Improved mitral valve coaptation and reduced mitral valve annular size after percutaneous mitral valve repair (PMVR) using the MitraClip system

Improved mitral valve coaptation and reduced mitral valve annular size after percutaneous mitral... Abstract Aims Improved mitral valve leaflet coaptation with consecutive reduction of mitral regurgitation (MR) is a central goal of percutaneous mitral valve repair (PMVR) with the MitraClip® system. As influences of PMVR on mitral valve geometry have been suggested before, we examined the effect of the procedure on mitral annular size in relation to procedural outcome. Methods and results Geometry of the mitral valve annulus was evaluated in 183 patients undergoing PMVR using echocardiography before and after the procedure and at follow-up. Mitral valve annular anterior–posterior (ap) diameter decreased from 34.0 ± 4.3 to 31.3 ± 4.9 mm (P < 0.001), and medio-lateral (ml) diameter from 33.2 ± 4.8 to 32.4 ± 4.9 mm (P < 0.001). Accordingly, we observed an increase in MV leaflet coaptation after PMVR. The reduction of mitral valve ap diameter showed a significant inverse correlation with residual MR. Importantly, the reduction of mitral valve ap diameter persisted at follow-up (31.3 ± 4.9 mm post PMVR, 28.4 ± 5.3 mm at follow-up). Conclusion This study demonstrates mechanical approximation of both mitral valve annulus edges with improved mitral valve annular coaptation by PMVR using the MitraClip® system, which correlates with residual MR in patients with MR. percutaneous mitral valve repair, mitral regurgitation, MitraClip®, mitral valve annulus diameter, mitral valve coaptation, echocardiography Introduction When classical surgical reconstruction techniques for mitral valve repair are applied, a major goal is stabilization [in degenerative mitral regurgitation (MR)] or reduction (in functional MR) of the mitral valve annulus diameter via annuloplasty in addition to reconstruction of the mitral valve leaflets. This approach was introduced by Carpentier in the 1960s using an annuloplasty ring. With respect to interventional mitral valve reconstruction, there are different principles. At the moment, five percutaneous systems exist for mitral valve repair. Four of those (the CardioBand® system, the Carillon® System, the Mitralign® system, and the Accucinch® device) aim to reduce the mitral annulus diameter via insertion of annuloplasty devices. The most often used device however, the MitraClip® system, is emulating the surgical technique of Alfieri, for which an edge-to-edge suture of both mitral valve leaflets creates a double orifice.1 Several studies using surgical techniques have described favourable results as well after edge-to-edge repair alone as after edge-to-edge repair in combination with annuloplasty.2,3 The initial surgical technique for mitral valve repair encompassed resection of superfluous leaflet material. Over time it was, however, discovered that additional tightening of the mitral annulus via insertion of a annuloplasty ring led to better long term results with lesser recurrence of MR, than reconstruction of the leaflets alone.4 Recently, a study reported a high recurrence rate of MR despite annuloplasty in patients with ischaemic MR.5 While ring-annuloplasty is part of most surgically performed mitral valve repair operations and its benefit is generally acknowledged, it is not clear, whether this also holds true for interventional mitral valve repair and if interventional annuloplasty should be combined with edge-to-edge repair using the MitraClip® system. This study was carried out to determine, whether percutaneous mitral valve repair (PMVR) using the MitraClip® system can per se achieve reduction in mitral valve annular diameter—one of the main goals of surgical mitral valve repair—and whether this is associated with procedural success. Methods Study population In this study, we included 183 patients with grade 2+ to 4 MR, who underwent PMVR using the MitraClip® system (Abbott Vascular) at the University hospital, Department of Cardiology and Cardiovascular Medicine, University of Tuebingen between May 2014 and July 2016. Echocardiograms acquired after induction of anaesthesia at the beginning and at the end of the PMVR procedure and at follow-up after a mean time of 6.7 ± 1.9 months were analysed. Clinical follow-up data of 151 of 183 patients (82.5%) were available. The study was approved by the local ethics committee (260/2015R). The decision for treatment by PMVR had been made by an interdisciplinary team of interventional cardiologists and cardiac surgeons based on either the EuroSCORE6 or on the presence of specific surgical risk factors not covered in the EuroSCORE. Exclusion criteria for PMVR were as previously described.7 Heart failure patients had to be on optimal medical treatment according to current guidelines for at least 3 months prior to PMVR treatment. PMVR procedure The procedure was carried out either in general anaesthesia or in deep sedation, generally as described before.8–10 Echocardiographic assessment Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) measurements were obtained in the heart catheter laboratory after induction of general anaesthesia or deep sedation, respectively. Furthermore, TTE and TEE were evaluated again at follow-up (mean: 6.7 ± 1.9 months). For echocardiography, we used a Philips CX 50 or iE 33 machine (Philips HealthCare, Hamburg, Germany). All echocardiographic parameters were assessed at the beginning and at the end of the PMVR procedure and at follow-up. For the measurements pre PMVR, general anaesthesia or deep sedation were already in a steady state. Arterial blood pressure was kept within normal ranges in both the deep sedation and the general anaesthesia group using catecholamines and intravenous volume supplementation when necessary. The second measurements at the end of the procedure were carried out before general anaesthesia or deep sedation were ended. MR severity and the etiology of regurgitation were determined according to the current European Association of Echocardiography guidelines, MR pre-intervention, MR post-intervention and MR at follow-up was assessed using the technique described by Foster et al. and by TEE.11,12 3D TEE using the simultaneous biplane mode was applied to evaluate mitral valve geometry. The intercomissural medio-lateral (ml) view of the mitral valve was obtained in a mid-esophageal view at 50–70° with visualization of both papillary muscle heads. Then, using a simultaneous biplane mode a second plane was generated orthogonally to the first plane in the centre of the A2 segment allowing for evaluation of the maximum anterior-posterior diameter of the mitral valve. All echocardiographic loops were recorded. Mitral valve annulus diameter in medio-lateral and anterior-posterior (ap) dimension was measured in the respective views at end-systole (Figure 1A). 3 additional investigators blinded to the results repeated measurements using the Centricity Enterprise Web 3.0 software (GE medical systems, 540 West Northwest Highway, Barrington IL, USA). The mean of measurements was calculated and reported as final value. Coaptation length pre intervention was measured in the anterior-posterior view also used for clip positioning. Using simultaneous biplane mode, this view was generated in a plane exactly in the centre of the A2 segment of the intercomissural view. Post intervention, coaptation length was calculated using echo-loops of the grasping maneuver: The length of the visible part (outside the clip) of a leaflet was subtracted from the length of the respective leaflet before the grasping maneuver in a recorded loop. The mean of this difference for anterior mitral leaflet (AML) and posterior mitral leaflet (PML) is reported as the final value. When more than one clip was implanted, this procedure was performed for each single clip and the mean of the single measurements was calculated as final value. Moreover, mitral valve ellipticity was calculated, defined as mitral valve anterior-posterior diameter divided by the medio-lateral diameter.13 Furthermore, we performed a parametric 3D quantification of the mitral valve annulus in a subset of 20 patients using the Philips Qlab 9.0 software (MVQ software) in zoomed 3D views of the mitral valve. Quantification was carried out in the end-systolic frame. Figure 1 View largeDownload slide Changes of mitral valve geometry caused by PMVR. (A) Schematic view of changes in mitral valve annulus diameter during PMVR. (1) Severe MR with baseline MV annulus ap diameter (2) after clip placement, MR and annulus ap diameter are reduced. Coaptation increases. (3) Sample TEE picture of midesophageal view with measurement of mitral valve annulus. White arrow indicates MitraClip®. (B) Mitral valve leaflet coaptation before and after PMVR was assessed. We observed a significant increase of MV coaptation length after PMVR (depicted is the median, the upper and the lower quartile, P < 0.001). (C) Haemodynamic parameters such as increase in cardiac output (CO) were comparable in patients undergoing deep sedation or general anaesthesia (depicted is the median, the upper and the lower quartile). n.s., no significant difference regarding change in CO after PMVR between the two groups. Figure 1 View largeDownload slide Changes of mitral valve geometry caused by PMVR. (A) Schematic view of changes in mitral valve annulus diameter during PMVR. (1) Severe MR with baseline MV annulus ap diameter (2) after clip placement, MR and annulus ap diameter are reduced. Coaptation increases. (3) Sample TEE picture of midesophageal view with measurement of mitral valve annulus. White arrow indicates MitraClip®. (B) Mitral valve leaflet coaptation before and after PMVR was assessed. We observed a significant increase of MV coaptation length after PMVR (depicted is the median, the upper and the lower quartile, P < 0.001). (C) Haemodynamic parameters such as increase in cardiac output (CO) were comparable in patients undergoing deep sedation or general anaesthesia (depicted is the median, the upper and the lower quartile). n.s., no significant difference regarding change in CO after PMVR between the two groups. Statistical analysis Statistical analysis was performed with SPSS (version 24, IBM Deutschland GmbH, Ehningen, Germany). Categorical variables are shown as absolute numbers or as percentage, continuous variables as means ± standard deviation (SD). Normal distribution of variables was tested using the Shapiro–Wilk test. For normally distributed data, paired t-Test was used to compare means. For not normally distributed data the Wilcoxon log rank test was used to compare means. The two-tailed P-values were calculated and a value of P < 0.05 was considered statistically significant. Echocardiographic views were assessed by four independent investigators, three of whom were blinded to the results. To evaluate reproducibility of echocardiographic measurements, the intra-class correlation coefficient for absolute agreement was used, with good agreement defined as ≥0.80. For the assessment of intra-observer reliability, 20 randomly chosen patients were analysed by 1 investigator twice. Absolute agreement among the observations was calculated using intraclass correlation coefficient analysis. To compare agreement of 2D (simultaneous biplane mode) and 3D (parametric 3D quantification) measurements, Bland Altman analysis was used.14 Results Baseline characteristics for all patients are depicted in Table 1. Functional NYHA class III–IV was present in the majority of patients, and there was a high percentage of patients with severely reduced (<35% ejection fraction) LV-function. 57.9% of patients had functional MR (FMR) and 42.1% had degenerative MR (DMR). Coronary artery disease was previously diagnosed in 73.2% of the patients, 67.8% had atrial fibrillation and 45.4% renal insufficiency. MitraClip® was implanted in all 183 patients, all of whom had moderate to severe or severe (2+ to 4) MR at baseline. All patients had successful clip implantation. MR reduction of at least 2 grades was achieved in 180 of the patients (98.4%). There was no difference in the proportion of patients achieving MR severity ≤2+ for patients with DMR or FMR. Table 1 Baseline patient characteristics (n = 183) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) NYHA, New York Heart Association; LVEDD, left ventricular end-diastolic diameter; MR, mitral regurgitation; ACE, angiotensine converting enzyme. * Definitions as used for EuroScore II. Table 1 Baseline patient characteristics (n = 183) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) NYHA, New York Heart Association; LVEDD, left ventricular end-diastolic diameter; MR, mitral regurgitation; ACE, angiotensine converting enzyme. * Definitions as used for EuroScore II. PMVR using the MitraClip® system causes changes in heart geometry associated with MR reduction.15,16,Figure 1A gives a schematic overview of the expected changes achieved by PMVR. By coaptation of the anterior and posterior leaflet of the mitral valve with increase in coaptation length, a reduction of mitral valve annulus size is accomplished and thereby MR is reduced. After clip implantation, we observed a significant increase in mitral valve coaptation length from 3.4 ± 1.0 to 8.4 ± 1.4 mm (P < 0.001, Figure 1B). Echocardiographic measurements were checked for inter- and intra-observer reliability as described in the methods section (Table 2). PMVR procedures are increasingly carried out under conscious sedation.17 Thus, clinical studies have to take any effects on haemodynamics into consideration. Here, we observed, however, no difference in haemodynamic parameters such as increase in cardiac output (CO) between patients treated in general anaesthesia (0.9 ± 1.4 L/min) vs. deep sedation (0.7 ± 1.2 L/min, P = 0.24, Figure 1C). In line with our observation of increased leaflet coaptation after clip implantation, we measured a reduction of mitral valve annulus diameter in ap dimension (from 34.0 ± 4.3 to 31.3 ± 4.9, P < 0.001, Figure 2A) and in ml dimension (from 33.2 ± 4.8 to 32.4 ± 4.9 mm, P < 0.001, Figure 2B). Interestingly, mitral valve ellipticity (defined as mitral valve anterior–posterior diameter divided by the medio-lateral diameter) decreased significantly from 1.03 ± 0.16 to 0.98 ± 0.17 (P ≤ 0.001, Figure 2C). To evaluate the agreement of this biplane imaging method with volume 3D-imaging, we performed a parametric quantification of the mitral valve annulus in a subset of 20 patients. Zoomed 3D views of the mitral valve before and after the clip deployment were analysed in end-systole (see Supplementary data online, Figure S1A). Bland Altman analysis showed good agreement of the two modes of analysis (mean difference 0.03 mm, 95% limits of agreement ± 7.1 mm, Supplementary data online, Figure S1B). A significant reduction in mitral valve annulus ap diameter was observed in subgroups of functional MR (FMR, from 34.9 ± 3.9 to 32.1 ± 4.7 mm, P < 0.001, Figure 3A) and degenerative MR (DMR, from 32.7 ± 4.5 to 30.3 ± 4.9 mm, P < 0.001, Figure 3C). This reduction was more pronounced in FMR than in DMR. The reduction in ml diameter was significant in FMR (from 33.8 ± 4.3 to 32.8 ± 4.5, P = 0.001, Figure 3B), however not in DMR (from 32.3± 5.4 to 31.8 ± 5.5, P = 0.16, Figure 3D). Table 2 Intraclass correlations for interobserver and intraobserver agreement of echocardiographic measurements Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 MV, mitral valve; ap, anterior-posterior; ml, medio-lateral. Table 2 Intraclass correlations for interobserver and intraobserver agreement of echocardiographic measurements Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 MV, mitral valve; ap, anterior-posterior; ml, medio-lateral. Figure 2 View largeDownload slide Changes in mitral valve geometry after PMVR. (A) Reduction of mitral valve annulus ap diameter (P < 0.001). (B) Reduction of mitral valve annulus ml diameter (P < 0.001). (C) Mitral valve ellipticity was calculated. We observed a reduction of mitral valve ellipticity (P ≤ 0.001). Boxplots are showing the median, the upper and the lower quartile. Figure 2 View largeDownload slide Changes in mitral valve geometry after PMVR. (A) Reduction of mitral valve annulus ap diameter (P < 0.001). (B) Reduction of mitral valve annulus ml diameter (P < 0.001). (C) Mitral valve ellipticity was calculated. We observed a reduction of mitral valve ellipticity (P ≤ 0.001). Boxplots are showing the median, the upper and the lower quartile. Figure 3 View largeDownload slide Reduction of mitral valve annulus diameter after PMVR in FMR and DMR. (A) Significant reduction in MV ap diameter in FMR (P < 0.001). (B) Significant reduction in MV ml diameter in FMR (P = 0.001). (C) Significant reduction in MV ap diameter in DMR (P < 0.001). (D) No significant reduction in MV ml diameter was observed in DMR (P = 0.16). Boxplots are showing the median, the upper and the lower quartile. Figure 3 View largeDownload slide Reduction of mitral valve annulus diameter after PMVR in FMR and DMR. (A) Significant reduction in MV ap diameter in FMR (P < 0.001). (B) Significant reduction in MV ml diameter in FMR (P = 0.001). (C) Significant reduction in MV ap diameter in DMR (P < 0.001). (D) No significant reduction in MV ml diameter was observed in DMR (P = 0.16). Boxplots are showing the median, the upper and the lower quartile. When we categorized our patient collective in two groups according to the number of implanted clips (1–2 clips vs. >2 clips), we found that patients requiring more than two clips were the ones with a larger left ventricular end-diastolic diameter (LVEDD) pre intervention (1–2 clips: 52.9 ± 9.8, more than two clips: 58.0 ± 9.0, P = 0.03, Figure 4A). We also observed a significant correlation between the number of implanted clips and LVEDD pre PMVR (r = 0.19, P = 0.01, Figure 4B) and the severity of MR at baseline (r = 0.21, P = 0.005, Figure 4C). Figure 4 View largeDownload slide Number of implanted clips in relation to LVEDD and MR. (A) Patients were divided into groups depending on the number of implanted clips. If more than two clips were implanted, this group displayed a significantly larger LVEDD (depicted is the median, the upper and the lower quartile P = 0.03). (B) A positive correlation was observed between the number of implanted clips and the LVEDD (r = 0.19, P = 0.01). (C) Furthermore, a significant positive correlation was observed between the number of implanted clips and baseline MR (r = 0.21, P = 0.005). Figure 4 View largeDownload slide Number of implanted clips in relation to LVEDD and MR. (A) Patients were divided into groups depending on the number of implanted clips. If more than two clips were implanted, this group displayed a significantly larger LVEDD (depicted is the median, the upper and the lower quartile P = 0.03). (B) A positive correlation was observed between the number of implanted clips and the LVEDD (r = 0.19, P = 0.01). (C) Furthermore, a significant positive correlation was observed between the number of implanted clips and baseline MR (r = 0.21, P = 0.005). We could demonstrate that the grade of residual MR shows a significant inverse correlation with the reduction in mitral valve annulus ap diameter (r = −0.15, P = 0.04, Figure 5A). Analysis of the reduction in ml diameter showed no significant correlation with residual MR (r = −0.02, P = 0.75, Figure 5B). Importantly, the reduction in MV annulus ap diameter was even more pronounced at follow-up after a mean time of 6.7 ± 1.9 months (31.3 ± 4.9 mm post PMVR, 28.4 ± 5.3 mm at follow-up, P < 0.001, Figure 5C). The mean MR decreased from 3.6 ± 0.5 to 1.2 ± 0.6 and was 1.7 ± 0.5 at follow-up after 6.7 ± 1.9 months (P ≤ 0.001 compared to baseline, Figure 5D). When dividing the study cohort into two groups according to the mitral valve annulus ap diameter post intervention, the group with an ap diameter smaller than 31.8 mm had a significantly smaller MR at follow-up than the group with a larger ap diameter (1.6 ± 0.5 vs. 1.8 ± 0.6, P = 0.01, Figure 5E). Finally, we found a significant positive correlation between MR at follow-up and MV ap diameter at follow-up (r = 0.31, P = 0.005, Figure 5F). Figure 5 View largeDownload slide Procedural outcomes. (A) Negative correlation between residual MR and reduction of mitral valve annulus ap diameter after PMVR (r = −0.15, P = 0.04). (B) For reduction of mitral valve annulus ml diameter, no significant correlation with residual MR was observed (r = −0.02, P = 0.75). (C) Reverse remodelling of the MV annulus with significantly reduced ap diameter at follow-up after 6.7 ± 1.9 months (34.0 ± 4.3 mm pre PMVR, 31.3 ± 4.9 mm post-PMVR, 28.4 ± 5.3 mm at follow-up, P < 0.001. (D) Decrease of mean MR after PMVR and at follow-up (depicted is the median, the upper and the lower quartile P ≤ 0.001 compared to baseline). (E) The group with an ap diameter of smaller than 31.8 mm post-intervention displays a significantly smaller residual MR at follow-up than the group with a larger ap diameter (1.6 ± 0.5 vs. 1.8 ± 0.6, P = 0.01). (F) Significant positive correlation between MR at follow-up and MV ap diameter at follow-up (r = 0.31, P = 0.005). Figure 5 View largeDownload slide Procedural outcomes. (A) Negative correlation between residual MR and reduction of mitral valve annulus ap diameter after PMVR (r = −0.15, P = 0.04). (B) For reduction of mitral valve annulus ml diameter, no significant correlation with residual MR was observed (r = −0.02, P = 0.75). (C) Reverse remodelling of the MV annulus with significantly reduced ap diameter at follow-up after 6.7 ± 1.9 months (34.0 ± 4.3 mm pre PMVR, 31.3 ± 4.9 mm post-PMVR, 28.4 ± 5.3 mm at follow-up, P < 0.001. (D) Decrease of mean MR after PMVR and at follow-up (depicted is the median, the upper and the lower quartile P ≤ 0.001 compared to baseline). (E) The group with an ap diameter of smaller than 31.8 mm post-intervention displays a significantly smaller residual MR at follow-up than the group with a larger ap diameter (1.6 ± 0.5 vs. 1.8 ± 0.6, P = 0.01). (F) Significant positive correlation between MR at follow-up and MV ap diameter at follow-up (r = 0.31, P = 0.005). Discussion The contribution of PMVR to mitral valve annular coaptation is not clear. Here, we describe for the first time in a larger patient collective that i) mitral annulus anterior posterior diameter is reduced and mitral valve coaptation length is enhanced after PMVR using the MitraClip® system and ii) that residual MR significantly correlates with reduction in ap diameter in patients undergoing PMVR. PMVR is a successful treatment option for patients with mitral regurgitation (MR) not eligible for conventional surgery.18 Recently, 5 year data of the EVERST trial confirmed that PMVR more commonly required surgery for residual MR during the first year after treatment, but demonstrated comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy after that period.19 We and others were able to document positive changes in haemodynamics after PMVR with immediate increase of cardiac output.9,20,21 Patients undergoing surgical mitral valve reconstruction are commonly treated with annuloplasty to achieve surgical plication and, thus, tightening of the mitral annulus diameter.22,23 PMVR using the MitraClip® system is considered to reduce MR primarily by reducing mitral valve orifice area, while in-depth knowledge on whether this approach is associated with tightening of the mitral valve annulus is not available in larger patient collectives, so far. In general, the mitral ring is rather flexible and we could document a reduction in mitral annulus diameter in patients ventilated with elevated positive endexspiratory pressure (PEEP) in a preceding study.7 Other previous reports using echocardiographic evaluation of PMVR suggested a reduction of mitral annulus diameter after edge-to-edge repair alone.15,16,24 Our results in a larger cohort of patients undergoing PMVR are in line with these observations, as we observed a significant reduction of the mitral valve annular ap and ml diameter. Significant reductions in mitral valve annulus were measured in FMR and DMR. For DMR, the reduction reached statistical significance only for the ap diameter. Previous studies found a significant reduction in MV annulus diameter in FMR only.15,16,24 The number of patients with DMR in these studies was 36,15 1416 and 24,24 respectively. This might explain the failure to demonstrate significant annulus reduction in those smaller cohorts. In the present study, we were able to demonstrate reduction in mitral valve annulus diameters in a larger cohort of 77 patients with DMR. A possible explanation, why annulus diameter reduction is less in DMR might be that the mitral valve tissue is more rigid and less prone to changes in geometry. Of the 183 patients included in the current study, 67 received 1 clip and 95 received two clips and 21 patients more than two clips. Patients receiving more than 2 clips had a significantly larger LVEDD. There was a significant positive correlation between the number of implanted clips and the baseline LVEDD and with baseline MR. This indicates that patients receiving more clips had a more dilated left ventricle with altered mitral valve geometry resulting in increased severity of MR. There are various approaches to achieve tightening of the mitral valve annulus by interventional techniques. Indirect annuloplasty using the Carrillon Mitral Contour® System (Cardiac Dimensions, Inc., Kirkland, Washington) needs an internal jugular vein access to place a device for narrowing the annular circumference within the coronary sinus.25 Furthermore, interventional devices such as the CardioBand® System (Valtech Cardio, Or Yehuda, Israel) imitating the surgical approach are developed and have been applied in early phase clinical trials.26 Currently, there is an ongoing and not conclusively resolved debate about the question, whether devices mediating tightening of the mitral valve annulus should be applied in addition or as pretreatment to PMVR using the MitraClip® system. Our study adds further important aspects to this discussion, as a reduction of ap diameter, which embodies one central aspect modulating mitral annular architecture, could be achieved with the MitraClip® system. Future prospective studies are needed to clarify the question of how many clips are needed for an optimal result and to define precise parameters when to choose to implant more than one clip. Study limitations This study has several limitations. One of the main limitations is the lack of a core laboratory for echocardiographic evaluation, although we calculated good inter-observer correlation. Furthermore, we cannot entirely rule out an influence of intraprocedural fluctuations of haemodynamics on mitral annular anatomy. We did not evaluate changes in mitral valve geometry over the complete heart cycle. All measurements of heart geometry were done at end-systole to obtain comparable results. We have to acknowledge the limited sample size, although this is—to our knowledge—the largest trial on mitral annular anatomy after PMVR, and given the complexity of the procedure, the patient number appeared reasonable to draw conclusions of potential clinical relevance. Nevertheless, while we demonstrate a reduction of mitral valve ap diameter associated with residual MR, future randomized studies will have to scrutinize the question, whether and in which chronology PMVR using the MitraClip® system should be combined with further interventional approaches to improve leaflet coaptation at the mitral annulus level. Volume 3D-imaging may provide more accurate image plane selection for measurements and may allow more specific annulus measurements such as MV area or circumference. Conclusions Here, we assessed whether PMVR with the MitraClip® system achieves tightening of the mitral valve annulus. We observed reduced mitral valve annulus diameter upon PMVR treatment associated with increased leaflet coaptation. Importantly, this diameter reduction was inversely correlated with residual MR. Thus, PMVR has effects on mitral valve annulus geometry and reduction of ap diameter may represent an important parameter to evaluate the success of the PMVR procedure. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements This study was supported by grants from the German research foundation (KFO 274), the Volkswagen foundation (Lichtenberg program) and the German Heart foundation. J. Schreieck has received speaker fees from Medtronic and St. Jude Medical. H.F. Langer and P. Seizer were reimbursed for training courses by Abbott Vascular. Funding This study was supported by grants from the German Research Foundation (KFO 274), the Volkswagen Foundation (Lichtenberg program) and the German Heart Foundation. Conflict of interest: J. Schreieck has received speaker fees from Medtronic and St. Jude Medical. H.F.L. was reimbursed for training courses by Abbott Vascular. References 1 Alfieri O , Maisano F , De Bonis M , Stefano PL , Torracca L , Oppizzi M et al. The double-orifice technique in mitral valve repair: a simple solution for complex problems . J Thorac Cardiovasc Surg 2001 ; 122 : 674 – 81 . Google Scholar CrossRef Search ADS PubMed 2 De Bonis M , Lapenna E , Lorusso R , Buzzatti N , Gelsomino S , Taramasso M et al. Very long-term results (up to 17 years) with the double-orifice mitral valve repair combined with ring annuloplasty for degenerative mitral regurgitation . J Thorac Cardiovasc Surg 2012 ; 144 : 1019 – 24 . Google Scholar CrossRef Search ADS PubMed 3 Maisano F , Caldarola A , Blasio A , De Bonis M , La Canna G , Alfieri O. Midterm results of edge-to-edge mitral valve repair without annuloplasty . J Thorac Cardiovasc Surg 2003 ; 126 : 1987 – 97 . Google Scholar CrossRef Search ADS PubMed 4 Oury JH , Peterson KL , Folkerth TL , Daily PO. Mitral valve replacement versus reconstruction. An analysis of indications and results of mitral valve procedures in a consecutive series of 80 patients . J Thorac Cardiovasc Surg 1977 ; 73 : 825 – 35 . Google Scholar PubMed 5 Goldstein D , Moskowitz AJ , Gelijns AC , Ailawadi G , Parides MK , Perrault LP et al. Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation . N Engl J Med 2016 ; 374 : 344 – 53 . Google Scholar CrossRef Search ADS PubMed 6 Nashef SA , Roques F , Michel P , Gauducheau E , Lemeshow S , Salamon R. European system for cardiac operative risk evaluation (EuroSCORE) . Eur J Cardiothorac Surg 1999 ; 16 : 9 – 13 . Google Scholar CrossRef Search ADS PubMed 7 Patzelt J , Zhang Y , Seizer P , Magunia H , Henning A , Riemlova V et al. Effects of mechanical ventilation on heart geometry and mitral valve leaflet coaptation during percutaneous edge-to-edge mitral valve repair . JACC Cardiovasc Interv 2015 ; 9 : 151 – 59 . Google Scholar CrossRef Search ADS PubMed 8 Patzelt J , Seizer P , Zhang YY , Walker T , Schreieck J , Gawaz M et al. Percutaneous mitral valve edge-to-edge repair with simultaneous biatrial intracardiac echocardiography: first-in-human experience . Circulation 2016 ; 133 : 1517 – 9 . Google Scholar CrossRef Search ADS PubMed 9 Patzelt J , Zhang Y , Magunia H , Jorbenadze R , Droppa M , Ulrich M et al. Immediate increase of cardiac output after percutaneous mitral valve repair (PMVR) determined by echocardiographic and invasive parameters: Patzelt: increase of cardiac output after PMVR . Int J Cardiol 2017 ; 236 : 356 – 62 . Google Scholar CrossRef Search ADS PubMed 10 Patzelt J , Zhang Y , Seizer P , Magunia H , Henning A , Riemlova V et al. Effects of mechanical ventilation on heart geometry and mitral valve leaflet coaptation during percutaneous edge-to-edge mitral valve repair . JACC Cardiovasc Interv 2016 ; 9 : 151 – 9 . Google Scholar CrossRef Search ADS PubMed 11 Lancellotti P , Moura L , Pierard LA , Agricola E , Popescu BA , Tribouilloy C et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease) . Eur J Echocardiogr 2010 ; 11 : 307 – 32 . Google Scholar CrossRef Search ADS PubMed 12 Foster E , Wasserman HS , Gray W , Homma S , Di Tullio MR , Rodriguez L et al. Quantitative assessment of severity of mitral regurgitation by serial echocardiography in a multicenter clinical trial of percutaneous mitral valve repair . Am J Cardiol 2007 ; 100 : 1577 – 83 . Google Scholar CrossRef Search ADS PubMed 13 Lee AP , Hsiung MC , Salgo IS , Fang F , Xie JM , Zhang YC et al. Quantitative analysis of mitral valve morphology in mitral valve prolapse with real-time 3-dimensional echocardiography: importance of annular saddle shape in the pathogenesis of mitral regurgitation . Circulation 2013 ; 127 : 832 – 41 . Google Scholar CrossRef Search ADS PubMed 14 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 15 Schueler R , Momcilovic D , Weber M , Welz A , Werner N , Mueller C et al. Acute changes of mitral valve geometry during interventional edge-to-edge repair with the MitraClip system are associated with midterm outcomes in patients with functional valve disease: preliminary results from a prospective single-center study . Circ Cardiovasc Interv 2014 ; 7 : 390 – 9 . Google Scholar CrossRef Search ADS PubMed 16 Schmidt FP , von Bardeleben RS , Nikolai P , Jabs A , Wunderlich N , Munzel T et al. Immediate effect of the MitraClip procedure on mitral ring geometry in primary and secondary mitral regurgitation . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 851 – 7 . Google Scholar CrossRef Search ADS PubMed 17 Horn P , Hellhammer K , Minier M , Stenzel MA , Veulemans V , Rassaf T et al. Deep sedation vs. general anesthesia in 232 patients undergoing percutaneous mitral valve repair using the MitraClip(R) system . Catheter Cardiovasc Interv 2017 ; doi:10.1002/ccd.26884. 18 Feldman T , Foster E , Glower DD , Kar S , Rinaldi MJ , Fail PS et al. Percutaneous repair or surgery for mitral regurgitation . N Engl J Med 2011 ; 364 : 1395 – 406 . Google Scholar CrossRef Search ADS PubMed 19 Feldman T , Kar S , Elmariah S , Smart SC , Trento A , Siegel RJ et al. Randomized comparison of percutaneous repair and surgery for mitral regurgitation: 5-year results of EVEREST II . J Am Coll Cardiol 2015 ; 66 : 2844 – 54 . Google Scholar CrossRef Search ADS PubMed 20 Gaemperli O , Biaggi P , Gugelmann R , Osranek M , Schreuder JJ , Buhler I et al. Real-time left ventricular pressure-volume loops during percutaneous mitral valve repair with the MitraClip system . Circulation 2013 ; 127 : 1018 – 27 . Google Scholar CrossRef Search ADS PubMed 21 Siegel RJ , Biner S , Rafique AM , Rinaldi M , Lim S , Fail P et al. The acute hemodynamic effects of MitraClip therapy . J Am Coll Cardiol 2011 ; 57 : 1658 – 65 . Google Scholar CrossRef Search ADS PubMed 22 Burr LH , Krayenbuhl C , Sutton MS. The mitral plication suture: a new technique of mitral valve repair . J Thorac Cardiovasc Surg 1977 ; 73 : 589 – 95 . Google Scholar PubMed 23 Enriquez-Sarano M , Schaff HV , Orszulak TA , Tajik AJ , Bailey KR , Frye RL. Valve repair improves the outcome of surgery for mitral regurgitation. A multivariate analysis . Circulation 1995 ; 91 : 1022 – 8 . Google Scholar CrossRef Search ADS PubMed 24 Schueler R , Kaplan S , Melzer C , Ozturk C , Weber M , Sinning JM et al. Impact of interventional edge-to-edge repair on mitral valve geometry . Int J Cardiol 2017 ; 230 : 468 – 75 . Google Scholar CrossRef Search ADS PubMed 25 Schofer J , Siminiak T , Haude M , Herrman JP , Vainer J , Wu JC et al. Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study . Circulation 2009 ; 120 : 326 – 33 . Google Scholar CrossRef Search ADS PubMed 26 Maisano F , Taramasso M , Nickenig G , Hammerstingl C , Vahanian A , Messika-Zeitoun D et al. Cardioband, a transcatheter surgical-like direct mitral valve annuloplasty system: early results of the feasibility trial . Eur Heart J 2016 ; 37 : 817 – 25 . 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

Improved mitral valve coaptation and reduced mitral valve annular size after percutaneous mitral valve repair (PMVR) using the MitraClip system

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Oxford University Press
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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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2047-2404
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10.1093/ehjci/jex173
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Abstract

Abstract Aims Improved mitral valve leaflet coaptation with consecutive reduction of mitral regurgitation (MR) is a central goal of percutaneous mitral valve repair (PMVR) with the MitraClip® system. As influences of PMVR on mitral valve geometry have been suggested before, we examined the effect of the procedure on mitral annular size in relation to procedural outcome. Methods and results Geometry of the mitral valve annulus was evaluated in 183 patients undergoing PMVR using echocardiography before and after the procedure and at follow-up. Mitral valve annular anterior–posterior (ap) diameter decreased from 34.0 ± 4.3 to 31.3 ± 4.9 mm (P < 0.001), and medio-lateral (ml) diameter from 33.2 ± 4.8 to 32.4 ± 4.9 mm (P < 0.001). Accordingly, we observed an increase in MV leaflet coaptation after PMVR. The reduction of mitral valve ap diameter showed a significant inverse correlation with residual MR. Importantly, the reduction of mitral valve ap diameter persisted at follow-up (31.3 ± 4.9 mm post PMVR, 28.4 ± 5.3 mm at follow-up). Conclusion This study demonstrates mechanical approximation of both mitral valve annulus edges with improved mitral valve annular coaptation by PMVR using the MitraClip® system, which correlates with residual MR in patients with MR. percutaneous mitral valve repair, mitral regurgitation, MitraClip®, mitral valve annulus diameter, mitral valve coaptation, echocardiography Introduction When classical surgical reconstruction techniques for mitral valve repair are applied, a major goal is stabilization [in degenerative mitral regurgitation (MR)] or reduction (in functional MR) of the mitral valve annulus diameter via annuloplasty in addition to reconstruction of the mitral valve leaflets. This approach was introduced by Carpentier in the 1960s using an annuloplasty ring. With respect to interventional mitral valve reconstruction, there are different principles. At the moment, five percutaneous systems exist for mitral valve repair. Four of those (the CardioBand® system, the Carillon® System, the Mitralign® system, and the Accucinch® device) aim to reduce the mitral annulus diameter via insertion of annuloplasty devices. The most often used device however, the MitraClip® system, is emulating the surgical technique of Alfieri, for which an edge-to-edge suture of both mitral valve leaflets creates a double orifice.1 Several studies using surgical techniques have described favourable results as well after edge-to-edge repair alone as after edge-to-edge repair in combination with annuloplasty.2,3 The initial surgical technique for mitral valve repair encompassed resection of superfluous leaflet material. Over time it was, however, discovered that additional tightening of the mitral annulus via insertion of a annuloplasty ring led to better long term results with lesser recurrence of MR, than reconstruction of the leaflets alone.4 Recently, a study reported a high recurrence rate of MR despite annuloplasty in patients with ischaemic MR.5 While ring-annuloplasty is part of most surgically performed mitral valve repair operations and its benefit is generally acknowledged, it is not clear, whether this also holds true for interventional mitral valve repair and if interventional annuloplasty should be combined with edge-to-edge repair using the MitraClip® system. This study was carried out to determine, whether percutaneous mitral valve repair (PMVR) using the MitraClip® system can per se achieve reduction in mitral valve annular diameter—one of the main goals of surgical mitral valve repair—and whether this is associated with procedural success. Methods Study population In this study, we included 183 patients with grade 2+ to 4 MR, who underwent PMVR using the MitraClip® system (Abbott Vascular) at the University hospital, Department of Cardiology and Cardiovascular Medicine, University of Tuebingen between May 2014 and July 2016. Echocardiograms acquired after induction of anaesthesia at the beginning and at the end of the PMVR procedure and at follow-up after a mean time of 6.7 ± 1.9 months were analysed. Clinical follow-up data of 151 of 183 patients (82.5%) were available. The study was approved by the local ethics committee (260/2015R). The decision for treatment by PMVR had been made by an interdisciplinary team of interventional cardiologists and cardiac surgeons based on either the EuroSCORE6 or on the presence of specific surgical risk factors not covered in the EuroSCORE. Exclusion criteria for PMVR were as previously described.7 Heart failure patients had to be on optimal medical treatment according to current guidelines for at least 3 months prior to PMVR treatment. PMVR procedure The procedure was carried out either in general anaesthesia or in deep sedation, generally as described before.8–10 Echocardiographic assessment Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) measurements were obtained in the heart catheter laboratory after induction of general anaesthesia or deep sedation, respectively. Furthermore, TTE and TEE were evaluated again at follow-up (mean: 6.7 ± 1.9 months). For echocardiography, we used a Philips CX 50 or iE 33 machine (Philips HealthCare, Hamburg, Germany). All echocardiographic parameters were assessed at the beginning and at the end of the PMVR procedure and at follow-up. For the measurements pre PMVR, general anaesthesia or deep sedation were already in a steady state. Arterial blood pressure was kept within normal ranges in both the deep sedation and the general anaesthesia group using catecholamines and intravenous volume supplementation when necessary. The second measurements at the end of the procedure were carried out before general anaesthesia or deep sedation were ended. MR severity and the etiology of regurgitation were determined according to the current European Association of Echocardiography guidelines, MR pre-intervention, MR post-intervention and MR at follow-up was assessed using the technique described by Foster et al. and by TEE.11,12 3D TEE using the simultaneous biplane mode was applied to evaluate mitral valve geometry. The intercomissural medio-lateral (ml) view of the mitral valve was obtained in a mid-esophageal view at 50–70° with visualization of both papillary muscle heads. Then, using a simultaneous biplane mode a second plane was generated orthogonally to the first plane in the centre of the A2 segment allowing for evaluation of the maximum anterior-posterior diameter of the mitral valve. All echocardiographic loops were recorded. Mitral valve annulus diameter in medio-lateral and anterior-posterior (ap) dimension was measured in the respective views at end-systole (Figure 1A). 3 additional investigators blinded to the results repeated measurements using the Centricity Enterprise Web 3.0 software (GE medical systems, 540 West Northwest Highway, Barrington IL, USA). The mean of measurements was calculated and reported as final value. Coaptation length pre intervention was measured in the anterior-posterior view also used for clip positioning. Using simultaneous biplane mode, this view was generated in a plane exactly in the centre of the A2 segment of the intercomissural view. Post intervention, coaptation length was calculated using echo-loops of the grasping maneuver: The length of the visible part (outside the clip) of a leaflet was subtracted from the length of the respective leaflet before the grasping maneuver in a recorded loop. The mean of this difference for anterior mitral leaflet (AML) and posterior mitral leaflet (PML) is reported as the final value. When more than one clip was implanted, this procedure was performed for each single clip and the mean of the single measurements was calculated as final value. Moreover, mitral valve ellipticity was calculated, defined as mitral valve anterior-posterior diameter divided by the medio-lateral diameter.13 Furthermore, we performed a parametric 3D quantification of the mitral valve annulus in a subset of 20 patients using the Philips Qlab 9.0 software (MVQ software) in zoomed 3D views of the mitral valve. Quantification was carried out in the end-systolic frame. Figure 1 View largeDownload slide Changes of mitral valve geometry caused by PMVR. (A) Schematic view of changes in mitral valve annulus diameter during PMVR. (1) Severe MR with baseline MV annulus ap diameter (2) after clip placement, MR and annulus ap diameter are reduced. Coaptation increases. (3) Sample TEE picture of midesophageal view with measurement of mitral valve annulus. White arrow indicates MitraClip®. (B) Mitral valve leaflet coaptation before and after PMVR was assessed. We observed a significant increase of MV coaptation length after PMVR (depicted is the median, the upper and the lower quartile, P < 0.001). (C) Haemodynamic parameters such as increase in cardiac output (CO) were comparable in patients undergoing deep sedation or general anaesthesia (depicted is the median, the upper and the lower quartile). n.s., no significant difference regarding change in CO after PMVR between the two groups. Figure 1 View largeDownload slide Changes of mitral valve geometry caused by PMVR. (A) Schematic view of changes in mitral valve annulus diameter during PMVR. (1) Severe MR with baseline MV annulus ap diameter (2) after clip placement, MR and annulus ap diameter are reduced. Coaptation increases. (3) Sample TEE picture of midesophageal view with measurement of mitral valve annulus. White arrow indicates MitraClip®. (B) Mitral valve leaflet coaptation before and after PMVR was assessed. We observed a significant increase of MV coaptation length after PMVR (depicted is the median, the upper and the lower quartile, P < 0.001). (C) Haemodynamic parameters such as increase in cardiac output (CO) were comparable in patients undergoing deep sedation or general anaesthesia (depicted is the median, the upper and the lower quartile). n.s., no significant difference regarding change in CO after PMVR between the two groups. Statistical analysis Statistical analysis was performed with SPSS (version 24, IBM Deutschland GmbH, Ehningen, Germany). Categorical variables are shown as absolute numbers or as percentage, continuous variables as means ± standard deviation (SD). Normal distribution of variables was tested using the Shapiro–Wilk test. For normally distributed data, paired t-Test was used to compare means. For not normally distributed data the Wilcoxon log rank test was used to compare means. The two-tailed P-values were calculated and a value of P < 0.05 was considered statistically significant. Echocardiographic views were assessed by four independent investigators, three of whom were blinded to the results. To evaluate reproducibility of echocardiographic measurements, the intra-class correlation coefficient for absolute agreement was used, with good agreement defined as ≥0.80. For the assessment of intra-observer reliability, 20 randomly chosen patients were analysed by 1 investigator twice. Absolute agreement among the observations was calculated using intraclass correlation coefficient analysis. To compare agreement of 2D (simultaneous biplane mode) and 3D (parametric 3D quantification) measurements, Bland Altman analysis was used.14 Results Baseline characteristics for all patients are depicted in Table 1. Functional NYHA class III–IV was present in the majority of patients, and there was a high percentage of patients with severely reduced (<35% ejection fraction) LV-function. 57.9% of patients had functional MR (FMR) and 42.1% had degenerative MR (DMR). Coronary artery disease was previously diagnosed in 73.2% of the patients, 67.8% had atrial fibrillation and 45.4% renal insufficiency. MitraClip® was implanted in all 183 patients, all of whom had moderate to severe or severe (2+ to 4) MR at baseline. All patients had successful clip implantation. MR reduction of at least 2 grades was achieved in 180 of the patients (98.4%). There was no difference in the proportion of patients achieving MR severity ≤2+ for patients with DMR or FMR. Table 1 Baseline patient characteristics (n = 183) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) NYHA, New York Heart Association; LVEDD, left ventricular end-diastolic diameter; MR, mitral regurgitation; ACE, angiotensine converting enzyme. * Definitions as used for EuroScore II. Table 1 Baseline patient characteristics (n = 183) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) Age 76.0 (38–90) Male gender 105 (57.4%) Coronary heart disease 134 (73.2%) Atrial fibrillation 124 (67.8%) Hypertension 133 (72.7%) Smoker 39 (21.3%) Hyperlipoproteinaemia 90 (49.2%) Diabetes 56 (30.1%) NYHA-class 3.2 (2 to 4) *Renal impairment 83 (45.4%) *Pulmonary hypertension 122 (66.7%) Euroscore II 12.9 (1 to 62) LVEDD 54.1 ± 9.6 mm LV Function  ≤35% 94 (51.4%)  36–50% 44 (24.0%)  >50% 45 (24.6%) Etiology of MR  Functional 106 (57.9%)  Degenerative 77 (42.1%)  Betablockers 165 (90.2%)  Aldosteronantagonist 95 (51.9%)  AT1 inhibitors 154 (84.2%)  Diuretics 165 (90.2%)  Digitalis 19 (10.4%)  Calcium antagonists 24 (13.1%)  Anticoagulation 126 (68.9%)  General anaesthesia 69 (37.7%)  Deep sedation 114 (62.3%) No. of implanted clips  1 67 (36.6%)  2 95 (51.9%)  3 20 (10.9%)  4 1 (0.5%) NYHA, New York Heart Association; LVEDD, left ventricular end-diastolic diameter; MR, mitral regurgitation; ACE, angiotensine converting enzyme. * Definitions as used for EuroScore II. PMVR using the MitraClip® system causes changes in heart geometry associated with MR reduction.15,16,Figure 1A gives a schematic overview of the expected changes achieved by PMVR. By coaptation of the anterior and posterior leaflet of the mitral valve with increase in coaptation length, a reduction of mitral valve annulus size is accomplished and thereby MR is reduced. After clip implantation, we observed a significant increase in mitral valve coaptation length from 3.4 ± 1.0 to 8.4 ± 1.4 mm (P < 0.001, Figure 1B). Echocardiographic measurements were checked for inter- and intra-observer reliability as described in the methods section (Table 2). PMVR procedures are increasingly carried out under conscious sedation.17 Thus, clinical studies have to take any effects on haemodynamics into consideration. Here, we observed, however, no difference in haemodynamic parameters such as increase in cardiac output (CO) between patients treated in general anaesthesia (0.9 ± 1.4 L/min) vs. deep sedation (0.7 ± 1.2 L/min, P = 0.24, Figure 1C). In line with our observation of increased leaflet coaptation after clip implantation, we measured a reduction of mitral valve annulus diameter in ap dimension (from 34.0 ± 4.3 to 31.3 ± 4.9, P < 0.001, Figure 2A) and in ml dimension (from 33.2 ± 4.8 to 32.4 ± 4.9 mm, P < 0.001, Figure 2B). Interestingly, mitral valve ellipticity (defined as mitral valve anterior–posterior diameter divided by the medio-lateral diameter) decreased significantly from 1.03 ± 0.16 to 0.98 ± 0.17 (P ≤ 0.001, Figure 2C). To evaluate the agreement of this biplane imaging method with volume 3D-imaging, we performed a parametric quantification of the mitral valve annulus in a subset of 20 patients. Zoomed 3D views of the mitral valve before and after the clip deployment were analysed in end-systole (see Supplementary data online, Figure S1A). Bland Altman analysis showed good agreement of the two modes of analysis (mean difference 0.03 mm, 95% limits of agreement ± 7.1 mm, Supplementary data online, Figure S1B). A significant reduction in mitral valve annulus ap diameter was observed in subgroups of functional MR (FMR, from 34.9 ± 3.9 to 32.1 ± 4.7 mm, P < 0.001, Figure 3A) and degenerative MR (DMR, from 32.7 ± 4.5 to 30.3 ± 4.9 mm, P < 0.001, Figure 3C). This reduction was more pronounced in FMR than in DMR. The reduction in ml diameter was significant in FMR (from 33.8 ± 4.3 to 32.8 ± 4.5, P = 0.001, Figure 3B), however not in DMR (from 32.3± 5.4 to 31.8 ± 5.5, P = 0.16, Figure 3D). Table 2 Intraclass correlations for interobserver and intraobserver agreement of echocardiographic measurements Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 MV, mitral valve; ap, anterior-posterior; ml, medio-lateral. Table 2 Intraclass correlations for interobserver and intraobserver agreement of echocardiographic measurements Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 Interobserver agreement P-value Intraobserver agreement P-value MV ap diameter pre 0.85 <0.001 0.76 <0.001 MV ap diameter post 0.96 <0.001 0.82 <0.001 MV ml diameter pre 0.90 <0.001 0.89 <0.001 MV ml diameter post 0.78 <0.001 0.90 <0.001 MV, mitral valve; ap, anterior-posterior; ml, medio-lateral. Figure 2 View largeDownload slide Changes in mitral valve geometry after PMVR. (A) Reduction of mitral valve annulus ap diameter (P < 0.001). (B) Reduction of mitral valve annulus ml diameter (P < 0.001). (C) Mitral valve ellipticity was calculated. We observed a reduction of mitral valve ellipticity (P ≤ 0.001). Boxplots are showing the median, the upper and the lower quartile. Figure 2 View largeDownload slide Changes in mitral valve geometry after PMVR. (A) Reduction of mitral valve annulus ap diameter (P < 0.001). (B) Reduction of mitral valve annulus ml diameter (P < 0.001). (C) Mitral valve ellipticity was calculated. We observed a reduction of mitral valve ellipticity (P ≤ 0.001). Boxplots are showing the median, the upper and the lower quartile. Figure 3 View largeDownload slide Reduction of mitral valve annulus diameter after PMVR in FMR and DMR. (A) Significant reduction in MV ap diameter in FMR (P < 0.001). (B) Significant reduction in MV ml diameter in FMR (P = 0.001). (C) Significant reduction in MV ap diameter in DMR (P < 0.001). (D) No significant reduction in MV ml diameter was observed in DMR (P = 0.16). Boxplots are showing the median, the upper and the lower quartile. Figure 3 View largeDownload slide Reduction of mitral valve annulus diameter after PMVR in FMR and DMR. (A) Significant reduction in MV ap diameter in FMR (P < 0.001). (B) Significant reduction in MV ml diameter in FMR (P = 0.001). (C) Significant reduction in MV ap diameter in DMR (P < 0.001). (D) No significant reduction in MV ml diameter was observed in DMR (P = 0.16). Boxplots are showing the median, the upper and the lower quartile. When we categorized our patient collective in two groups according to the number of implanted clips (1–2 clips vs. >2 clips), we found that patients requiring more than two clips were the ones with a larger left ventricular end-diastolic diameter (LVEDD) pre intervention (1–2 clips: 52.9 ± 9.8, more than two clips: 58.0 ± 9.0, P = 0.03, Figure 4A). We also observed a significant correlation between the number of implanted clips and LVEDD pre PMVR (r = 0.19, P = 0.01, Figure 4B) and the severity of MR at baseline (r = 0.21, P = 0.005, Figure 4C). Figure 4 View largeDownload slide Number of implanted clips in relation to LVEDD and MR. (A) Patients were divided into groups depending on the number of implanted clips. If more than two clips were implanted, this group displayed a significantly larger LVEDD (depicted is the median, the upper and the lower quartile P = 0.03). (B) A positive correlation was observed between the number of implanted clips and the LVEDD (r = 0.19, P = 0.01). (C) Furthermore, a significant positive correlation was observed between the number of implanted clips and baseline MR (r = 0.21, P = 0.005). Figure 4 View largeDownload slide Number of implanted clips in relation to LVEDD and MR. (A) Patients were divided into groups depending on the number of implanted clips. If more than two clips were implanted, this group displayed a significantly larger LVEDD (depicted is the median, the upper and the lower quartile P = 0.03). (B) A positive correlation was observed between the number of implanted clips and the LVEDD (r = 0.19, P = 0.01). (C) Furthermore, a significant positive correlation was observed between the number of implanted clips and baseline MR (r = 0.21, P = 0.005). We could demonstrate that the grade of residual MR shows a significant inverse correlation with the reduction in mitral valve annulus ap diameter (r = −0.15, P = 0.04, Figure 5A). Analysis of the reduction in ml diameter showed no significant correlation with residual MR (r = −0.02, P = 0.75, Figure 5B). Importantly, the reduction in MV annulus ap diameter was even more pronounced at follow-up after a mean time of 6.7 ± 1.9 months (31.3 ± 4.9 mm post PMVR, 28.4 ± 5.3 mm at follow-up, P < 0.001, Figure 5C). The mean MR decreased from 3.6 ± 0.5 to 1.2 ± 0.6 and was 1.7 ± 0.5 at follow-up after 6.7 ± 1.9 months (P ≤ 0.001 compared to baseline, Figure 5D). When dividing the study cohort into two groups according to the mitral valve annulus ap diameter post intervention, the group with an ap diameter smaller than 31.8 mm had a significantly smaller MR at follow-up than the group with a larger ap diameter (1.6 ± 0.5 vs. 1.8 ± 0.6, P = 0.01, Figure 5E). Finally, we found a significant positive correlation between MR at follow-up and MV ap diameter at follow-up (r = 0.31, P = 0.005, Figure 5F). Figure 5 View largeDownload slide Procedural outcomes. (A) Negative correlation between residual MR and reduction of mitral valve annulus ap diameter after PMVR (r = −0.15, P = 0.04). (B) For reduction of mitral valve annulus ml diameter, no significant correlation with residual MR was observed (r = −0.02, P = 0.75). (C) Reverse remodelling of the MV annulus with significantly reduced ap diameter at follow-up after 6.7 ± 1.9 months (34.0 ± 4.3 mm pre PMVR, 31.3 ± 4.9 mm post-PMVR, 28.4 ± 5.3 mm at follow-up, P < 0.001. (D) Decrease of mean MR after PMVR and at follow-up (depicted is the median, the upper and the lower quartile P ≤ 0.001 compared to baseline). (E) The group with an ap diameter of smaller than 31.8 mm post-intervention displays a significantly smaller residual MR at follow-up than the group with a larger ap diameter (1.6 ± 0.5 vs. 1.8 ± 0.6, P = 0.01). (F) Significant positive correlation between MR at follow-up and MV ap diameter at follow-up (r = 0.31, P = 0.005). Figure 5 View largeDownload slide Procedural outcomes. (A) Negative correlation between residual MR and reduction of mitral valve annulus ap diameter after PMVR (r = −0.15, P = 0.04). (B) For reduction of mitral valve annulus ml diameter, no significant correlation with residual MR was observed (r = −0.02, P = 0.75). (C) Reverse remodelling of the MV annulus with significantly reduced ap diameter at follow-up after 6.7 ± 1.9 months (34.0 ± 4.3 mm pre PMVR, 31.3 ± 4.9 mm post-PMVR, 28.4 ± 5.3 mm at follow-up, P < 0.001. (D) Decrease of mean MR after PMVR and at follow-up (depicted is the median, the upper and the lower quartile P ≤ 0.001 compared to baseline). (E) The group with an ap diameter of smaller than 31.8 mm post-intervention displays a significantly smaller residual MR at follow-up than the group with a larger ap diameter (1.6 ± 0.5 vs. 1.8 ± 0.6, P = 0.01). (F) Significant positive correlation between MR at follow-up and MV ap diameter at follow-up (r = 0.31, P = 0.005). Discussion The contribution of PMVR to mitral valve annular coaptation is not clear. Here, we describe for the first time in a larger patient collective that i) mitral annulus anterior posterior diameter is reduced and mitral valve coaptation length is enhanced after PMVR using the MitraClip® system and ii) that residual MR significantly correlates with reduction in ap diameter in patients undergoing PMVR. PMVR is a successful treatment option for patients with mitral regurgitation (MR) not eligible for conventional surgery.18 Recently, 5 year data of the EVERST trial confirmed that PMVR more commonly required surgery for residual MR during the first year after treatment, but demonstrated comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy after that period.19 We and others were able to document positive changes in haemodynamics after PMVR with immediate increase of cardiac output.9,20,21 Patients undergoing surgical mitral valve reconstruction are commonly treated with annuloplasty to achieve surgical plication and, thus, tightening of the mitral annulus diameter.22,23 PMVR using the MitraClip® system is considered to reduce MR primarily by reducing mitral valve orifice area, while in-depth knowledge on whether this approach is associated with tightening of the mitral valve annulus is not available in larger patient collectives, so far. In general, the mitral ring is rather flexible and we could document a reduction in mitral annulus diameter in patients ventilated with elevated positive endexspiratory pressure (PEEP) in a preceding study.7 Other previous reports using echocardiographic evaluation of PMVR suggested a reduction of mitral annulus diameter after edge-to-edge repair alone.15,16,24 Our results in a larger cohort of patients undergoing PMVR are in line with these observations, as we observed a significant reduction of the mitral valve annular ap and ml diameter. Significant reductions in mitral valve annulus were measured in FMR and DMR. For DMR, the reduction reached statistical significance only for the ap diameter. Previous studies found a significant reduction in MV annulus diameter in FMR only.15,16,24 The number of patients with DMR in these studies was 36,15 1416 and 24,24 respectively. This might explain the failure to demonstrate significant annulus reduction in those smaller cohorts. In the present study, we were able to demonstrate reduction in mitral valve annulus diameters in a larger cohort of 77 patients with DMR. A possible explanation, why annulus diameter reduction is less in DMR might be that the mitral valve tissue is more rigid and less prone to changes in geometry. Of the 183 patients included in the current study, 67 received 1 clip and 95 received two clips and 21 patients more than two clips. Patients receiving more than 2 clips had a significantly larger LVEDD. There was a significant positive correlation between the number of implanted clips and the baseline LVEDD and with baseline MR. This indicates that patients receiving more clips had a more dilated left ventricle with altered mitral valve geometry resulting in increased severity of MR. There are various approaches to achieve tightening of the mitral valve annulus by interventional techniques. Indirect annuloplasty using the Carrillon Mitral Contour® System (Cardiac Dimensions, Inc., Kirkland, Washington) needs an internal jugular vein access to place a device for narrowing the annular circumference within the coronary sinus.25 Furthermore, interventional devices such as the CardioBand® System (Valtech Cardio, Or Yehuda, Israel) imitating the surgical approach are developed and have been applied in early phase clinical trials.26 Currently, there is an ongoing and not conclusively resolved debate about the question, whether devices mediating tightening of the mitral valve annulus should be applied in addition or as pretreatment to PMVR using the MitraClip® system. Our study adds further important aspects to this discussion, as a reduction of ap diameter, which embodies one central aspect modulating mitral annular architecture, could be achieved with the MitraClip® system. Future prospective studies are needed to clarify the question of how many clips are needed for an optimal result and to define precise parameters when to choose to implant more than one clip. Study limitations This study has several limitations. One of the main limitations is the lack of a core laboratory for echocardiographic evaluation, although we calculated good inter-observer correlation. Furthermore, we cannot entirely rule out an influence of intraprocedural fluctuations of haemodynamics on mitral annular anatomy. We did not evaluate changes in mitral valve geometry over the complete heart cycle. All measurements of heart geometry were done at end-systole to obtain comparable results. We have to acknowledge the limited sample size, although this is—to our knowledge—the largest trial on mitral annular anatomy after PMVR, and given the complexity of the procedure, the patient number appeared reasonable to draw conclusions of potential clinical relevance. Nevertheless, while we demonstrate a reduction of mitral valve ap diameter associated with residual MR, future randomized studies will have to scrutinize the question, whether and in which chronology PMVR using the MitraClip® system should be combined with further interventional approaches to improve leaflet coaptation at the mitral annulus level. Volume 3D-imaging may provide more accurate image plane selection for measurements and may allow more specific annulus measurements such as MV area or circumference. Conclusions Here, we assessed whether PMVR with the MitraClip® system achieves tightening of the mitral valve annulus. We observed reduced mitral valve annulus diameter upon PMVR treatment associated with increased leaflet coaptation. Importantly, this diameter reduction was inversely correlated with residual MR. Thus, PMVR has effects on mitral valve annulus geometry and reduction of ap diameter may represent an important parameter to evaluate the success of the PMVR procedure. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Acknowledgements This study was supported by grants from the German research foundation (KFO 274), the Volkswagen foundation (Lichtenberg program) and the German Heart foundation. J. Schreieck has received speaker fees from Medtronic and St. Jude Medical. H.F. Langer and P. Seizer were reimbursed for training courses by Abbott Vascular. Funding This study was supported by grants from the German Research Foundation (KFO 274), the Volkswagen Foundation (Lichtenberg program) and the German Heart Foundation. Conflict of interest: J. Schreieck has received speaker fees from Medtronic and St. Jude Medical. H.F.L. was reimbursed for training courses by Abbott Vascular. References 1 Alfieri O , Maisano F , De Bonis M , Stefano PL , Torracca L , Oppizzi M et al. The double-orifice technique in mitral valve repair: a simple solution for complex problems . 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Percutaneous mitral valve edge-to-edge repair with simultaneous biatrial intracardiac echocardiography: first-in-human experience . Circulation 2016 ; 133 : 1517 – 9 . Google Scholar CrossRef Search ADS PubMed 9 Patzelt J , Zhang Y , Magunia H , Jorbenadze R , Droppa M , Ulrich M et al. Immediate increase of cardiac output after percutaneous mitral valve repair (PMVR) determined by echocardiographic and invasive parameters: Patzelt: increase of cardiac output after PMVR . Int J Cardiol 2017 ; 236 : 356 – 62 . Google Scholar CrossRef Search ADS PubMed 10 Patzelt J , Zhang Y , Seizer P , Magunia H , Henning A , Riemlova V et al. Effects of mechanical ventilation on heart geometry and mitral valve leaflet coaptation during percutaneous edge-to-edge mitral valve repair . JACC Cardiovasc Interv 2016 ; 9 : 151 – 9 . Google Scholar CrossRef Search ADS PubMed 11 Lancellotti P , Moura L , Pierard LA , Agricola E , Popescu BA , Tribouilloy C et al. 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Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study . Circulation 2009 ; 120 : 326 – 33 . Google Scholar CrossRef Search ADS PubMed 26 Maisano F , Taramasso M , Nickenig G , Hammerstingl C , Vahanian A , Messika-Zeitoun D et al. Cardioband, a transcatheter surgical-like direct mitral valve annuloplasty system: early results of the feasibility trial . Eur Heart J 2016 ; 37 : 817 – 25 . 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)

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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Aug 1, 2017

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