We consecutively enrolled all patients who underwent TEER with the MitraClip mitral valve repair system at St. Marianna University Hospital in a prospective registry. The registry is part of a multicenter registry approved by the local institutional review board (No. 4209) and registered with the University Hospital Medical Information Network (Treatment and prognosis of heart valve registry, UMIN-ID: 000023653). All patients provided written informed consent to participate in the registry, and the study was conducted in accordance with the Declaration of Helsinki.

For the purpose of the present study, patients with primary MR who underwent TEER either with the MitraClip G2 or G4 between 2018 and 2021 were included and retrospectively analyzed.

All procedures were discussed and planned by the Heart Team in accordance with established best practice guidelines [3]. Prior to the procedure, a standardized transthoracic echocardiography was performed by an echocardiography specialist. The procedures were performed under general anesthesia with the guidance of two- and three-dimensional transesophageal echocardiography and fluoroscopy in a hybrid operating room. The MitraClip G4 system has been available at our center since October 2020, and it offers four different clip sizes and allows for independent grasping of the anterior and posterior mitral valve leaflets. The selection of clip size was based on careful anatomical assessment of the mitral valve using intraprocedural transesophageal echocardiography. Transthoracic echocardiography was performed on day 3 after the procedure or at the latest, before hospital discharge.

Clinical, echocardiographic, procedural, and follow-up data were prospectively collected in an institutional integrated data system. Regular clinical follow-up was scheduled at 30 days, at 1 year, and yearly thereafter. Clinical follow-up data were obtained through documentation from referring physicians, hospital discharge summaries, and standardized telephone interviews. Technical success and device success were retrospectively adjudicated by experienced cardiologists based on the Mitral Valve Academic Research Consortium (MVARC) criteria [7, 8]. Technical success included the following criteria: (1) absence of procedural mortality; (2) successful access, delivery, and retrieval of the device delivery system; (3) successful deployment and correct positioning of the first intended device; and (4) freedom from emergency surgery or reintervention related to the device or access procedure. Device success included the following criteria: (1) absence of procedural mortality or stroke; (2) proper placement and positioning of the device; (3) freedom from unplanned surgical or interventional procedures related to the device or access procedure; and (4) continued intended safety and performance of the device. Intended safety and performance of the device was included: (a) no evidence of structural or functional failure; (b) no specific device-related technical failure issues and complications; (c) and reduction of MR to either optimal or acceptable levels (reduction by at least 1 class/grade from baseline and to no more than 2+ in severity) without significant mitral stenosis (post-procedure effective orifice area is $\ge$1.5 mm${}^2$ with a transmitral gradient 5 mmHg). Mitral valve effective orifice area was measured by using the planimetry method. Mitral regurgitation was graded as 0, 1+, 2+, 3+, 4+ according to the MVARC criteria. Optimal mitral valve anatomy for TEER was defined as having: (1) a central jet (A2/P2), (2) a mitral valve area $>$4 cm${}^2$, (3) a posterior leaflet length $>$10 mm, (4) a flail gap 10 mm, and (5) flail width 15 mm [1].

Categorical data are represented as frequencies and percentages and the differences between groups are evaluated with the Chi-square test or Fisher’s exact test. Continuous variables are expressed as median values and interquartile ranges (IQR) and compared between groups using Mann-Whitney’s U test. Event-free survival curves were constructed using the Kaplan-Meier method and Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI). Throughout the present study, a p-value of 0.05 was considered significant. Statistical analyses were performed using EZR software 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) which is a graphical user interface for R 4.2.1 (The R Foundation for Statistical Computing, Vienna, Austria).

During the study period, 223 patients underwent TEER with the MitraClip mitral valve repair system at our center. Among them, 71 patients with primary MR who met the inclusion criteria were retrospectively analyzed. Of these, 34 patients were treated with the G2 system and 37 patients with the G4 system. Baseline characteristics are summarized in Table 1. There were no significant differences in baseline clinical characteristics, except for a higher surgical risk in the G2 group than in the G4 group (Society of Thoracic Surgeons Predicted Risk of Mortality: 7.74 [5.04–14.97], G2 vs. 5.26 [3.98–6.40], G4; p 0.01).

Baseline echocardiographic data are detailed in Table 2. The volume of mitral regurgitation was greater in the G4 group than in the G2 group (regurgitant volume: 63 [41–76] mL, G2 vs. 68 [62–84] mL, G4; p = 0.04; effective regurgitant orifice area: 0.43 [0.30–0.49] cm${}^2$, G2 vs. 0.47 [0.41–0.58] cm${}^2$, G4; p = 0.07). The flail gap was significantly greater in the G4 group than in the G2 group (4.5 [3.5–5.5] mm, G2 vs. 5.4 [4.5–7.1] mm, G4; p = 0.04), while flail width was comparable between the two groups (9.1 [7.6–10.7] mm, G2 vs. 10.2 [8.1–12.3] mm, G4; p = 0.18). Mitral valve area by planimetry was significantly greater in the G4 group than in the G2 group (4.9 [4.4–5.7] cm${}^2$, G2 vs. 5.9 [5.0–6.6] cm${}^2$, G4; p = 0.01), while mean transmitral gradient was comparable between the two groups (2.0 [1.3–2.3] mmHg, G2 vs. 1.7 [1.4–2.1] mmHg, G4; p = 0.98). There was no significant difference in the length of posterior leaflet (11.2 [9.3–13.0] mm, G2 vs. 11.0 [9.5–12.0] mm, G4; p = 0.81). The mitral valve anatomy was considered optimal for TEER in 52.9% of the G2 group, while in 38.3% of the G4 group (p = 0.20). The other echocardiographic parameters including left ventricular (LV) systolic function, LV dimensions, prevalence of moderate or greater tricuspid regurgitation, tricuspid annular plane systolic excursion (TAPSE), and systolic pulmonary artery pressure (SPAP), were comparable between the two groups.

Procedural characteristics and outcomes are shown in Table 3. No significant differences were observed in the median procedural time and the number of clips used. In the G4 group, 54.1% of patients were treated with at least one extended arm clip and 31 out of 37 patients (83.8%) received at least one wide clip (NTW or XTR). Procedural complications were rare in both groups; single leaflet device attachment occurred in one case in the G4 group, and emergency surgery related to the device occurred in one case in the G2 group. MVARC technical success was achieved in more than 95% of patients without a difference between the two groups (97.1%, G2 vs. 97.3%, G4; p $>$ 0.99) (Fig. 1).

Fig. 1.

Procedural outcomes of the G2 versus G4 MitraClip system. (a) Acceptable level of MR reduction ($\le$2+) was achieved in approximately 90% of patients without difference between the two groups (5.9% vs. 10.8%; p = 0.68). (b) There was no significant difference in the occurrence of mitral stenosis (post-procedure effective orifice area is 1.5 mm${}^2$ with a transmitral gradient $\ge$5 mmHg) after MitraClip between the two groups (35.3% vs. 27.0%; p = 0.61). (c) MVARC technical success was achieved in more than 95% of patients without difference between groups (97.1% vs. 97.3%; p $>$ 0.99). (d) MVARC device success was achieved in 61.8% in the G2 group, and in 70.3% in the G4 group, with no significant difference between the two groups (p = 0.47). MR, mitral regurgitation; MS, mitral stenosis; MVARC, Mitral Valve Academic Research Consortium.

Echocardiographic data at discharge are also shown in Table 3. After MitraClip, an acceptable level of MR reduction ($\le$2+) was achieved in approximately 90% of patients without a difference between the two groups (5.9%, G2 vs. 10.8%, G4; p = 0.68) (Fig. 1). There was no significant difference in the occurrence of mitral stenosis (post-procedure effective orifice area is 1.5 mm${}^2$ with a transmitral gradient $\ge$5 mmHg) after MitraClip between the two groups (35.3%, G2 vs. 27.0%, G4; p = 0.61) (Fig. 1). MVARC device success was achieved in 61.8% of the G2 group and in 70.3% of the G4 group, with no significant difference between the two groups (p = 0.47) (Fig. 1).

Clinical outcomes were assessed in all patients in the G2 group and in 20 out of 37 patients in the G4 group who reached 1-year clinical follow-up. At 30 days, there were no deaths in either group. Residual heart failure symptoms (NYHA $\ge$3) were observed in 6.5% in the G2 group, while no patients in the G4 group had residual heart failure symptoms (p = 0.22). At 1 year, the composite endpoint of all-cause death and heart failure rehospitalization occurred in 2 patients in the G2 group and in 1 patient in the G4 group (HR 0.85; 95% CI 0.08–9.35; p = 0.89) (Table 4). Residual heart failure symptoms (NYHA $\ge$3) at 1 year were observed in 3.7% of the G2 group, while no patients in the G4 group had residual heart failure symptoms (p $\mathrm{>}$ 0.99).

The results of the present analysis need to be interpreted in light of several important limitations. First, the study population in the present analysis was small, which may have been insufficient to detect small differences in procedural and clinical outcomes between devices. The low event rate of rare procedural complications and clinical outcomes warrants cautious interpretation. In turn, the robustness of the findings on device outcomes, including MVARC technical and device success, was reinforced by the independent event adjudication based on detailed documentation of endpoints prospectively collected in the registry. Second, this was a before-and-after study by its nature and is subject to bias due to temporal changes in clinical practice, as well as the effect of the learning curve of the procedure. The small number of patients did not allow us to adequately adjust for confounding factors. Lastly, the results of the present study reflect the experience of a single high-volume center, and the results may not be generalizable to other centers. Thus, the findings need to be corroborated by larger, multicenter studies.