global or regional LV dysfunction and atrial dilatation have different geometric causes, the direction of the jet and its mechanism, such as the pattern of the annular dilatation and leaflet tethering, may be crucial for improving therapeutic strategies for FMR. MV geometrical effect of MitraClip and its association with MR improvement Percutaneous edge-to-edge repair with the MitraClip system alters MV geometry10–13; yet there is a paucity of data on the relationship between geometrical effect and MR improvement after MitraClip. Thus far, several 3D TOE studies have suggested geometrical effect during MitraClip implantation.10–12 Schmidt et al.10 first evaluated the changes in annular diameter and area during MitraClip on adjusted cut planes from end-systolic 3D volume datasets in 55 patients with severe MR (75% functional) and found that a post-procedural A-P diameter reduced by 2.8 mm in FMR. Schueler et al.11 outlined annulus and traced leaflets to obtain 3D reconstruction model immediately before and after MitraClip in 111 patients with severe MR (64% functional) and showed that only FMR patients experienced an acute reduction of A-P diameter by 4.0 mm at end-diastole. Al Amri et al.12 analysed 42 patients with FMR treated with the MitraClip and found that the MV annulus became more elliptical with a slight reduction in A-P diameter by 1.0 mm and the coaptation area significantly increased. These seemingly conflicting results likely reflect differences in the methodology of the annular measurement in the respective populations. Patzelt et al.13 recently confirmed the effect of the procedure on MV annular size in larger-scale (n = 183) and longer-term study and demonstrated that the reduction in A-P diameter and increase in coaptation area were inversely correlated with residual MR. In these previous studies, the relationship between MV geometrical changes during MitraClip and subsequent MR improvement were analysed with FMR being categorized as one group, often against the other group, the organic MV disease. Our 3D TOE study shows for the first time (i) that two different types of FMR exist in terms of anatomical causes of FMR and (ii) that different responses to the clip procedure occur in these two subgroups. In central FMR, MR improvement after MitraClip therapy was associated with the reduction in A-P diameter and improved MV coaptation, whereas it was mainly associated with the improvement of asymmetrical leaflet tethering pattern in eccentric FMR. Furthermore, our findings indicate that the posterior Pap-leaflet distance has a crucial role of MR improvement in eccentric FMR. However, the precise mechanism by which the posterior Pap-to-AML approximation leads to MR reduction is yet to defined. Clinical implications We believe there is practical clinical value to the findings of this study on MV clipping according to FMR subtypes. Detecting the exact location of a pseudo-prolapse of AML (usually the origin of MR) and firstly trying to capture the tethered PML correctly may be of great importance during MitraClip placement in eccentric FMR. In contrast, grasping the central aspect of both leaflets more closely may be vital for MR reduction in central FMR by reducing the A-P diameter and increasing MV coaptation area. Therefore, this 3D TOE information can be widely utilized for greater procedural success. Limitations First, this is a retrospective study from a tertiary referral centre and therefore this study is not free of referral bias. Although the feasibility for quantifying increase in coaptation area during the clip was acceptable in this study, its accuracy needs to be validated. The reverberation at the place taken by the clips may confound the accurate surface of the leaflets post-clip. Second, serial MR assessment following the MitraClip procedure was not performed; therefore, the actual impact of geometrical effect remains unclear. Finally, clinical follow-up data are lacking. However, residual MR of ≥ grade 3+ has been observed in up to 20% after MitraClip,1 and when present may be accompanied by lack of late recovery of LV function and remodelling and worse prognosis4,6,7; therefore, freedom from residual MR is recognized as an important goal to attain after MitraClip therapy. Conclusions During MitraClip therapy, MV geometrical effect and its association with MR improvement differ according to FMR subtypes. Our results indicate that the MR jet direction and its mechanism, such as the leaflet tethering pattern, may be considered in the strategy for percutaneous treatment for FMR. Practically if there is a pseudo-prolapse of AML, causing or associated with FMR, at the pre-clip TOE, one should focus on the location of the pseudo-prolapse and the tethering of PML to be treated during MitraClip implantation. If the FMR jet is central at the pre-clip TOE, the importance of a reduction in A-P diameter and increase in coaptation area should be taken into consideration during the procedure. The current data are for generating hypothesis and thus need to be validated in prospective and multicentre trials. Acknowledgements We would like to thank Nobuo Ninomiya, Yuusaku Hosoi, and Takayuki Hataoka, from Philips Electronics Japan, for their technical assistance. Funding This work was partially supported by MSD Life Science Foundation, Public Interest Incorporated Foundation. This work was also supported by Takeda Science Foundation and JSPS KAKENHI [17K16008]. Conflict of interest: R.J.S. and T.S. are speakers for Philips Ultrasound. 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TI - Comparison of mitral valve geometrical effect of percutaneous edge-to-edge repair between central and eccentric functional mitral regurgitation: clinical implications
JF - European Heart Journal - Cardiovascular Imaging
DO - 10.1093/ehjci/jey117
DA - 2019-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/comparison-of-mitral-valve-geometrical-effect-of-percutaneous-edge-to-PgHv0m4HFh
SP - 455
VL - 20
IS - 4
DP - DeepDyve
ER -