J. of Cardiovasc. Trans. Res. DOI 10.1007/s12265-014-9543-y

Devices for Mitral Valve Repair Paolo Denti & Francesco Maisano & Ottavio Alfieri

Received: 31 October 2013 / Accepted: 14 January 2014 # Springer Science+Business Media New York 2014

Abstract The natural history of severe mitral regurgitation (MR) is unfavorable, leading to left ventricular failure, atrial fibrillation, stroke, and death. Many patients affected by severe regurgitation (MR) do not currently undergo surgery, mainly due to the perceived risk of the procedure (old age, impaired left ventricular function, and comorbidities). Mitral transcatheter interventions carry the hope of minimizing risks while preserving clinical efficacy of surgical repair, as an alternative to conventional treatment. Multiple technologies and diversified approaches are under development with the purpose of treating MR in less invasive ways. They can be categorized based on the anatomical and patho-physiological addressed target. Among them, MitraClip (Abbott Vascular, Inc., Menlo Park, California) has emerged as a clinically safe and effective method for percutaneous mitral valve repair in patients either with degenerative and functional regurgitation. This device mimics the surgical edge-to-edge repair initially described by Alfieri in the early 1990s. Other repair technologies include percutaneous direct and indirect annuloplasty, neochordae implantation, and left ventricular reshaping. They are still in early phase clinical trials or preclinical studies. The combination of different repair techniques is likely to be required to achieve good long-lasting results. In the future, novel devices, improved knowledge, more efficient imaging, and transcatheter mitral prosthetic valve implantation may expand the indications to those patients currently not treated, as well as improve the results both in terms of early efficacy Associate Editor Craig Stolen oversaw the review of this article. P. Denti (*) : O. Alfieri San Raffaele University Hospital, Via Olgettina, 60 20100 Milan, Italy e-mail: [email protected] O. Alfieri e-mail: [email protected] F. Maisano University Hospital Zurich, Zurich, Switzerland

and long-term durability. These treatments are currently reserved to high-risk and inoperable patients, and their application requires an integrated Heart-Team approach. They represent the natural evolution of surgery and promise to expand treatment options and improve patients’ outcomes in the near future. Keywords Transcatheter . Percutaneous . Mitral . Repair

Introduction Mitral regurgitation (MR) is the most prevalent valve disease in the western population [1–3]. When MR is severe, freedom from events and life expectancy are reduced [2, 4–6]. According to guidelines, symptomatic patients with severe MR should be submitted to surgery [7, 8]. Conventional treatment of significant MR is surgery, either repair (better) or replacement. This is particularly true for degenerative mitral regurgitation (DMR). Surgery for DMR is very safe and effective, and in relatively young patients with few comorbidities, hospital mortality is below 1 % [9]. As a consequence, the current approach is to perform early surgery with mitral valve reconstruction to guarantee preservation of life expectancy and quality of life similar to a comparable healthy population [10]. Freedom from reoperation is 93.8 % at 10 years [11]. On the other hand, the landscape of functional mitral regurgitation (FMR) therapies is wide and full of controversies. Functional MR is loading condition-dependent, and timing of surgery can be difficult to establish, particularly when patients are evaluated under aggressive therapy and in resting state [12]. Surgery for FMR carries higher risk compared with DMR; there is a 25–30 % of recurrence of MR at mid -term [13], and its prognostic value as well as the best surgical treatment is still debated [14, 15]. Euro Heart survey showed that up to 50 % of symptomatic patients hospitalized with the diagnosis of severe MR are not

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referred to surgery due to the risk of the procedure [16]. These patients are usually elderly (above 70 years), affected by many comorbidities, and they have a depressed left ventricular (LV) function, so that the risk of surgery is considered too high. With the recent developments in the field of transcatheter aortic valve replacement for aortic stenosis, there has been a similar advance in the field of transcatheter mitral valve therapy for MR. Both the anatomy of the mitral apparatus and the spectrum of pathology of MR are more complex than for aortic valve disease, and thus the development of MR therapies has been more complicated and less rapid. To reduce the invasiveness of the surgical approach, multiple technologies and diversified minimally invasive transcatheter techniques are emerging to treat MR in high-risk and elderly patients, as an alternative to conventional surgery (Table 1). As such, transcatheter interventions may improve outcomes by reducing risks in elderly patients, with reduced LV function or with comorbidities, as well as open the way for earlier interventions, particularly in the field of FMR [17]. These devices can be categorized by the anatomical and patho-physiological addressed target. A classification of percutaneous mitral valve repair technologies on the basis of functional anatomy is proposed; it groups the devices into those targeting the leaflets, the annulus, the chordae, or the LV. The purpose of this review is to discuss all the transcatheter repair techniques, presenting those currently available in the clinical setting along with those still in the development phase, explaining the rationale behind them and their future perspectives.

Devices for Transcatheter Mitral Valve Repair On the basis of the anatomical target addressed by the device, transcatheter mitral repair techniques can be mainly divided in devices that work at the leaflets level and at the annulus level.

Leaflet Repair All these procedures act directly at the leaflet level with the final goal of improving leaflet coaptation and reducing the effective regurgitant orifice. The most advanced technology under this category is the MitraClip System (Abbott Vascular, Inc., Menlo Park, California). It is the most widely used transcatheter mitral device (more than 10,000 procedures worldwide). The MitraClip system was almost directly derived from the surgical edgeto-edge technique [18, 19] that corrects MR regardless of the underlying mechanism of dysfunction (Fig. 1). MitraClip is effective to treat both degenerative DMR and FMR. The surgical technique consists in suturing the free margins of both mitral leaflets at the origin of regurgitation, under

direct vision with extracorporeal circulation and cardioplegic arrest. In the case of percutaneous treatment, the leaflets are joined by applying a clip under echocardiography guidance on beating heart. The MitraClip device is a single-sized, percutaneously implanted mechanical Clip. The MitraClip device grasps and coapts the mitral valve leaflets, resulting in fixed approximation of them throughout the cardiac cycle. Before release of the clip, the device can be locked and unlocked and repeatedly opened and closed. The procedure is performed in the cardiac catheterization laboratory with echocardiographic and fluoroscopic guidance while the patient is under general anesthesia. To access the left heart, standard transseptal catheterization is performed; then the delivery catheter is inserted into the left atrium, and the Clip is positioned above the mitral valve in order to capture the leaflets. More than one clip can be delivered, and each one remains repositionable until detachment. Compared with the surgical edge-to-edge procedure, the percutaneous MitraClip implant offers the advantage of a reduced trauma. Of note, it also allows real-time assessment of the hemodynamic effects of the clip implant by online echocardiography. In case the result is suboptimal, the clip can be repositioned or additional clips can be implanted. The edge-to-edge surgical experience has proven to be effective and versatile. Versatility is a characteristic retained also by the percutaneous device. In fact, MitraClip implant can be performed either in DMR and FMR. The percutaneous technique was introduced in 2003 [20], and up to now, more than 10,000 patients have been treated with this device all over the world. The majority of cases have been performed in Europe. Moreover, MitraClip therapy has been evaluated in several trials and registries (Table 2). The EVEREST study (Endovascular Valve Edge-to-edge REpair of mitral regurgitation STudy) comprises a series of trials [21–24], including the first randomized controlled trial in which the percutaneous approach was compared with surgical treatment in selected patients with MR (mainly with degenerative etiology). Patients included were selected with inclusion and exclusion criteria (Table 3), but, most important they had particular anatomical characteristics evaluated by echocardiography (Table 4). In a post hoc analysis, the MitraClip therapy seemed to be non-inferior to surgery in terms of effectiveness in three subgroups of patients: patients older than 70 years, those with LV dysfunction, and those with FMR [22], of course with all the limit of this type of testing. At landmark analysis, it became evident that the eventual failure of the procedure occurs mainly in the first 6 months after implantation. After this time, patients who require surgical revision after MitraClip are rare and their number is not significantly different from that observed in the cohort randomized to surgical treatment. This failure is potentially preventable with better patient selection and improved implantation technique.

Neochordae using suction and clipping to leaflet connection and helical anchor to papillary muscle fixation

V-Chordal

Segmental leaflet ablation or plication

Used permanent thin alloy rods to displace anteriorly the posterior annulus

After coronary sinus implant transverses the myocardium to re-enter the right chambers, reduces also septo- Trans-jugular, femoral vein, and lateral diameter femoral artery

PTMA

Cerclage

BACE basal annuloplasty of the cardia externally, CE European conformity, MI minimally invasive, PTMA percutaneous catheter-based mitral annuloplasty

Sternotomy/thoracotomy; percutaneous scheduled

External ventricle compression by four saline chambers

BACE

iCoapsys

“Asymmetrical”; 2 anchors connected by bridge element that is tensioned to reduce the septal-lateral Trans-jugular and trans-septal dimension of valve; uses 2 magnetic catheters that align at a right angle Adaptation of surgical system comprising anterior and posterior epicardial pads implanted in heart, connected Sub-xyphoid and drawn together by trans-ventricular cord

Trans-subclavian

PS3 Device

Cinching devices

Nitinol self-expanding device with a tension bridge segment that foreshortens over 3–4 weeks

Trans-jugular

Nitinol wire with distal and proximal anchors connected by an intervening cable

Monarc

Trans-jugular

Trans-septal

Carillon

Coronary sinus

Energy-mediated; uses high-intensity ultrasound to “scar” the annulus

Trans-septal

QuantumCor Energy-mediated; uses radiofrequency to shrink mitral annulus

ReCor

Trans-septal

Sutureless adjustable partial ring (helical anchors)

Cardioband

Trans-femoral artery, retrograde

Subvalvular implant, placed below the mitral annulus

Transventricular annular plication using sutures and pledgets

Mitralign

Trans-femoral artery, retrograde

Trans-septal Trans-femoral artery, retrograde

Space occupier, sealing surface between the leaflets

Trans-septal and trans-apical; modified for MI surgery

Minithoracotomy; transapical scheduled

AccuCinch

Direct

Thermocool smart touch Annuloplasty

Percu-pro

Others

Babic device Docking adapters and locking loop knot

Neochordae anchored to LV apex

NeoChord

Trans-apical

Trans-apical

Edge-to-edge clip (may add simultaneous chordal implantation)

MitraFlex

Chordal implantation

Trans-septal

Access

Edge-to-edge clip

Technique

MitraClip

Edge-to-edge

Leaflet repair

Device

Table 1 Overview of main transcatheter mitral valve repair devices

Percutaneous device preclinical

Preclinical; surgical device discontinued because of funding issues.

Few clinical cases

Preclinical

Clinical trial suspended

Clinical trial suspended

In clinical trial. CE mark obtained.

Preclinical

Preclinical

In clinical trial

In clinical trial

In clinical trial

Preclinical

Preclinical

Preclinical

Surgical device tested in clinical trial; percutaneous approach is preclinical.

First clinical trial completed. CE mark obtained. Registry ongoing.

Preclinical

CE mark obtained. Available for clinical use in Europe

Status

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J. of Cardiovasc. Trans. Res. Fig. 1 The MitraClip System. A polyester-covered clip with opened grips shown on the left. Intraprocedural leaflet capture guided by 3-D trans-esophageal echocardiography and final double orifice valve on the right

On the other hand, in the high-risk registry (HRR), enrolled patients had clinical or anatomical exclusion criteria for the MitraClip arm of the EVEREST randomized trial. The outcomes were compared with a control group represented by patients who were not treated because of anatomical contraindications to the implant. Compared with the control group, despite a trend in favor of Mitraclip, the 30-day and 1 year mortality of patients treated with MitraClip was similar [25]. In the HRR registry, the group of patients treated with the MitraClip showed a decreased number of hospitalizations (reduced by a factor of 55 % as compared with the year before implantation) with a documented benefit observed in both the DMR and FMR groups. In the ACCESS-EU registry, data were collected from 567 patients treated in 14 high-volume centers in Europe. This study is a prospective, observational, multicenter post-market trial. The European ACCESS registry offers a snapshot of the characteristics of patients who currently undergo the procedure in the real word: mainly elderly patients with comorbidities, high surgical risk, and a high prevalence of FMR. The etiology of MR was functional in 77 % of patients, equally distributed between idiopathic and post-ischemic forms. The majority of patients were severely symptomatic (NYHA class III–IV in 85 % of cases), and an ejection fraction less than 40 % was present in 53 %. Procedural success rate was Table 2 Mitraclip results of randomized clinical trial and registries Study name

N°

30-day 1-year 1-year freedom % MR≥ mortality mortality from surgery 2+ at 1 (%) (%) (%) year

EVEREST II RCT REALISM EVEREST High-Risk Registry ACCESS EU TRAMI Registry

184

1.5

9.6

78.9 %

21

272 351

1.1 4.8

6.2 22.8

90.4 98

17 17

567 3.4 1,064 2.8

17.3 –

93.7 –

21 –

TRAMI is the German TRAnscatheter Mitral valve Interventions [66]

99.6 %, with only two patients out of 566 in whom it was not possible to implant a clip. Mortality at 30 days was 3.4 %. This mortality rate is notably low, especially if we consider that the majority of patients were at high surgical risk and affected by MR secondary to chronic heart failure (HF). In 80 % of the cases, patients were discharged home, with no need of rehabilitative or home care. At 1 year, there were no cases of embolization of the clip while, in 27 (4.8 %) cases, there was a partial clip detachment (single leaflet attachment). At 12 months, the survival rate was 82 % and 79 % of patients showed residual MR less than or equal to 2+. In addition to the efficacy in reducing regurgitation, the ACCESS registry demonstrated remarkable clinical effectiveness: 1 year after the procedure, 71 % of patients were in NYHA functional class I or II, have an improvement in quality of life (with a mean reduction of Minnesota Living with HF Questionnaire of −13.5±20.5 points, from 41 to 28) and a gain Table 3 Key eligibility criteria and key exclusion criteria of Everest trial Key inclusion criteria Age 18 years or older Candidate for mitral valve repair or replacement surgery including Moderate to severe (3+) or severe (4+) chronic mitral valve regurgitation and symptomatic with LVEF >25 % and LVID-s ≤55 mm or asymptomatic with 1 or more of the following: EF >25 % to 60 % LVID-s ≤40 to 55 mm New onset of atrial fibrillation Pulmonary hypertension defined as pulmonary artery systolic pressure >50 mmHg at rest or >60 mmHg with exercise Transeptal deemed feasible Key exclusion criteria Recent myocardial infarction Any interventional or surgical procedure within 30 days of the index procedure Mitral valve orifice area ≤4 cm2 Renal insufficiency, endocarditis, rheumatic heart disease Previous mediastinal surgery in the first 27 patients CBP cardio-pulmonary bypass, LVEF left ventricular ejection fraction, LVID-s left ventricular internal diameter-systole

J. of Cardiovasc. Trans. Res. Table 4 Everest anatomical criteria

Schematic in the center, favorable echo image on the left, unfavorable on the right

in functional capacity (mean increase of 59±120 m from baseline at the 6-min walking test).

In the so-called “real world,” the MitraClip therapy, despite reports of worse results in terms of reduction MR compared

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with surgery, is usually reserved to high-risk patients, and it has confirmed an excellent safety profile (30 days mortality 2– 5 %) and acceptable mid-term outcomes (1 year survival 75– 85 %, 1 year freedom from MR >2+ 80 %) especially in terms of improvements in symptoms and quality of life [25–28]. European guidelines assigned an indication class IIb, level of evidence C, signifying that MitraClip may be considered in patients with symptomatic severe MR despite optimal medical therapy, who are judged inoperable or at high surgical risk by an Heart-team and with life expectancy greater than 1 year [8]. Longer and larger follow-up will be needed to verify MitraClip outcomes in terms of survival, MR recurrence impact, and quality of life. Two randomized trials, the RESHAPE in Europe and the COAPT in the US, are currently ongoing to evaluate the benefit of MitraClip with optimal medical therapy. A different approach to obtain transcatheter leaflet repair is off-pump adjustable chordal implantation, for which several devices are currently under development. Chordal implantation is a well suited technique for percutaneous application: It does not require resections; it allows multiple “devices” implantation, and it is perfectly fitted for live adjustment. The MitraFlex device (TransCardiac Therapeutics, Atlanta, USA) is still undergoing preclinical testing and uses a combined approach. Via a thoracoscopic trans-apical route, it deploys a clip to the mitral leaflets, allowing artificial chord implantation at the same time: It places an anchor in the inner LV and another on the leaflet and connects them with a synthetic chord. The NeoChord (NeoChord Inc., Minnetonka, USA) [29] uses a mini-thoracotomy transapical access to capture the leaflet (confirmed by four fiber-optic channels with corresponding indicator lights on the device monitor); the ePTFE chords are then exteriorized, adjusted, and tightened to the left ventricular myocardium using real-time echocardiographic guidance and secured to the apex itself. After a preliminary animal study a clinical trial on 30 patients has shown good safety results and promising MR reduction which appears to be directly associated with a higher number of neochords implanted [30]. A European registry is currently ongoing to confirm these data. The V-Chordal (Valtech Cardio Ltd., Or-Yehuda, Israel) [31] use a slow rotation of a helical element to fixate the chordae to the posterior papillary muscle (Fig. 2). Currently, the chordae are then sutured to the leaflets by direct vision through a mini-thoracotomy left atriotomy approach. A novel clip device to attach the leaflets is already under development to allow transapical access soon. The Babic device (Uros Babic, M.D.) [32] creates two continuous guiding tracks from the left ventricular puncture site through puncture sites of the target leaflet and exteriorized via the transseptal catheter and femoral vein. A polymer loop

Fig. 2 Schematic depicting the concept of anchoring the papillary muscle to the free margin of the mitral leaflet with a synthetic chordae

is apposed onto the venously exteriorized guiding tracks via docking adapters and is anchored onto the atrial leaflet surface by retracting the guiding tracks from the epicardial end. An elastic polymer tube is interposed between the leaflet and the free myocardial wall and secured to the epicardial surface by an adjustable knot. The device has also been modified for transapical approach. Alternative techniques for leaflet repair have been proposed. The Percu-Pro (Cardiosolutions, Stoughton, USA) is a space occupying “buoy” anchored at the LV apex through a trans-septal approach that should fill the gap between leaflets. This device acts as a spacer across the valve orifice providing a surface against which the leaflets can coapt. It is undergoing phase 1 trial and could be applied to both DMR and FMR. Open issues are the possible formation of thrombus on the device and the possibility of iatrogenic mitral stenosis. In addition, durability of the inflatable device needs to be investigated, as well as the consequences of chronic impact of the leaflet on the device. The Thermocool irrigation ablation electrode (Biosense Webster, Inc., Diamond Bar, California) is a radiofrequency ablation catheter delivered retrogradely through the femoral artery into the LV. The catheter is then placed in contact with the prolapsing leaflet and energy is delivered, causing scarring and fibrosis and reduced leaflet motion. Of course it was specifically designed to address DMR and tested in an animal setting [33]. The main challenge with this technology is that collagen shrinking is unpredictable and energy delivery has to

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be precisely controlled in order to avoid the risk of structural damages to the leaflet or other cardiac structures.

Annulus Repair The lack of a reliable annuloplasty device is probably the most important limitation to the expansion of the percutaneous mitral valve intervention field either in DMR and FMR. Annuloplasty is a fundamental step to achieve effective and durable results after surgery [34, 35]. The impact of annuloplasty is both reduction of MR due to the increase of the overall coaptation surface of the leaflets and control of stresses acting on leaflets [36]. Surgical correction of FMR is usually obtained by simply over-reducing the annular dimensions with undersized rings. Undersizing the annuloplasty prosthesis increases the surface of coaptation and overcomes leaflet tethering in most patients. Currently, the unavailability of a reliable annuloplasty device is reducing the chance of eligibility for transcatheter interventions. Up to 1/3 of patients screened for MitraClip are refused due to anatomical ineligibility, including annular dilatation [37]. Transcatheter annuloplasty may therefore both improve outcomes and expand therapeutic indications (from a pure anatomical standpoint). Different devices to reduce and reshape the mitral annulus are under development, addressing different anatomical and physio-pathological concepts. There are several devices that work on mitral annulus, the cinching ones, in different ways, trying to reduce septo-lateral dimension. On the other hand the sinoplasty ones reduce annular posterior dimension acting on internal portion of coronary sinus through the insertion of stents or rigid tubes of different shape. Newer tools, nowadays under evaluation, are grouped into two families: direct annuloplasty and energy/ waves remodeling. The direct devices tempt to resemble standard surgical technique with percutaneous approach. The second family utilizes percutaneous catheters radiating circumferentially ultrasound or radiofrequency waves that blaze annular tissue in order to shrink it. Annuloplasty therefore is currently a major unmet need in the transcatheter armamentarium that could widen therapeutic indications and improve results.

coronary sinus and an interatrial septal anchor at the level of the fossa ovalis linked by an adjustable bridge; the device is designed for specific septal–lateral reduction at the P2 level. Clinical experience is very limited today [39]; however, long experience in the animal has got promising results both in terms of safety and efficacy [40]. The Myocor i-Coapsys (Edwards Lifesciences Inc., Irvine, CA) is the percutaneous version of the surgical Coapsys, a device for LV-reshaping. The interventional device consists of two epicardial pads (anterior and posterior) connected by a load-bearing transventricular chord, all deliverable through a port inserted in the pericardium, with a percutaneous sub-xyphoid approach. Large-scale data from the surgical RESTOR-MV trial suggest that, besides the MR reduction, the Coapsys can produce a significant LV restoration effect [41], also reducing myocardial fiber stress [42]. The Coapsys was reported to be one of the few therapies to show a significant survival benefit in functional MR patients, but the surgical RESTOR-MV Trial was stopped due to funding reasons. Feasibility and safety of the i-Coapsys has been demonstrated in preclinical animal setting [43], and human initial experience has also been reported (Pedersen W. Failure Analysis for Percutaneous MV Repair Devices, TCT Meeting, San Francisco 2009). After Edwards acquired the device, development has been discontinued. The Mardil BACE (Basal Annuloplasty of the Cardia Externally, Mardil, Inc., and Morrisville, North Carolina) brings the concept of ventricular restoration to MR reduction even further. Via a conventional median sternotomy or thoracotomy, a wide band with an inflatable chambers is slipped externally around the base of the beating heart without cardiopulmonary bypass and secured by sutures deployed on both the atrial and ventricular sides of the atrio-ventricular groove [44]. The chamber can be inflated by saline through subcutaneous ports and their volume can be adjusted intraand post-operatively, thus remodeling mitral valve annulus and sub-valvular apparatus. After animal models, successful surgical use in human patients submitted to CABG has already been described [45], and a percutaneous version has been projected.

Cinching Devices

Coronary Sinus Devices (Sinoplasties)

These technologies force septo-lateral annular reduction through the approximation of two devices connected by a bridge. This has been shown to be a fundamental pathological component in functional MR [38] (Fig. 3). The reduction can be achieved either by intracardiac pulling or by external pushing. The Ample PS3 System (Ample Medical Inc., Foster City, CA, USA) consists of an anchor (“T bar”) inserted in the

The coronary sinus (CS) encircles about two thirds of the mitral annulus and can be used as a route to produce tension which is transmitted to the mitral annulus, pushing the posterior annulus anteriorly and reducing the septolateral dimension. This approach has been particularly attractive because the cannulation of the CS is an easy and well-established venous access technique. CS devices therefore were historically among the first to emerge.

J. of Cardiovasc. Trans. Res. Fig. 3 Cinching devices. a The Ample PS3; b the i-Coapsys; c the BACE

Regarding sinoplasty devices data are available about three systems (Fig. 4): the MONARCH, the Carillon, and the PTMA system. The MONARCH (Edwards Lifesciences, Irvine, California) consisted in a distal anchor placed between the anterior interventricular vein and the great cardiac vein, a connecting spring-like bridge and a proximal anchor placed in the ostial CS. The data published on the MONARCH are 1-year results from the EVOLUTION Phase I Study (Clinical Evaluation of the Edwards Lifesciences Percutaneous Mitral Annuloplasty System for the treatment of mitral regurgitation using the sinoplasty MONARC System) [46]. In this study, the feasibility of the device was tested in 72 patients with MR grade >2 enrolled at eight participating centers in four countries. The MONARC device was implanted in 59 of 72 patients (82 %). The primary safety end point (freedom from death, tamponade, or myocardial infarction at 30 days) was met in 91 % of patients at 30 days and in 82 % at 1 year. The procedure was associated with angiographic coronary artery compression in 15 patients (in whom the coronary sinus/great cardiac vein courses over the circumflex artery) and late myocardial infarction in two patients (3.4 %). After this initial high complication rate, further clinical evaluation had been suspended. The Cardiac Dimension Carillon (Cardiac Dimension, Kirkland, USA) is composed by two nitinol anchors (distal anchor placed in the great cardiac vein and proximal anchor in Fig. 4 Coronary sinus annuloplasty and the corresponding clinical trials

the proximal CS linked by a bridge element. Tension applied on the system results in cinching of the posterior mitral annulus. It is recapturable and repositionable. Numerous subsequent versions of the devices have been already developed to reduce the risk of stent fracture and optimize efficacy. The impact of Carillon Mitral was evaluated in HF patients with at least moderate FMR in the TITAN trial (Transcatheter Implantation of Carillon Mitral Annuloplasty Device) [47]. Safety and key functional data were assessed in the implanted cohort up to 24 months. Thirty-six patients received a permanent implant; 17 had the device recaptured. The 30-day major adverse event rate was 1.9 %. The implanted cohort demonstrated significant reductions in FMR as represented by regurgitant volume [baseline 34.5 ± 11.5 mL to 17.4 ± 12.4 mL at 12 months (P45°, distal anterior leaflet-annular plane angle >20° for FMR), these patients could be future candidates for trans-catheter mitral valve replacement and not percutaneous repair.

Notes on Transcatheter Mitral Replacement Valve in Valve/in Ring The transcatheter Edwards-SAPIEN (Edwards Lifesciences, Inc, Irvine, US) prosthesis designed for TAVI has been often used for mitral valve-in-valve or valve-in-ring implantation in the clinical setting. The annular rigid artificial structure is a perfect landing. Data from the world registry [Dvir D. Transcatheter Mitral/Tricuspid Valve Implantation in Failed Surgical Valves-Update from the Global Registry, TVT Meeting, Vancouver 2013] confirmed a significant acute mortality likely due to the high-risk patient’s profile, but a remarkable symptoms improvement after the procedure. Although the procedure is feasible via a totally percutaneous approach via transfemoral trans-septal anterograde route [64], the most used approach remains transapical (88 %). Mitral Valve Implantation Percutaneous mitral valve implantation will be available in the near future to complete the therapeutic portfolio, potentially

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expanding the indications to patients with rheumatic disease or with anatomy unsuitable for repair (Table 5). There are still several obstacles to the development of a reliable device for transcatheter mitral valve implantation. Compared with the aortic valve, the mitral valve anatomy is more complex and far from a cylindrical geometry. Moreover, the larger size of the annulus compared with the aortic valve prevents the use of conventional stent technology. Anchoring of the implant is another challenge, since radial force cannot be applied for the large dimensions of the valve and because a real annulus does not exist, neither is usually calcified, as for the aortic valve. Using radial force would be suboptimal also due to the risk of impingement into the aortic valve. The anatomy of the mitral valve is totally asymmetric, therefore mitral implantation devices should be designed to accommodate this feature. In particular, the anterior leaflet of the mitral valve is directed towards the LVOT. A mitral implant has to take care of this and should not protrude in the outflow tract to avoid obstruction. Last but not least, if perivalvular leaks are tolerated in the aortic position, they will not be acceptable in the mitral position, since they will be more clinically relevant and may induce severe hemolysis. The ideal MV prosthesis would be implanted without any obstruction of LV outflow, without impingement into the aortic root, and no (or only minimal) perivalvular leakage (Table 4). Perivalvular Leak Closure Perivalvular leakage is a frequent complication of prosthetic valve implantation occurring in up to 17 % of mitral valve replacement operations. Surgical re-intervention is associated with high morbidity. Leak closure has emerged as a valid option for high-risk or inoperable patients. Procedural outcomes have improved along the years, with a success rate around 70–80 % among the different series and a low acute

mortality of 2 % [65]. Different kinds of occluders (vascular, atrial septal defect, patent ductus arteriosus plugs) are available, as well as different accesses (venous transfemoral transeptal route or transapical). These procedures must be reserved at the moment to symptomatic high-risk patients with suitable anatomy.

Image Guidance and Technical Aspects Key to all these percutaneous transcatheter therapies is the use of imaging to guide patient selection as well as intra-procedure performance. Careful patient selection remains paramount for success with imaging determination of mitral pathology and accurate comprehension of the mechanism of MR. Technical success is dependent on skills with echocardiographic imaging, with three-dimensional trans-esophageal echocardiography particularly. An important point is the transseptal puncture, since is the prime step in the majority of the procedures. This point needs has to be in a specific position relative to the pathology of the MR, and therefore, intra-procedure imaging is critical to determine this location (Fig. 8). The traditional imaging modalities in the catheterization laboratory of fluoroscopy and cineradiography are of minimal utility as they cannot visualize the mitral leaflets. Therefore, the procedure is guided by simultaneous 3D trans-esophageal echocardiography (TEE). The introduction of 3D real-time imaging is mandatory for all these type of procedure. We can obtain a real surgical view of the mitral valve from the atrium or from the ventricle, and with the X-plane function, we can precisely position our device in the desired position. The transseptal puncture is also guided by 3D-TEE. The transseptal puncture, for every specific device should be in a different point. For Mitraclip, this location is usually superior and mid-posterior; it needs to be over the

Table 5 Mitral valve implantation devices for transcatheter delivery device Approach

Description

CardiAQ

Transeptal

“Lutter prosthesis” CardioValve

Transapical

Tiara

Transapical

Medtronic Mitral Program EndoValve

Transeptal

Self-positioning, self-anchoring and self-conforming in three dimensions; fixation does not First-in-man involve the use of radial force. performed in 2012 [67] Nitinol structure featuring an atrial fixation, a tubular intrannular segment and a ventricular Preclinical [68] chordal fixation system. Two-stage implant: atrial skirt assuring adequate fixation and landing zone onto which the Preclinical [69] prosthesis is deployed. D-shaped atrial frame to respect LVOT and aorta; anchoring structures to fibrous trigones Preclinical [70] and posterior leaflet Wide atrial inflow and short profile ventricular outflow; uses gripper to leaflet capture. Preclinical [71]

“von Segesser prosthesis”

Transeptal

Trans-septal

Status

Tripod-shaped nitinol and stainless steel frame leverages claw-like gripping features for Preclinical fixation and a support ring for bioprosthetic leaflets. Minithoracotomy Porcine valve sutured into a Dacron conduit, onto which two nitinol Z-stents were sutured Preclinical to form two self-expanding crowns for fixation, ventricular and atrial.

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Fig. 8 Schematic of coordinates for transeptal puncture (left) and corresponding navigation TEE views (right). Using TEE bicaval (view 100°– 110° on the multiplane), we can reach the height of the puncture. The short axis at the base view (∼45° on the multiplane) allows determination of the anterior/posterior position and the distance from the aortic valve. In

the four-chamber view, we evaluate both the distance of the puncture to the line of coaptation. The Mitraclip puncture has to be in the superior part of the fossa, mid-posterior from the aorta, 3,5/4 cm distant from the aorta in FMR, 4–4.5 in DMR to allow efficient grasping

line of coaptation of the mitral valve, which is generally a posterior point, higher in patient with FMR and lower in patients with DMR. Using TEE bicaval (view 100°–110° on the multiplane), we can reach the height of the puncture. The short axis at the base view (which is usually ∼45° on the multiplane) allows determination of the anterior/posterior relationship and the distance from the aortic valve; in Mitraclip procedure, the optimal location is generally mid-posterior. Finally, in the four-chamber view, we evaluate both the point of transseptal puncture and the mitral valve. For example, in Mitraclip procedure, it must be positioned ∼4 cm above the point of mitral coaptation line; for the Cardioband, an inferior puncture is preferable. Proper location of the transeptal puncture is critical to provide a smooth procedure. The transeptal puncture may be particularly challenging in case of thick septum (as in case of post cardiotomy patients), large left or right atrium, in presence of bulging septum and in presence of intracardiac pacing leads. In Mitraclip therapy, possible complications due to suboptimal puncture are aortic hugging (too anterior puncture), inability to cross the mitral valve (too high puncture), inability to pull back the clip and tether the leaflets (too low puncture), and perforation (too posterior puncture). Three-dimensional trans-esophageal echocardiography is also mandatory during all the procedures in order to evaluate the exact positioning of any device in relation to cardiac structure and to assess the success of the procedure in terms of reduction of MR. Newer probes and 3D softwares with better spatial and temporal-resolution are under evaluation. Another interesting future application could be the ICE (Intra Cardiac Echocardiography). The ICE device is an 8/10Fr. probe inserted via an introducer into the human vessel. With ultrasound and echo Doppler technology, it provides meaningful, real-time anatomic information occurring within the structures of the heart (Fig. 9). Nowadays, ICE is already adopted in Electrophysiology Laboratories for ablation procedures or during the implant of coronary sinus leads (procedure similar to sinoplasty). Thus, the introduction of ICE could open the way to

a totally percutaneous mitral valve plasty without the need of TEE and therefore the absence of intubation. Ultimately, cardiac-gated computed tomographic (CT) scan is increasingly playing a relevant role during decision making and to plan the strategy for transcatheter mitral intervention. It is fundamental not only to identify any coronary disease, but also to calculate the exact distance between them (coronary artery and CS) and to evaluate the structure and relation of the mitral annulus with the surrounding tissues in order to prevent damage with a specific device, to define the diameter and the EF of the ventricles and to determine accurately the anatomy of vessels and to plan the possible access route (trans-femoral or transapical). Currently, during the procedure, the fluoroscopy tool with pre-operative CT scan and the TEE images are complementary modalities and are visualized in separate coordinate systems and on separate monitors creating a challenging clinical workflow. Thus, different companies are working on fusion imaging that allows superimposing on fluoroscopic screen the soft tissue images obtained by echocardiography interconnecting them with previously collected CT images. All these new improvements in technology, especially the development of fusion imaging, will help us to be more

Fig. 9 ICE cardiac image during Cardioband implantation in swine (right), fluoroscopic guidance (bottom left), and the device (top left)

J. of Cardiovasc. Trans. Res.

precise, to speed up the procedures, and to be more appropriate in patient selection.

Conclusion A relevant number of patients in need of MR reduction do not undergo surgery because of a high perioperative risk. Given the technological progress of the present day, transcatheter valve technologies represent the natural evolution of minimally invasive surgery, aiming to reduce the procedural risk and invasiveness. To date, MitraClip therapy has proved excellent safety results and good efficacy in high-risk patients and is already a real and valid option in such a population. In particular, the lack of a reliable annuloplasty device is probably the most important limitation to the expansion of the percutaneous mitral valve intervention field either in degenerative and in functional disease. For all these reasons, several devices, addressing many different anatomical and pathophysiological concepts (from annuloplasty to chordal implantation or LV remodeling), are under development to improve outcomes and expand patients’ indications. Finally, transcatheter mitral valve implantation will be considered in the next future to complete the therapeutic portfolio. Imaging is fundamental for pre-operative planning and intra-procedural guidance and relies on 3D trans-esophageal echocardiography, 3D coronary CT scan, fluoroscopy, and fusion imaging techniques. The patient-centered care and the Heart-Team approaches are fundamental to obtain procedural success and, more importantly, patient health.

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