Journal of Clinical Medicine Article Safety and Feasibility of MitraClip Implantation in Patients with Acute Mitral Regurgitation after Recent Myocardial Infarction and Severe Left Ventricle Dysfunction Dan Haberman 1, *,† , Rodrigo Estévez-Loureiro 2,† , Tomas Benito-Gonzalez 3 , Paolo Denti 4 , Dabit Arzamendi 5 , Marianna Adamo 6 , Xavier Freixa 7 , Luis Nombela-Franco 8 , Pedro Villablanca 9 , Lian Krivoshei 10 , Neil Fam 11 , Konstantinos Spargias 12 , Andrew Czarnecki 13 , Isaac Pascual 14 , Fabien Praz 15 , Doron Sudarsky 16 , Arthur Kerner 17 , Vlasis Ninios 18 , Marco Gennari 19,20 , Ronen Beeri 21 , Leor Perl 22 , Haim Danenberg 21 , Lion Poles 1 , Sara Shimoni 1 , Sorel Goland 1 , Berenice Caneiro-Queija 2 , Salvatore Scianna 20 , Igal Moaraf 10 , Davide Schiavi 4 , Claudia Scardino 23 , Noé Corpataux 15 , Julio Echarte-Morales 3 , Michael Chrissoheris 12 , Estefanía Fernández-Peregrina 5 , Mattia Di Pasquale 6 , Ander Regueiro 7 , Carlos Vergara-Uzcategui 8 , Andres Iñiguez-Romo 2 , Felipe Fernández-Vázquez 3 , Danny Dvir 24 , Maurizio Taramasso 20,† and Mony Shuvy 21,24,† 1 Heart Center, Kaplan Medical Center, Affiliated to the Hebrew University, Jerusalem 9190501, Israel; Lion_P@clalit.org.il (L.P.); sarah_s2@clalit.org.il (S.S.); Sorel_G@clalit.org.il (S.G.)  2 Interventional Cardiology Unit, Hospital Álvaro Cunqueiro, 36321 Vigo, Spain;  roiestevez@hotmail.com (R.E.-L.); bcanque@gmail.com (B.C.-Q.); andres.iniguez.romo@sergas.es (A.I.-R.) 3 Interventional Cardiology Unit, Complejo Asistencial Universitario de Leon, 24071 Leon, Spain; Citation: Haberman, D.; Estévez- Loureiro, R.; Benito-Gonzalez, T.; tomasbenito@outlook.com (T.B.-G.); juliocecharte@gmail.com (J.E.-M.); ffernandez@secardiologia.es (F.F.-V.) 4 Cardiovascular Surgery Department, San Raffaele University Hospital, 20132 Milan, Italy; Denti, P.; Arzamendi, D.; Adamo, M.; denti.paolo@hsr.it (P.D.); lanci82@gmail.com (D.S.) Freixa, X.; Nombela-Franco, L.; 5 Interventional Cardiology Unit, Hospital Sant Pau i Santa Creu, 08041 Barcelona, Spain; Villablanca, P.; Krivoshei, L.; et al. dabitarza@gmail.com (D.A.); efernandezperegrina@gmail.com (E.F.-P.) Safety and Feasibility of MitraClip 6 Cardiac Catheterization Laboratory, ASST Spedali Civili di Brescia, 25123 Brescia, Italy; Implantation in Patients with Acute mariannaadamo@hotmail.com (M.A.); m.dipa91@gmail.com (M.D.P.) 7 Interventional Cardiology Unit, Hospital Clinic, 08036 Barcelona, Spain; xavierfreixa@hotmail.com (X.F.); Mitral Regurgitation after Recent Myocardial Infarction and Severe Left anderregueiro@gmail.com (A.R.) 8 Hospital Clínico San Carlos, Instituto de Investigacion Sanitaria San Carlos, IdISSC, 28040 Madrid, Spain; Ventricle Dysfunction. J. Clin. Med. 2021, 10, 1819. https://doi.org/ luisnombela@yahoo.com (L.N.-F.); carting1@gmail.com (C.V.-U.) 9 Interventional Cardiology, The Center for Structural Heart Disease, Henry Ford Hospital, 10.3390/jcm10091819 Detroit, MI 48202, USA; pedrovillablanca@hotmail.com 10 Department of Cardiology, Kantonsspital Baden, 5404 Baden, Switzerland; liank@me.com (L.K.); Academic Editor: Bernward Lauer Igalmoaraf@gmail.com (I.M.) 11 Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada; Received: 25 February 2021 neil.fam@unityhealth.to Accepted: 13 April 2021 12 Department of Transcatheter Heart Valves, HYGEIA Hospital, 15123 Athens, Greece; Published: 22 April 2021 kspargias@hygeia.gr (K.S.); mchrissoheris@hotmail.com (M.C.) 13 Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada; Andrew.Czarnecki@sunnybrook.ca Publisher’s Note: MDPI stays neutral 14 Department of Cardiology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; with regard to jurisdictional claims in ipascua@live.com published maps and institutional affil- 15 Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Fabien.Praz@insel.ch (F.P.); iations. noe.corpataux@insel.ch (N.C.) 16 Cardiovascular Institute, Baruch Padeh Medical Center, Poriya 1520800, Israel; DSudarsky@poria.health.gov.il 17 Department of Cardiology, Rambam Medical Center, and B. Rappaport Faculty of Medicine, Technion Medical School, Haifa 3109601, Israel; a_kerner@rambam.health.gov.il 18 Department of Cardiology, Interbalkan European Medical Center, 55535 Thessaloniki, Greece; Copyright: © 2021 by the authors. vninios@gmail.com Licensee MDPI, Basel, Switzerland. 19 Department of Cardiovascular Surgery, IRCCS Centro Cardiologico Monzino, 20138 Milan, Italy; This article is an open access article Marco.Gennari@usz.ch 20 Heart Valve Clinic, University Hospital of Zurich, 8006 Zurich, Switzerland; Salvatore.Scianna@usz.ch (S.S.); distributed under the terms and conditions of the Creative Commons Maurizio.Taramasso@usz.ch (M.T.) 21 Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ ronenbe@ekmd.huji.ac.il (R.B.); danen040@gmail.com (H.D.); monysh@gmail.com (M.S.) 4.0/). J. Clin. Med. 2021, 10, 1819. https://doi.org/10.3390/jcm10091819 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1819 2 of 14 22 Cardiology Department, Rabin Medical Center and the “Sackler” Faculty of Medicine, Tel-Aviv University, Tel-Aviv 49100, Israel; leorperl@gmail.com 23 Department of Cardiology, Joan XXIII University Hospital, 43005 Tarragona, Spain; claudia.scardino85@gmail.com 24 Jesselson Integrated Heart Centre, Shaare Zedek Medical Center, Hebrew University, Jerusalem 9103102, Israel; danny.dvir@gmail.com * Correspondence: haberdan@gmail.com † Equal Contribution. Abstract: Patients with severe mitral regurgitation (MR) after myocardial infarction (MI) have an increased risk of mortality. Transcatheter mitral valve repair may therefore be a suitable therapy. However, data on clinical outcomes of patients in an acute setting are scarce, especially those with reduced left ventricle (LV) dysfunction. We conducted a multinational, collaborative data analysis from 21 centers for patients who were, within 90 days of acute MI, treated with MitraClip due to severe MR. The cohort was divided according to median left ventricle ejection fraction (LVEF)—35%. Included in the study were 105 patients. The mean age was 71 ± 10 years. Patients in the LVEF < 35% group were younger but with comparable Euroscore II, multivessel coronary artery disease, prior MI and coronary artery bypass graft surgery. Procedure time was comparable and acute success rate was high in both groups (94% vs. 90%, p = 0.728). MR grade was significantly reduced in both groups along with an immediate reduction in left atrial V-wave, pulmonary artery pressure and improvement in New York Heart Association (NYHA) class. In-hospital and 1-year mortality rates were not significantly different between the two groups (11% vs. 7%, p = 0.51 and 19% vs. 12%, p = 0.49) and neither was the 3-month re-hospitalization rate. In conclusion, MitraClip intervention in patients with acute severe functional mitral regurgitation (FMR) due to a recent MI in an acute setting is safe and feasible. Even patients with severe LV dysfunction may benefit from transcatheter mitral valve intervention and should not be excluded. Keywords: mitral regurgitation; percutaneous mitral valve repair; acute myocardial infarction; left ventricle dysfunction 1. Introduction Mitral regurgitation (MR) complicating acute Myocaridial Infarction (MI) can be the result of papillary muscle rupture (Primary) or imbalance between closing and tethering forces (Functional). Primary MR in this acute setting is a medical emergency often requires emergent intervention [1]. Functional mitral regurgitation (FMR) usually develops over the course of days and is associated with adverse outcomes [2]. Currently, medical ther- apy is the mainstay approach for this condition. However, some patients remain very symptomatic with prolonged hospitalization and frequent heart failure (HF) admissions [3]. Data obtained from large-scale registries suggest that percutaneous transcatheter edge-to-edge mitral valve repair implantation with MitraClip device improves functional capacity and quality of life [4–7]. Furthermore, the recent randomized trial entitled, ‘Cardio- vascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation’ (COAPT) showed that MitraClip improved clinical outcomes, including mortality in patients with severe FMR, when compared to medical therapy alone [8]. Conversely, the results of the ‘Multicentre Study of Percuta- neous Mitral Valve Repair MitraClip Device in Patients with Severe Secondary Mitral Regurgitation’ (MITRA-FR) illustrated that enrolled patients with lower LVEF showed no clinical benefit from the MitraClip procedure in an advanced HF population [9], thereby suggesting that patients with lower LVEF may benefit less from the MitraClip procedure. Focusing on patients with reduced left ventricle (LV) function, previous studies have addressed this issue with mixed results. In the German transcatheter mitral valve interven- tions (TRAMI) registry, the clinical benefit for patients with severely reduced LV function was comparable to patients with preserved LV [6]. However, a recent paper by Pascual J. Clin. Med. 2021, 10, 1819 3 of 14 et al. showed that patients in the LVEF > 30% group had better clinical outcomes [10]. Percutaneous edge-to-edge repair for functional MR was recently implemented in the American Heart Association 2020 clinical guidelines [11]. However, it is still not clear how effective it is for patients with a severe reduction in LV function. While the positive value of MitraClip implantation on outcomes in chronic severe symptomatic ischemic FMR was shown before [12], data regarding patients with severe acute ischemic FMR, who are generally not included in registries or in randomized trials, are lacking, especially in patients with severely reduced LV function. Our group previously published two case series showing that the MitraClip procedure is safe in patients with pulmonary congestion due to severe functional MR complicating MI [13,14]. MR reduction was significant with favorable hemodynamics and clinical improvement. The mortality rate after 30 days was as low as 10%. A recent publication by our group showed that even patients in cardiogenic shock may benefit from percutaneous edge-to-edge repair [15]. However, it is unknown how effective the MitraClip procedure is in severe LV dys- function patients in an acute setting. 2. Methods The International Registry of MitraClip in Acute Mitral Regurgitation following acute myocardial infarction (IREMMI) was established to assess the safety and outcomes of patients who underwent MitraClip in an acute setting following MI. In this multinational, multicenter retrospective registry, we evaluated the short and intermediate outcomes based on left ventricle ejection fraction. The procedure was performed in 21 centers in Europe, North America and Israel using the MitraClip device (Abbott, Menlo Park, CA, USA). 2.1. Study Population We included patients who were treated with the MitraClip device due to at least mod- erate to severe (3+) MR, within 90 days of acute myocardial infarction (MI) between Jan- uary 2014 and January 2020. Although treated medically, patients remained symptomatic (NYHA class > 3) and were evaluated by a multidisciplinary team of a non-interventional cardiologist, an interventional cardiologist and a cardiothoracic surgeon. All patients were deemed to be high risk for surgery and therefore a MitraClip procedure was performed in order to allow recovery. Patients who were anatomically unsuitable for edge-to-edge mitral valve repair were excluded. We evaluated immediate, 3-month and 1-year outcomes in those patients 2.2. Echocardiographic Evaluation The severity of MR, left ventricle ejection fraction (LVEF), pulmonary artery pressure (PAP) and Mitral valve (MV) gradient were measured and graded according to the Ameri- can Society of Echocardiography guidelines [16–18]. The severity of MR was assessed with an integrated multiparametric visual evaluation tool in accordance with standard clinical practice (incorporating 2D, spectral and color Doppler images), using an ordinal scale (grading 0− no MR, 1+ mild MR, 2+ moderate MR, 3+ moderate to severe MR, 4+ severe MR). A transesophageal echocardiogram (TEE) was completed in all patients prior to the procedure. MR grade, Mitral valve area (MVA) and MV gradient, calcium at grasping area and coaptation features were assessed in order to evaluate MitraClip feasibility. 2.3. MitraClip A MitraClip procedure was performed under general anesthesia; fluoroscopy and transesophageal echocardiography (TEE) were routinely used for guidance. After transsep- tal puncture, the delivery system was advanced to the left atrium (LA), LV and retracted back to grasp the anterior and posterior leaflets. Procedural success was defined as the successful grasping of the anterior and posterior leaflets together with a reduction of at J. Clin. Med. 2021, 10, 1819 4 of 14 least two MR grades. V-wave and left atrial pressures (LAP) were measured and recorded immediately before and after MitraClip implantation. 2.4. Outcomes Procedural and clinical adverse events during follow-up were defined according to the Mitral Valve Academic Research Consortium (MVARC) [13]. Outcomes of interest were procedural success, safety, hospital discharge, clinical outcomes and hemodynamics. Acute procedural success was defined as successful implantation of one or more clips with a reduction of the MR to <2+. Safety outcomes included procedural and periprocedural complications, namely, clip detachment, cerebrovascular event, MI, bleeding requiring transfusion and cardiac tamponade and urgent cardiovascular surgery. Clinical outcomes included weaning from mechanical ventilation and/or an LV support device and an NYHA class at follow-up. Hemodynamic parameters, LAP and V-wave were measured during the procedure. In cases where right heart catheterization was used, pulmonary artery wedge pressure (PCWP) was measured simultaneously with the procedure. After discharge, patients were followed up by individual centers in outpatient clinic visits in which clinical evaluation and echocardiography were performed. 2.5. Statistical Analysis Our analyses were performed using the entire cohort, drawing comparisons between patients with EF lower or higher than 35%. Patient characteristics are reported according to variable properties. Categorical variables (ex. MR grade) are reported as % (n), and differences between subgroups were tested, when appropriate, using the chi-square test of Fischer’s exact test. Continuous variables (ex. LVEF, PCWP, V-wave, sPAP) are reported according to their distribution. Those with a normal distribution are reported as mean (±standard deviation), and differences between subgroups were tested using the student’s T-test. Those without a normal distribution are reported as median (interquartile range), and differences between subgroups were tested using the Mann-Whitney U. A p-value less than 0.05 was considered to be statistically significant. Kaplan-Meier estimates were used to calculate survival curves, which were adjusted to age and compared using the log-rank test. All clinical events were analyzed by time-to first event for Kaplan-Meier analysis. The IBM Statistical Package for the Social Sciences (SPSS) Statistics 26.0 (IBM Corp., Armonk, NY, USA) was utilized to perform the analyses. 3. Results From January 2014 to January 2020, 105 patients were included in the registry. 3.1. Patient Characteristics The mean age of patients was 70.5 ± 10.3 years and 50% were female. All patients had at least MR grade 3 before the intervention. Patients suffered pulmonary congestion despite initial medical therapy, including intravenous diuretics. Of the patients, 52 (55%) were in cardiogenic shock and were further supported by an intra-aortic balloon pump (IABP) or intravenous vasopressors, whilst 41 patients (43%) required mechanical ventilation unrelated to the procedure. The patient population was divided into two groups based on the median LVEF of 35%. The LVEF < 35% group included 47 patients, whilst LVEF ≥ 35% included 58 patients with a mean LVEF of 26 ± 6% and 44 ± 9%, p < 0.01, respectively. Baseline characteristics are listed in Table 1. Patients in the LVEF < 35% group were younger when compared to patients with LVEF ≥ 35% (68.4 ± 9.1 vs. 72.4 ± 11.0, p = 0.05), as well as having a higher body–mass index (BMI) (27.9 ± 4.7 vs. 25.5 ± 5.3, p = 0.04). There was no difference in other risk factors for cardiovascular disease, past MI, past Coronary Artery Bypass Graft (CABG) or in the surgical risk assessment by Euroscore II. J. Clin. Med. 2021, 10, 1819 5 of 14 Table 1. Baseline Patient Characteristics. Parameter 1 2 Total LVEF < 35% LVEF ≥ 35% p-Value Population n 105 47 58 Demographics Age, years 70.5 ± 10.3 68.4 ± 9.1 72.4 ± 11.0 0.05 Sex, Female, % (n) 50 (53) 43 (20) 57 (33) 0.17 BMI (Kg/M2 ) 26.5 ± 5.2 27.9 ± 4.7 25.5 ± 5.3 0.04 Hypertension, % (n) 70.5 (74) 68.1 (32) 70.7 (41) 0.83 Diabetes, % (n) 45.7 (48) 51.1 (24) 41.4 (24) 0.33 Dyslipidemia, % (n) 62.9 (66) 70.0 (31) 60.3 (35) 0.69 COPD, % (n) 17.1 (18) 19.1 (9) 15.5 (9) 0.80 CKD ≥ grade 2, % (n) 29.5 (31) 25.5 (12) 32.8 (19) 0.82 Prior stroke, % (n) 13.3 (14) 6.4 (3) 19.0 (11) 0.08 Prior MI, % (n) 55.2 (58) 61.7 (29) 50 (29( 0.24 Prior CABG, % (n) 26.7 (28) 23.4 (11) 29.3 (17) 0.51 Euroscore 2, % 17.2 ± 16.7 20.1 ± 18.5 14.9 ± 15.0 0.14 Presentation STEMI, % (n) 71.4 (75) 66.0 (31) 75.9 (44) 0.25 Killip Class 3+, % (n) 68.6 (72) 78.7 (37) 60.3 (35) 0.06 Echocardiographic MR Grade 4+, % (n) 81.0 (85) 83.0 (39) 79.3 (46) 0.80 Papillary muscle rapture, 5.7 (6) 2.1 (1) 8.6 % (5) 0.22 % (n) Ejection Fraction (%) 35.8 ± 11.9 25.8 ± 5.7 44 ± 8.9 <0.01 sPAP, mmHg 53.6 ± 18.6 54.4 ± 16.1 53.1 ± 20.3 0.75 Coronary Angiography Multivessel disease, % (n) 80 (84) 83.0 (39) 77.6 (45) 0.63 RCA, % (n) 11 (5) 41 (24) Infarct Related Artery LCX, % (n) 32 (15) 33 (19) <0.01 (IRA) LAD, % (n) 53 (25) 22 (13) PCI, % (n) 94.3 (99) 95.7 (45) 95.7 (54) 0.69 Anterior 51 (24) 19 (11) Wall Involved Inferior 30 (14) 59 (34) <0.01 Lateral and/or Posterior 19 (9) 22 (13) ICCU Status and Treatment Cardiogenic Shock 54.3 (57) 63.8 (30) 46.6 (27) 0.12 Mechanical Ventilation 42.9 (45) 46.8 (22) 39.7 (23) 0.55 Vasoactive medication 42.9 (45) 48.9 (23) 37.9 (22) 0.32 Any MSD 37.1 (39) 42.6 (20) 32.8 (19) 0.32 Abbreviations: BMI—Body Mass Index; CABG—Coronary Artery Bypass Grafting; CAD—Coronary Artery Disease; CKD—Chronic Kidney Disease; COPD—Chronic Obstructive Lung Disease; Euroscore II—European System for Cardiac Operative Risk Evaluation; ICCU—Intensive Coronary Care Unit; LAD—Left Anterior Descending; LCX—Left Circumflex; LVEF—Left Ventricle Ejection Fraction; MSD—Mechanical Support Device; PCI—Percutaneous Coronary Intervention; RCA—Right Coronary Artery; sPAP—Systolic Pulmonary artery pressure; STEMI—ST Elevation myocardial infarction. Out of 105 patients, 75 presented with STEMI but there was no significant difference between the two groups (66% vs. 76%, respectively, p = 0.14). In both groups there was a high rate of multi-vessel disease (80% vs. 78%, p = 0.63). The common infarct related artery (IRA) was the LAD in the LVEF < 35% group (53% vs. 22%), and the RCA in the LVEF ≥ 35% group (41% vs. 11%, p < 0.01). The anterior LV wall was involved in 51% of patients in the LVEF < 35% group vs. 19% of patients in the LVEF ≥ 35% group. Accordingly, the inferior wall was more involved in the LVEF ≥ 35% group (59% vs. 30%, p < 0.01). 3.2. Procedural and Safety Outcomes Procedure characteristics, safety and outcomes are listed in Table 2. J. Clin. Med. 2021, 10, 1819 6 of 14 Table 2. Procedure and Outcomes. Parameter 1 2 Total LVEF < 35% LVEF ≥ 35% p-Value Population n 105 47 58 Procedure Procedure Time, min 115 ± 90 122 ± 84 109 ± 95 0.51 Major Complications 6.7 (7) 8.5 (4) 5.2 (3) 0.70 MI to Procedure, days 27 ± 22 35 ± 26 20 ± 17 <0.01 Clips Implanted, mean 1.7 ± 0.7 1.8 ± 0.7 1.6 ± 0.6 0.22 MR > 2 at discharge, % (n) 8.6 (9) 8.5 (4) 8.6 (5) 1 MV Gradient post 3.7 ± 1.7 3.7 ± 1.6 3.7 ± 1.8 0.91 Outcomes Procedure success 91.4 (96) 93.6 (44) 89.7 (52) 0.73 In hospital mortality 8.6 (9) 10.6 (5) 6.9 (4) 0.51 Major Complications 6.7 (7) 8.5 (4) 5.2 (3) 0.70 Mortality at 3 months 11.4 (12) 14.9 (7) 8.6 (5) 0.50 Rehospitalizations at 3 months 13.3 (14) 19.1 (9) 15.5 (9) 0.77 1-year mortality 15.2 (16) 19.1 (9) 12.1 (7) 0.49 Abbreviations: LVEF—Left Ventricle Ejection Fraction; MI—Myocardial Infarction; MO—Month; MR—Mitral Regurgitation; MV—Mitral Valve. A MitraClip procedure was performed, on average, 27 ± 22 days after the date of the index MI. When drawing comparisons based on LVEF, procedures were delayed in the LVEF ≥ 35% group, where the MitraClip procedure was performed, on average, at 37 ± 26 days vs. 21 ± 18 days, p = 0.001 in the LVEF < 35% group. Procedure success was 91.4% (96 out of 105 patients). There was no significant difference between the two LVEF groups, 96% vs. 90%, p = 0.73. The procedure’s mean duration was 115 min ± 90 min. There was no difference in duration between the LVEF < 35% group (122 min ± 84 min) and the LVEF ≥ 35% group (109 min ± 95 min), p = 0.51. MR reduction to grade 1 was achieved in 64 patients and to 2+ in 32 patients (Figure 1). The grade of MR significantly decreased after the procedure, p < 0.01. No difference was observed between the two LV groups. One to four clips were implanted in each case; 42 patients were implanted with a single clip, 52 were implanted with two clips, 9 were implanted with three clips and one patient was implanted with four clips. The mean mitral valve gradient was 3.7 mmHg ± 1.7 and there was no significant difference based on LVEF. Hemodynamic features from presentation to discharge were improved in both groups. Left atrial V-Wave was reduced from 45.1 ± 15.9 mmHg to 20.2 ± 7.0 mmHg, p < 0.01 in the LVEF < 35% group and from 31.3 ± 17.1 mmHg to 17.1 ± 5.7 mmHg, p < 0.01, in the LVEF ≥ 35% group (Figure 2a). There was no significant change in EF from presentation to discharge in either group (26% to 27%, p = 0.18 and 44% to 45%, p = 0.31, respectively) (Figure 2b). SPAP reduction was observed in both groups from presentation to discharge (54.1 ± 14.8 mmHg to 43.9 ± 16.3 mmHg, p < 0.01, in the LEVF < 35% group and from 52.9 ± 22.8 mmHg to 41.7 ± 21.7 mmHg, p < 0.01, in the LVEF ≥ 35% group) (Figure 3a). Major complications following the procedure were relatively low in both groups (7% vs. 9%, p = 0.70). Clin. Med. . Med. 2021, 2021, 10, 10, x FOR x FOR PEER PEER REVIEW REVIEW 7 of 7 of 14 14 J. Clin. Med. 2021, 10,3a). 1819 3a). Major Major complications complications following following thethe procedure procedure were were relatively relatively lowlow in in both both groups groups (7%(7% 7 of 14 vs.vs. 9%,9%, p =p0.70). = 0.70). Figure 1. MR Figure Figure grades 1. MR 1. MR at grades grades at presentation, at presentation, presentation, discharge, discharge, discharge, 3-month 3-month 3-month and and 1-year and 1-year 1-year follow-up. follow-up. follow-up. MR wasMR MR waswas signifi- signifi- significantly reduced from cantly cantly reduced reduced from from presentation presentation to discharge to discharge in both in both LVEF LVEF groups. groups. MRMR reduction reduction remains remains con-con- presentation to discharge in both LVEF groups. MR reduction remains consistent after discharge and throughout follow-up sistent sistent after after discharge discharge andand throughout throughout follow-up follow-up in both in both groups. groups. in both groups. (a)(a) LVEF LVEF Figure 2. Cont. Med. 2021,J.10, x FOR Clin. Med.PEER 2021,REVIEW 10, 1819 8 of 14 8 of 14 n. Med. 2021, 10, x FOR PEER REVIEW 8 of 14 (b) LAP, V-Wave Figure 2. Left Ventricle Figure 2.Ejection Fraction Left Ventricle (LVEF)Fraction Ejection and Left(LVEF) Atrial Pressure (LAP) Pressure and Left Atrial before and afterbefore (LAP) the and after the procedure. (a) There was no significant change in Left ventricle ejection fraction (LVEF) before and procedure. (a) There was no significant change in Left ventricle ejection fraction (LVEF) before and after MitraClip after procedure in both MitraClip LVEF < in procedure 35% and both LVEF LVEF ≥ 35% < 35% groups; and LVEF (b) There ≥ 35% was a(b) groups; significant There was a significant reduction in LAP before and after MitraClip procedure in both LVEF < 35% and LVEF ≥ 35% groups. reduction in LAP before and after MitraClip procedure in both LVEF < 35% and LVEF ≥ 35% groups. 3.3. Mortality Analysis In-hospital mortality (b)was LAP,low in both the LVEF < 35% and LVEF ≥ 35% groups (11% V-Wave vs. 7%, p = 0.51). One-year mortality was also low and non-significant when comparing Figure 2. Left Ventricle Ejection Fraction (LVEF) and Left Atrial Pressure (LAP) before and after the the two groups (19% vs. 12%, p = 0.49). Age-adjusted survival curves for mortality are procedure. (a) There was no significant change in Left ventricle ejection fraction (LVEF) before and after MitraClipshown in Figure procedure in both4.LVEF There was < 35% noLVEF and significant difference ≥ 35% groups; between (b) There was athe two groups at the significant 1-year reduction in LAP follow-up before and after(Log p = 0.221). Rank,procedure MitraClip in both LVEF < 35% and LVEF ≥ 35% groups. (a) sPAP (a) sPAP Figure 3. Cont. n. Med. 2021, 10, xMed. J. Clin. FOR 2021, PEER10, REVIEW 1819 9 of 14 9 of 14 (b) NYHA Class Figure Figure 3. Clinical and3.Echocardiographic Clinical and Echocardiographic evaluation at discharge, evaluation at presentation, presentation, discharge, 3-month 3-month and 1-year and 1-year follow-up. (a) Systolic follow-up. (a) Systolic Pulmonary Artery Pressure (sPAP) was significantly reduced Pulmonary Artery Pressure (sPAP) was significantly reduced from presentation to discharge in both LVEF from presenta- groups. sPAP tion to discharge in both LVEF groups. sPAP reduction from presentation to 1-year follow up was reduction from presentation to 1-year follow up was consistent only for patients in the LVEF > 35%. (b) NYHA class was consistent only for patients in the LVEF > 35%. (b) NYHA class was significantly improved from significantly improved from presentation to discharge in both LVEF groups. NYHA class improvement remain consistent presentation to discharge in both LVEF groups. NYHA class improvement remain consistent throughout follow-up throughout in follow-up both groups; 36 out in both of 42 36 groups; patients out of in 42 the LVEFin 30% group had better clinical outcomes [10]. We found that patients with severe acute MR and LVEF < 35% had similar mortality rates to patients with LVEF ≥ 35%. This finding may suggest that, rather than low EF, severe acute MR is the dominant factor in deterioration and clinical instability and should therefore be treated regardless of EF. However, we cannot exclude that the similar survival rates were related to a lack of statistical power. Revascularization for acute MI can provide improvement of LV function and may decrease the ischemic FMR. Nishino et al. showed that shorter reperfusion time and successful revascularization at presentation were the independent predictors of improvement in FMR [21]. The Acute Myocardial Infarction Contrast Imaging (AMICI) multicenter study showed that a short time to revasculariza- tion (<2.5 h) independently predicts reverse remodeling which affects the magnitude of FMR [27]. While the negative prognostic effect of ischemic FMR is well recognized, the impact of surgical repair of MR on LV remodeling and outcomes is still controversial, especially in patients with severely reduced LV function, who are poor candidates for surgery [28–30]. Theoretically, the less invasive MitraClip procedure may be considered as an alternative to surgery in high-risk patients. In fact, recent trials suggest that MitraClip therapy improves quality of life and may even reduce mortality among patients with severe chronic ischemic MR [4,6]. However, in most of these clinical trials, patients who had acute or subacute MR due to a recent MI were excluded. The impact of MitraClip in an acute setting was initially only evaluated in case reports and a small case series [31–34]. The two largest case series were previously published by our group [13,14]. Our findings confirm that MitraClip is a safe and effective procedure in acute settings for a selected high-risk group, both with LVEF < 35% and LVEF ≥ 35%, and that in most of the patients the effectiveness of mitral intervention was sustainable in long term follow up. The study has several limitations that merit consideration. First, although several centers were involved, the sample size is relatively small, and the results should be in- terpreted with caution. Second, our analysis used retrospectively analyzed observational data and therefore the associations between baseline characteristics and outcomes may be confounded by unmeasured variables. Third, in all our cases, MitraClip was performed as a salvage procedure in acutely ill patients. Therefore, the findings cannot be generalized for stable patients who develop ischemic FMR after MI. Large, multicenter and randomized trials are needed to confirm this data among acute ischemic FMR. 5. Conclusions MitraClip intervention in patients with acute severe FMR due to a recent MI in an acute setting is safe and feasible. Even patients with severe LV dysfunction may benefit from transcatheter mitral valve intervention and should not be excluded. J. Clin. Med. 2021, 10, 1819 12 of 14 Author Contributions: Conceptualization, D.H., R.E.-L., D.D., M.T. and M.S.; methodology, D.D. and L.K.; validation, D.D. and M.T.; formal analysis, D.H. and R.E.-L.; investigation, D.H., R.E.-L., T.B.-G., P.D., D.A., M.A., X.F., L.N.-F., P.V., L.K., N.F., K.S., A.C., I.P., F.P., D.S. (Doron Sudarsky), A.K., V.N., M.G., R.B., L.P. (Leor Perl), H.D., L.P. (Lion Poles), S.S. (Sara Shimoni), S.G., B.C.-Q., S.S. (Salvatore Scianna), I.M., D.S. (Davide Schiavi), C.S., N.C., J.E.-M., M.C., E.F.-P., M.D.P., A.R., C.V.-U., A.I.-R., F.F.-V., D.D., M.T. and M.S.; data curation, D.H.; writing—original draft preparation, D.H. and M.S.; writing—review and editing, R.E.-L., D.D. and M.T.; visualization, D.H. and M.S.; supervision, R.E.-L., D.D., M.T. and M.S.; project administration, D.H. and M.S.; funding acquisition, L.P. (Lion Poles) and M.S. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki Ethical Principles and was approved by individual local ethics committees (KMC-68-2010). Informed Consent Statement: All patients provided written informed consent prior to the intervention. Data Availability Statement: The data that supports the findings of this study are available from the corresponding author, D.H., upon reasonable request. Conflicts of Interest: Dan Haberman is an Abbott CEC member. Rodrigo Estévez-Loureiro, Dabit Arzamendi, Paolo Denti, Xavier Freixa, are consultants for Abbott. Andrew Czarnecki received speaker fee from Abbott and consultant for Caisson Interventional and Baylis Medical. Marco Gennari is consultant for Medtronic. Luis Nombela-Franco has served as a proctor of Abbott Vascular and received speakers’ honoraria from Boston Scientific and Abbott Vascular. Francesco Maisano has served as a consultant for Abbott Vascular, Edwards Lifesciences, Cardiovalve, Valtech, and Medtronic; and is cofounder of 4tech. Maurizio Taramasso is Consultant for Abbott, Boston Scientific, 4tech and receives personal fees from Edwards Lifescience, CoreMedic, Swissvortex and Mitraltech. Mony Shuvy is a proctor and consultant for Abbott and consultant for Edwards Lifesciences. All other authors have reported that they have no relationship relevant to the contents of this paper to disclose. References 1. 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