Devices for Mitral Valve Repair

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, atrialfibrillation, stroke, and death. Many patients affected by se-vere regurgitation (MR) do not currently undergo surgery,mainly due to the perceived risk of the procedure (old age,impaired left ventricular function, and comorbidities). Mitraltranscatheter interventions carry the hope of minimizing riskswhile preserving clinical efficacy of surgical repair, as analternative to conventional treatment. Multiple technologiesand diversified approaches are under development with thepurpose of treating MR in less invasive ways. They can becategorized based on the anatomical and patho-physiologicaladdressed target. Among them, MitraClip (Abbott Vascular,Inc., Menlo Park, California) has emerged as a clinically safeand effective method for percutaneous mitral valve repair inpatients either with degenerative and functional regurgitation.This device mimics the surgical edge-to-edge repair initiallydescribed by Alfieri in the early 1990s. Other repair technol-ogies include percutaneous direct and indirect annuloplasty,neochordae implantation, and left ventricular reshaping. Theyare still in early phase clinical trials or preclinical studies. Thecombination of different repair techniques is likely to berequired to achieve good long-lasting results. In the future,novel devices, improved knowledge, more efficient imaging,and transcatheter mitral prosthetic valve implantation mayexpand the indications to those patients currently not treated,as well as improve the results both in terms of early efficacy

and long-term durability. These treatments are currently re-served to high-risk and inoperable patients, and their applica-tion requires an integrated Heart-Team approach. They repre-sent the natural evolution of surgery and promise to expandtreatment options and improve patients’ outcomes in the nearfuture.

Keywords Transcatheter . Percutaneous .Mitral . Repair

Introduction

Mitral regurgitation (MR) is the most prevalent valve diseasein the western population [1–3]. WhenMR is severe, freedomfrom events and life expectancy are reduced [2, 4–6]. Accord-ing to guidelines, symptomatic patients with severe MRshould be submitted to surgery [7, 8].

Conventional treatment of significant MR is surgery, eitherrepair (better) or replacement. This is particularly true fordegenerative mitral regurgitation (DMR). Surgery for DMRis very safe and effective, and in relatively young patients withfew comorbidities, hospital mortality is below 1 % [9]. As aconsequence, the current approach is to perform early surgerywith mitral valve reconstruction to guarantee preservation oflife expectancy and quality of life similar to a comparablehealthy population [10]. Freedom from reoperation is 93.8 %at 10 years [11]. On the other hand, the landscape of functionalmitral regurgitation (FMR) therapies is wide and full of con-troversies. Functional MR is loading condition-dependent,and timing of surgery can be difficult to establish, particularlywhen patients are evaluated under aggressive therapy and inresting state [12]. Surgery for FMR carries higher risk com-pared with DMR; there is a 25–30 % of recurrence of MR atmid -term [13], and its prognostic value as well as the bestsurgical treatment is still debated [14, 15].

Euro Heart survey showed that up to 50 % of symptomaticpatients hospitalized with the diagnosis of severe MR are not

Associate Editor Craig Stolen oversaw the review of this article.

P. Denti (*) :O. AlfieriSan Raffaele University Hospital, Via Olgettina, 6020100 Milan, Italye-mail: [email protected]

O. Alfierie-mail: [email protected]

F. MaisanoUniversity Hospital Zurich, Zurich, Switzerland

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

referred to surgery due to the risk of the procedure [16]. Thesepatients are usually elderly (above 70 years), affected bymanycomorbidities, 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 transcatheteraortic valve replacement for aortic stenosis, there has been asimilar advance in the field of transcatheter mitral valve ther-apy for MR. Both the anatomy of the mitral apparatus and thespectrum of pathology of MR are more complex than foraortic valve disease, and thus the development of MR thera-pies has been more complicated and less rapid.

To reduce the invasiveness of the surgical approach, mul-tiple technologies and diversified minimally invasive trans-catheter techniques are emerging to treat MR in high-risk andelderly patients, as an alternative to conventional surgery(Table 1). As such, transcatheter interventions may improveoutcomes by reducing risks in elderly patients, with reducedLV function or with comorbidities, as well as open the way forearlier interventions, particularly in the field of FMR [17].

These devices can be categorized by the anatomical andpatho-physiological addressed target. A classification of per-cutaneous mitral valve repair technologies on the basis offunctional anatomy is proposed; it groups the devices intothose targeting the leaflets, the annulus, the chordae, or the LV.

The purpose of this review is to discuss all the transcatheterrepair techniques, presenting those currently available in theclinical setting along with those still in the development phase,explaining the rationale behind them and their futureperspectives.

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 indevices that work at the leaflets level and at the annulus level.

Leaflet Repair

All these procedures act directly at the leaflet level with thefinal goal of improving leaflet coaptation and reducing theeffective regurgitant orifice.

The most advanced technology under this category is theMitraClip System (Abbott Vascular, Inc., Menlo Park, Cali-fornia). It is the most widely used transcatheter mitral device(more than 10,000 procedures worldwide). The MitraClipsystem was almost directly derived from the surgical edge-to-edge technique [18, 19] that corrects MR regardless of theunderlying mechanism of dysfunction (Fig. 1). MitraClip iseffective to treat both degenerative DMR and FMR.

The surgical technique consists in suturing the free marginsof both mitral leaflets at the origin of regurgitation, under

direct vision with extracorporeal circulation and cardioplegicarrest. In the case of percutaneous treatment, the leaflets arejoined by applying a clip under echocardiography guidance onbeating heart. The MitraClip device is a single-sized, percuta-neously implanted mechanical Clip. The MitraClip devicegrasps and coapts the mitral valve leaflets, resulting in fixedapproximation of them throughout the cardiac cycle. Beforerelease of the clip, the device can be locked and unlocked andrepeatedly opened and closed. The procedure is performed inthe cardiac catheterization laboratory with echocardiographicand fluoroscopic guidance while the patient is under generalanesthesia. To access the left heart, standard transseptal cath-eterization is performed; then the delivery catheter is insertedinto the left atrium, and the Clip is positioned above the mitralvalve in order to capture the leaflets. More than one clip can bedelivered, and each one remains repositionable untildetachment.

Compared with the surgical edge-to-edge procedure, thepercutaneous MitraClip implant offers the advantage of areduced trauma. Of note, it also allows real-time assessmentof the hemodynamic effects of the clip implant by onlineechocardiography. In case the result is suboptimal, the clipcan be repositioned or additional clips can be implanted.

The edge-to-edge surgical experience has proven to beeffective and versatile. Versatility is a characteristic retainedalso by the percutaneous device. In fact, MitraClip implantcan 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 treatedwith this device all over the world. The majority of cases havebeen performed in Europe. Moreover, MitraClip therapy hasbeen evaluated in several trials and registries (Table 2).

The EVEREST study (Endovascular Valve Edge-to-edgeREpair of mitral regurgitation STudy) comprises a series oftrials [21–24], including the first randomized controlled trialin which the percutaneous approach was compared with sur-gical treatment in selected patients with MR (mainly withdegenerative etiology). Patients included were selected withinclusion and exclusion criteria (Table 3), but, most importantthey had particular anatomical characteristics evaluated byechocardiography (Table 4). In a post hoc analysis, theMitraClip therapy seemed to be non-inferior to surgery interms of effectiveness in three subgroups of patients: patientsolder than 70 years, those with LV dysfunction, and those withFMR [22], of course with all the limit of this type of testing.

At landmark analysis, it became evident that the eventualfailure of the procedure occurs mainly in the first 6 monthsafter implantation. After this time, patients who require surgi-cal revision after MitraClip are rare and their number is notsignificantly different from that observed in the cohort ran-domized to surgical treatment. This failure is potentially pre-ventable with better patient selection and improved implanta-tion technique.

J. of Cardiovasc. Trans. Res.

Table1

Overviewof

maintranscathetermitralvalverepairdevices

Device

Technique

Access

Status

Leafletrepair

Edge-to-edge

MitraC

lipEdge-to-edgeclip

Trans-septal

CEmarkobtained.A

vailableforclinicalusein

Europe

MitraFlex

Edge-to-edgeclip

(may

addsimultaneouschordalimplantatio

n)Trans-apical

Preclin

ical

Chordalim

plantation

NeoChord

Neochordaeanchored

toLV

apex

Trans-apical

Firstclin

icaltrialcom

pleted.C

Emarkobtained.

Registryongoing.

V-Chordal

Neochordaeusingsuctionandclipping

toleafletconnectionandhelicalanchor

topapillary

musclefixatio

nMinith

oracotom

y;transapical

scheduled

Surgicaldevice

tested

inclinicaltrial;

percutaneous

approach

ispreclinical.

Babicdevice

Docking

adaptersandlockingloop

knot

Trans-septaland

trans-apical;

modifiedforMIsurgery

Preclinical

Others

Percu-pro

Spaceoccupier,sealingsurfacebetweentheleaflets

Trans-septal

Preclinical

Therm

ocool

smart

touch

Segm

entalleafletablatio

nor

plication

Trans-fem

oralartery,retrograde

Preclin

ical

Annuloplasty

Direct

AccuC

inch

Subvalvularim

plant,placed

belowthemitralannulus

Trans-fem


Inclinicaltrial

Mitralign

Transventricularannularplicationusingsuturesandpledgets

Trans-fem


Inclinicaltrial

Cardioband

Sutureless

adjustablepartialring(helicalanchors)

Trans-septal

Inclinicaltrial

Quantum

Cor

Energy-mediated;

uses

radiofrequency

toshrink

mitralannulus

Trans-septal

Preclinical

ReC

orEnergy-mediated;

uses

high-intensity

ultrasound

to“scar”

theannulus

Trans-septal

Preclinical

Coronarysinus

Carillon

Nitinolw

irewith

distalandproxim

alanchorsconnectedby

aninterveningcable

Trans-jugular

Inclinicaltrial.CEmarkobtained.

Monarc

Nitinolself-expandingdevice

with

atensionbridge

segm

entthatforeshortensover

3–4weeks

Trans-jugular

Clin

icaltrialsuspended

PTMA

Usedperm

anentthinalloyrods

todisplace

anteriorly

theposteriorannulus

Trans-subclavian

Clin

icaltrialsuspended

Cerclage

After

coronary

sinusim

planttransverses

themyocardium

tore-enter

therightchambers,reduces

also

septo-

laterald

iameter

Trans-jugular,fem

oralvein,and

femoralartery

Preclinical

Cinchingdevices

PS3Device

“Asymmetrical”;2

anchorsconnectedby

bridge

elem

entthatistensionedto

reduce

theseptal-lateral

dimension

ofvalve;uses

2magnetic

cathetersthatalignatarightangle

Trans-jugular

andtrans-septal

Fewclinicalcases

iCoapsys

Adaptationof

surgicalsystem

comprisinganterior

andposteriorepicardialpadsim

plantedinheart,connected

anddraw

ntogether

bytrans-ventricularcord

Sub-xyphoid

Preclinical;surgicald

evicediscontinued

becauseof

fundingissues.

BACE

Externalv

entriclecompression

byfour

salinecham

bers

Sternotomy/thoracotom

y;percutaneous

scheduled

Percutaneous

device

preclin

ical

BACEbasalannuloplastyof

thecardiaexternally,C

EEuropeanconformity,M

Iminim

ally

invasive,P

TMApercutaneous

catheter-based

mitralannuloplasty


On the other hand, in the high-risk registry (HRR), enrolledpatients had clinical or anatomical exclusion criteria for theMitraClip arm of the EVEREST randomized trial. The out-comes were compared with a control group represented bypatients who were not treated because of anatomical contra-indications to the implant. Compared with the control group,despite a trend in favor of Mitraclip, the 30-day and 1 yearmortality of patients treated with MitraClip was similar [25].

In the HRR registry, the group of patients treated with theMitraClip showed a decreased number of hospitalizations(reduced by a factor of 55 % as compared with the year beforeimplantation) with a documented benefit observed in both theDMR and FMR groups.

In the ACCESS-EU registry, data were collected from 567patients treated in 14 high-volume centers in Europe. Thisstudy is a prospective, observational, multicenter post-markettrial.

The European ACCESS registry offers a snapshot of thecharacteristics of patients who currently undergo the proce-dure in the real word: mainly elderly patients with comorbid-ities, high surgical risk, and a high prevalence of FMR. Theetiology of MR was functional in 77 % of patients, equallydistributed between idiopathic and post-ischemic forms. Themajority of patients were severely symptomatic (NYHA classIII–IV in 85 % of cases), and an ejection fraction less than40 % was present in 53 %. Procedural success rate was

99.6 %, with only two patients out of 566 in whom it wasnot possible to implant a clip. Mortality at 30 days was 3.4 %.This mortality rate is notably low, especially if we considerthat the majority of patients were at high surgical risk andaffected by MR secondary to chronic heart failure (HF). In80 % of the cases, patients were discharged home, with noneed of rehabilitative or home care. At 1 year, there were nocases 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 patientsshowed residual MR less than or equal to 2+.

In addition to the efficacy in reducing regurgitation, theACCESS registry demonstrated remarkable clinical effective-ness: 1 year after the procedure, 71 % of patients were inNYHA functional class I or II, have an improvement in qualityof life (with a mean reduction of Minnesota Living with HFQuestionnaire of −13.5±20.5 points, from 41 to 28) and a gain

Fig. 1 The MitraClip System. Apolyester-covered clip withopened grips shown on the left.Intraprocedural leaflet captureguided by 3-D trans-esophagealechocardiography and finaldouble orifice valve on the right

Table 2 Mitraclip results of randomized clinical trial and registries

Study name N° 30-daymortality(%)

1-yearmortality(%)

1-year freedomfrom surgery(%)

% MR≥2+ at 1year

EVEREST IIRCT

184 1.5 9.6 78.9 % 21

REALISM 272 1.1 6.2 90.4 17

EVERESTHigh-RiskRegistry

351 4.8 22.8 98 17

ACCESS EU 567 3.4 17.3 93.7 21

TRAMIRegistry

1,064 2.8 – – –

TRAMI is the German TRAnscatheter Mitral valve Interventions [66]

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 valveregurgitation 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 indexprocedure

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


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

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

Table 4 Everest anatomical criteria

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


with surgery, is usually reserved to high-risk patients, and ithas confirmed an excellent safety profile (30 daysmortality 2–5 %) and acceptable mid-term outcomes (1 year survival 75–85 %, 1 year freedom fromMR >2+ 80%) especially in termsof improvements in symptoms and quality of life [25–28].

European guidelines assigned an indication class IIb, levelof evidence C, signifying that MitraClip may be considered inpatients with symptomatic severeMR despite optimal medicaltherapy, who are judged inoperable or at high surgical risk byan Heart-team and with life expectancy greater than 1 year [8].

Longer and larger follow-up will be needed to verifyMitraClip outcomes in terms of survival, MR recurrenceimpact, and quality of life. Two randomized trials, the RE-SHAPE in Europe and the COAPT in the US, are currentlyongoing to evaluate the benefit of MitraClip with optimalmedical therapy.

A different approach to obtain transcatheter leafletrepair is off-pump adjustable chordal implantation, forwhich several devices are currently under development.Chordal implantation is a well suited technique for percu-taneous application: It does not require resections; it allowsmultiple “devices” implantation, and it is perfectly fitted forlive adjustment.

TheMitraFlex device (TransCardiac Therapeutics, Atlanta,USA) is still undergoing preclinical testing and uses a com-bined approach. Via a thoracoscopic trans-apical route, itdeploys a clip to the mitral leaflets, allowing artificial chordimplantation at the same time: It places an anchor in the innerLV and another on the leaflet and connects them with asynthetic chord.

The NeoChord (NeoChord Inc., Minnetonka, USA) [29]uses a mini-thoracotomy transapical access to capture theleaflet (confirmed by four fiber-optic channels with corre-sponding indicator lights on the device monitor); the ePTFEchords are then exteriorized, adjusted, and tightened to the leftventricular myocardium using real-time echocardiographicguidance and secured to the apex itself. After a preliminaryanimal study a clinical trial on 30 patients has shown goodsafety results and promising MR reduction which appears tobe directly associated with a higher number of neochordsimplanted [30]. A European registry is currently ongoing toconfirm these data.

The V-Chordal (Valtech Cardio Ltd., Or-Yehuda, Israel)[31] use a slow rotation of a helical element to fixate thechordae to the posterior papillary muscle (Fig. 2). Currently,the chordae are then sutured to the leaflets by direct visionthrough a mini-thoracotomy left atriotomy approach. A novelclip device to attach the leaflets is already under developmentto allow transapical access soon.

The Babic device (Uros Babic, M.D.) [32] creates twocontinuous guiding tracks from the left ventricular puncturesite through puncture sites of the target leaflet and exteriorizedvia the transseptal catheter and femoral vein. A polymer loop

is apposed onto the venously exteriorized guiding tracks viadocking adapters and is anchored onto the atrial leaflet surfaceby retracting the guiding tracks from the epicardial end. Anelastic polymer tube is interposed between the leaflet and thefree myocardial wall and secured to the epicardial surface byan adjustable knot. The device has also been modified fortransapical approach.

Alternative techniques for leaflet repair have beenproposed.

The Percu-Pro (Cardiosolutions, Stoughton, USA) is aspace occupying “buoy” anchored at the LV apex through atrans-septal approach that should fill the gap between leaflets.This device acts as a spacer across the valve orifice providinga surface against which the leaflets can coapt. It is undergoingphase 1 trial and could be applied to both DMR and FMR.Open issues are the possible formation of thrombus on thedevice and the possibility of iatrogenic mitral stenosis. Inaddition, durability of the inflatable device needs to be inves-tigated, as well as the consequences of chronic impact of theleaflet on the device.

The Thermocool irrigation ablation electrode (BiosenseWebster, Inc., Diamond Bar, California) is a radiofrequencyablation catheter delivered retrogradely through the femoralartery into the LV. The catheter is then placed in contact withthe prolapsing leaflet and energy is delivered, causing scarringand fibrosis and reduced leaflet motion. Of course it wasspecifically designed to address DMR and tested in an animalsetting [33]. The main challenge with this technology is thatcollagen shrinking is unpredictable and energy delivery has to

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


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

Annulus Repair

The lack of a reliable annuloplasty device is probably the mostimportant limitation to the expansion of the percutaneousmitral valve intervention field either in DMR and FMR.Annuloplasty is a fundamental step to achieve effective anddurable results after surgery [34, 35]. The impact ofannuloplasty is both reduction of MR due to the increase ofthe overall coaptation surface of the leaflets and control ofstresses acting on leaflets [36]. Surgical correction of FMR isusually obtained by simply over-reducing the annular dimen-sions with undersized rings. Undersizing the annuloplastyprosthesis increases the surface of coaptation and overcomesleaflet tethering in most patients. Currently, the unavailabilityof a reliable annuloplasty device is reducing the chance ofeligibility for transcatheter interventions. Up to 1/3 of patientsscreened for MitraClip are refused due to anatomical ineligi-bility, including annular dilatation [37]. Transcatheterannuloplasty may therefore both improve outcomes and ex-pand therapeutic indications (from a pure anatomical stand-point). Different devices to reduce and reshape the mitralannulus are under development, addressing different anatom-ical and physio-pathological concepts.

There are several devices that work on mitral annulus, thecinching ones, in different ways, trying to reduce septo-lateraldimension. On the other hand the sinoplasty ones reduceannular posterior dimension acting on internal portion ofcoronary sinus through the insertion of stents or rigid tubesof different shape. Newer tools, nowadays under evaluation,are grouped into two families: direct annuloplasty and energy/waves remodeling. The direct devices tempt to resemble stan-dard surgical technique with percutaneous approach. Thesecond family utilizes percutaneous catheters radiatingcircumferentially ultrasound or radiofrequency waves thatblaze annular tissue in order to shrink it.

Annuloplasty therefore is currently a major unmet need inthe transcatheter armamentarium that could widen therapeuticindications and improve results.

Cinching Devices

These technologies force septo-lateral annular reductionthrough the approximation of two devices connected by abridge. This has been shown to be a fundamental pathologicalcomponent in functional MR [38] (Fig. 3). The reduction canbe achieved either by intracardiac pulling or by externalpushing.

The Ample PS3 System (Ample Medical Inc., Foster City,CA, USA) consists of an anchor (“T bar”) inserted in the

coronary sinus and an interatrial septal anchor at the level ofthe fossa ovalis linked by an adjustable bridge; the device isdesigned for specific septal–lateral reduction at the P2 level.Clinical experience is very limited today [39]; however, longexperience in the animal has got promising results both interms of safety and efficacy [40].

The Myocor i-Coapsys (Edwards Lifesciences Inc., Irvine,CA) is the percutaneous version of the surgical Coapsys, adevice for LV-reshaping. The interventional device consists oftwo epicardial pads (anterior and posterior) connected by aload-bearing transventricular chord, all deliverablethrough a port inserted in the pericardium, with a per-cutaneous sub-xyphoid approach. Large-scale data fromthe surgical RESTOR-MV trial suggest that, besides theMR reduction, the Coapsys can produce a significantLV restoration effect [41], also reducing myocardialfiber stress [42]. The Coapsys was reported to be oneof the few therapies to show a significant survival benefitin functional MR patients, but the surgical RESTOR-MVTrial was stopped due to funding reasons. Feasibility andsafety of the i-Coapsys has been demonstrated in preclinicalanimal setting [43], and human initial experience has alsobeen reported (PedersenW. Failure Analysis for PercutaneousMV Repair Devices, TCT Meeting, San Francisco 2009).After Edwards acquired the device, development has beendiscontinued.

The Mardil BACE (Basal Annuloplasty of the CardiaExternally, Mardil, Inc., and Morrisville, North Carolina)brings the concept of ventricular restoration to MR reductioneven further. Via a conventional median sternotomy or thora-cotomy, a wide band with an inflatable chambers is slippedexternally around the base of the beating heart without car-diopulmonary bypass and secured by sutures deployed onboth the atrial and ventricular sides of the atrio-ventriculargroove [44]. The chamber can be inflated by saline throughsubcutaneous ports and their volume can be adjusted intra-and post-operatively, thus remodeling mitral valve annulusand sub-valvular apparatus. After animal models, successfulsurgical use in human patients submitted to CABG has al-ready been described [45], and a percutaneous version hasbeen projected.

Coronary Sinus Devices (Sinoplasties)

The coronary sinus (CS) encircles about two thirds of themitral annulus and can be used as a route to produce tensionwhich is transmitted to the mitral annulus, pushing the poste-rior annulus anteriorly and reducing the septolateral dimen-sion. This approach has been particularly attractive becausethe cannulation of the CS is an easy and well-establishedvenous access technique. CS devices therefore were histori-cally among the first to emerge.


Regarding sinoplasty devices data are available about threesystems (Fig. 4): the MONARCH, the Carillon, and thePTMA system.

The MONARCH (Edwards Lifesciences, Irvine, Califor-nia) consisted in a distal anchor placed between the anteriorinterventricular vein and the great cardiac vein, a connectingspring-like bridge and a proximal anchor placed in the ostialCS. The data published on the MONARCH are 1-year resultsfrom the EVOLUTION Phase I Study (Clinical Evaluation ofthe Edwards Lifesciences Percutaneous Mitral AnnuloplastySystem for the treatment of mitral regurgitation using thesinoplasty MONARC System) [46]. In this study, the feasi-bility of the device was tested in 72 patients withMR grade >2enrolled at eight participating centers in four countries. TheMONARC 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 in91 % of patients at 30 days and in 82 % at 1 year. Theprocedure was associated with angiographic coronary arterycompression in 15 patients (in whom the coronary sinus/greatcardiac vein courses over the circumflex artery) and latemyocardial infarction in two patients (3.4 %). After this initialhigh complication rate, further clinical evaluation had beensuspended.

The Cardiac Dimension Carillon (Cardiac Dimension,Kirkland, USA) is composed by two nitinol anchors (distalanchor placed in the great cardiac vein and proximal anchor in

the proximal CS linked by a bridge element. Tension appliedon the system results in cinching of the posterior mitral annu-lus. It is recapturable and repositionable. Numerous subse-quent versions of the devices have been already developed toreduce the risk of stent fracture and optimize efficacy. Theimpact of Carillon Mitral was evaluated in HF patients with atleast moderate FMR in the TITAN trial (Transcatheter Im-plantation of CarillonMitral Annuloplasty Device) [47]. Safe-ty and key functional data were assessed in the implantedcohort up to 24 months. Thirty-six patients received a perma-nent implant; 17 had the device recaptured. The 30-day majoradverse event rate was 1.9 %. The implanted cohort demon-strated significant reductions in FMR as represented byregurgitant volume [baseline 34.5±11.5 mL to 17.4±12.4 mL at 12 months (P<0.001)]. There was a correspondingreduction in LV diastolic volume [baseline 208.5±62.0 mL to178.9±48.0 mL at 12 months (P=0.015)] and systolic volume[baseline 151.8±57.1 mL to 120.7±43.2 mL at 12 months(P=0.015)], compared with progressive LV dilation in thecomparator. The 6MWT markedly improved for the im-planted patients by 102.5±164 m at 12 months (P=0.014)and 131.9±80 m at 24 months (P<0.001). With these resultsin terms of reduction of mitral regurgitation, the TITAN II trialis ongoing with the enrolment of new patients. Although nodata have yet been published, initial reports show no fracturesat 1 year with comparable efficacy results in terms or MRreduction. With these initial promising results, the device

Fig. 3 Cinching devices. a TheAmple PS3; b the i-Coapsys; c theBACE

Fig. 4 Coronary sinusannuloplasty and thecorresponding clinical trials


obtained the CE mark in 2011, and it is available for commer-cial implantation in Europe within a prospective postmarketregistry (PRIME), ongoing to assess long-term safety andefficacy in up to 300 patients.

The Viacor PTMA (Viacor, Wilmington, USA) was madeup of a Teflon CS catheter containing up to three nitinol rodsto provide incremental cinching/pushing of the posterior an-nulus. In the PTOLEMY-2 trial (Percutaneous TransvenOusMitral AnnuloplastY, succeeding to PTOLEMY-1) [48], atotal of 43 patients were recruited, and 30 patients (70 %)were implanted with a permanent PTMA device with a meanfollow-up of 5.8±3.8 months. The primary safety end point(freedom from death, myocardial infarction, stroke, or emer-gency surgery) at 30 days was met in 28 patients, whereas twopatients died of device-related complications. The primaryefficacy end point (MR reduction of at least 1.0 grade orreduction of regurgitant orifice area by 0.1 cm2 or regurgitantvolume by 15 mL or regurgitant fraction by 10 % comparedwith baseline) was obtained in 13 patients. No significantchanges were noted in MR parameters, ventricular volumes,or QOL. Distance walked on 6 min testing at 6-month follow-up increased from 331±167 m to 417±132 m (P=.65). Com-pared with nonresponders, responders had a higher baselineregurgitant orifice area N0.2 cm2 (P=.001) and less priorhistory of myocardial infarction (P=.02), coronary artery by-pass surgery (P=.03), and ischemic MR (P=.04). In conclu-sion, PTMA demonstrated mild impact on MR reduction, leftventricular remodeling, QOL, and exercise capacity. Duringfollow-up, the risk/benefit ratio remained suboptimal. PTMAinvestigations have been suspended due to a series of device-related adverse events, including circumflex artery occlusionand fatal CS perforation [49–51].

Finally, a more aggressive concept has been developed bythe National Institute of Health. The Mitral Valve CerclageAnnuloplasty (NIH, Rockville, USA) creates a loop aroundthe mitral annulus and LVOTentering through the CS ostium.It passes through the anterior interventricular vein, perforatesthe myocardium in the direction of the right ventricle passingthrough the anterior tricuspid commissure, or directly comingout through the septum in the right atrium. The loop is tight-ened and secured near the CS ostium [52]. Differently fromthe other coronary sinus devices, the mitral Cerclage offers theopportunity of circumferential remodeling of the mitral annu-lus, using the CS as a support. This system in under preclinicalevaluation.

However, some major limitations to the use of these ap-proaches were soon observed: First, the coronary sinus isvariably located at a significant distance from the mitral an-nulus behind the left atrial wall, and the distance is increasedin case of severe MR with annular dilation, thus significantlyreducing device efficacy; second, the risk of coronary arterycompression has been frequently observed (mainly circumflexartery, which crosses between the CS and the mitral annulus in

64-80 % of the cases) [53–56]; third, the risk of damage of thecoronary sinus itself has also been observed.

Due to these issues, these devices have gradually lost favorin respect to direct devices in recent years, and among themajor three technologies that had reached some clinical expe-rience, only one currently remains under active clinicalinvestigation.

Direct Annuloplasty

The aim of the direct annuloplasty technologies is to reshapethe mitral annulus, directly cinching the mitral annulus bysutures or other devices. The implantation of devices directlyinto the mitral annulus can theoretically more closely repro-duce surgical annuloplasty, and therefore, it is expected to beparticularly effective. Annulus calcification, circumflex artery,and leaflet damage, however, remain of concern for directannulus approach. Moreover, the disappointing surgical re-sults of incomplete and non-rigid rings in functional MR [57]leave open questions about effectiveness and durability ofcurrently available transcatheter devices, although much moreknowledge and experience must be achieved to solve such adifficult comparison. Three main different devices have beenproposed in recent years. These devices gradually collectedapproval, expectations, and enthusiasm over the recent years.

The Accucinch (Guided Delivery System, Santa Clara,USA) (Fig. 5) is a ventriculoplasty device delivered througha retrograde transfemoral route. It consists in the placement ofa series of anchor elements under the posterior mitral annulusfrom trigone to trigone so that cinching reduces both mitralannulus and basal LV. At the moment, it is designed to addressleft ventricle diameter no more than 70 mm. Initial reports onfew patients showed an excellent safety profile along with amitral regurgitant volume reduction of about 50 % and aventricle diastolic volume reduction of 25 % up to 6 months.Since theoretically the native annulus is not directly altered bythe procedure, the Accucinch could leave more room forfuture annular interventions, including open heart surgery.No data have been available, other than conference reports[Starksen N., A novel therapy for functional mitral regurgita-tion, TVT Meeting June 2013, Vancouver Canada].

TheMitralign device (Mitralign, Tewksbury, USA) (Fig. 6)is also a transfemoral retrograde device. It implants pairs ofpledgets connected with a suture at the medial and lateraledges of the posterior leaflet, creating an arch in order to cinchthe annulus circumference at the commissures. More pledgetscan be implanted along the posterior annulus to improve theannular reduction. A prospective, single-arm feasibility andsafety study is ongoing to obtain CE mark (results expectedfor 2014). Available data reported 24/36 patients have beenenrolled, and five of them have reached 1 year follow-up.Although final results are not yet available, in the first 15patients, no procedural death and one pericardial tamponade


occurred. After 1 year, a reduction of 1 grade of MR wasobserved along with a certain reduction in LV dimensions(Nickenig G., Progress with the Mitralign PercutaneousAnnuloplasty System: EU andUS Studies, TVTMeeting June2013, Vancouver Canada).

The Cardioband System (Valtech Cardio Ltd., Or-Yehuda,Israel) is a surgical band delivered by transeptal approach(Fig. 7). A sequence of multiple anchors is implanted fromthe antero-lateral to the postero-medial commissure. The allprocedure is done from the atrial site with no interaction withthe left ventricle; therefore, the procedure is well tolerated alsoin patients with a low ejection fraction. Once the Cardiobandis completely implanted, it could be precisely adjusted underecho-guidance on the beating heart in order to improvecoaptation and to reduce MR. Results in 15 swinesusing a trans-atrial access have been promising withno sign of damage of the mitral valve nor the surround-ing structures [58], and direct vision implant in thehuman has been safely and successfully performed.The totally percutaneous transfemoral transeptal ap-proach has been already developed and implanted inten patients with 100 % of procedural success and noadverse events. Today, the major strength of the Cardioband inrespect of the other direct devices is that this is the onlyconcept with a proved and long-standing experience derivedfrom surgery.

Despite all of these three devices claiming to address FMR,none achieve a complete annuloplasty. Posterior annulus, up

to mitral trigones, is usually targeted, since the anterior annu-lus remains a more delicate structure, and safe direct trans-catheter technologies are still to be developed. However, it iswell known from the surgical experience that, while in degen-erative setting incomplete rings works fine, in the functionalscenario, they are associated with a higher rate of failure andMR recurrence in comparison to complete rigid rings [57, 59].

Finally, we present the energy-mediated annuloplasty.They aim to reduce annular length by collagen shrinkingthrough delivering of different kinds of energy. First concernis still safety, in terms of damage to surrounding structures(leaflets, myocardium, CS and circumflex artery, aortic valve)and thrombus formation.

The QuantumCor (QuantumCor, San Clemente, CA, USA)delivers radiofrequency energy via a multiple-electrodesprobe. Available pre-clinical data showed significant antero-posterior annular reduction with a certain degree of MRdecrease and no sign of damage of surrounding structures[46, 60, 61].

The ReCor (Recor Medical, Ronkonkoma, NY, USA) is aballoon catheter with a cylindrical piezoelectric transducerthat delivers ultrasound energy. It reaches the mitral annulusfrom transeptal approach. The chronic canine model achieveda certain degree of annular reduction in absence of periannulardamage (acute annular diameter reduction 8.4 %, P<0.001,one death due to energy-induced ventricular fibrillation) [62].

The main limitations of the energy-mediated cinching isthat the scarring induced might not be precisely controlled,

Fig. 5 The Accucinch directannuloplasty device. Left imageshows the concept; right oneshows procedural fluoroscopystep

Fig. 6 The Mitralign directannuloplasty device. Left imageshows the concept; right oneshows procedural fluoroscopystep


with the potential risk of induced mitral stenosis, residualMR,or structural damage to the other cardiac structures.

State-of-the-Art of Percutaneous Mitral Valve Repairand Future Perspective

As discussed previously, conventional treatment of significantMR is repair surgery, particularly for DMR. However, theappropriate and timely correction of DMR is associated witha life expectancy and quality of life similar to a healthypopulation [10]. By contrast, the prognostic vantage and bestsurgical treatment for FMR is still debated. Transcathetermitral repair techniques can be divided in devices that workat the leaflets level and at the annulus level. Only one device isused for any procedure. It is so very difficult to compare theseresults with the surgical population, where a procedure on theleaflet is always associated to an annuloplasty. Once we willable to combine percutaneous leaflet and annulus procedures,then wewill be able to have a totally percutaneous valve repairand match the results. What we could expect is that the closerthe device is to a surgical procedure, the more reliable andpredictable will be the results.

Despite an initial panel skepticism [63], recently, Mitracliptherapy received FDA approval for patients with DMR atprohibitive or high surgical risk, mostly basing on thequality-of-life results of randomized EVEREST II trial andHigh Risk Registry. Again, this highlights the importance of aHeart-Team approach to assure that only inoperable patientswill be submitted to this therapy, reserving surgery to others.

For patients judged inoperable that also have anatomicalcharacteristics not suitable for standard surgical repair

(complex Barlow’s disease for DMR, complex multiple jets,no annular dilatation, excessive tethering with tented area>4 cm2 or coaptation depth >1.5 cm, posterior leaflet-annular plane angle >45°, distal anterior leaflet-annular planeangle >20° for FMR), these patients could be future candi-dates for trans-catheter mitral valve replacement and not per-cutaneous 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 oftenused for mitral valve-in-valve or valve-in-ring implantation inthe clinical setting. The annular rigid artificial structure is aperfect landing. Data from the world registry [Dvir D. Trans-catheter Mitral/Tricuspid Valve Implantation in Failed Surgi-cal Valves-Update from the Global Registry, TVT Meeting,Vancouver 2013] confirmed a significant acute mortality like-ly due to the high-risk patient’s profile, but a remarkablesymptoms improvement after the procedure. Although theprocedure is feasible via a totally percutaneous approach viatransfemoral trans-septal anterograde route [64], the most usedapproach remains transapical (88 %).

Mitral Valve Implantation

Percutaneous mitral valve implantation will be available in thenear future to complete the therapeutic portfolio, potentially

Fig. 7 The Cardioband directannuloplasty device. Upper rowshows the concept; lower rowshows procedural steps, from TCscan study to echo- and fluoro-guided implantation


expanding the indications to patients with rheumatic diseaseor with anatomy unsuitable for repair (Table 5). There are stillseveral obstacles to the development of a reliable device fortranscatheter mitral valve implantation. Compared with theaortic valve, the mitral valve anatomy is more complex and farfrom a cylindrical geometry. Moreover, the larger size of theannulus compared with the aortic valve prevents the use ofconventional stent technology. Anchoring of the implant isanother challenge, since radial force cannot be applied for thelarge dimensions of the valve and because a real annulus doesnot exist, neither is usually calcified, as for the aortic valve.Using radial force would be suboptimal also due to the risk ofimpingement into the aortic valve. The anatomy of the mitralvalve is totally asymmetric, therefore mitral implantation de-vices should be designed to accommodate this feature. Inparticular, the anterior leaflet of the mitral valve is directedtowards the LVOT. A mitral implant has to take care of thisand should not protrude in the outflow tract to avoid obstruc-tion. Last but not least, if perivalvular leaks are tolerated in theaortic position, they will not be acceptable in the mitral posi-tion, since they will be more clinically relevant and mayinduce severe hemolysis. The ideal MV prosthesis would beimplanted without any obstruction of LV outflow, withoutimpingement into the aortic root, and no (or only minimal)perivalvular leakage (Table 4).

Perivalvular Leak Closure

Perivalvular leakage is a frequent complication of prostheticvalve implantation occurring in up to 17 % of mitral valvereplacement operations. Surgical re-intervention is associatedwith high morbidity. Leak closure has emerged as a validoption for high-risk or inoperable patients. Procedural out-comes have improved along the years, with a success ratearound 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 avail-able, as well as different accesses (venous transfemoral tran-septal route or transapical). These procedures must be re-served at the moment to symptomatic high-risk patients withsuitable anatomy.

Image Guidance and Technical Aspects

Key to all these percutaneous transcatheter therapies is the useof imaging to guide patient selection as well as intra-procedureperformance. Careful patient selection remains paramount forsuccess with imaging determination of mitral pathology andaccurate comprehension of the mechanism of MR. Technicalsuccess is dependent on skills with echocardiographic imag-ing, with three-dimensional trans-esophageal echocardiogra-phy particularly.

An important point is the transseptal puncture, since is theprime step in the majority of the procedures. This point needshas to be in a specific position relative to the pathology of theMR, and therefore, intra-procedure imaging is critical to de-termine this location (Fig. 8). The traditional imaging modal-ities in the catheterization laboratory of fluoroscopy andcineradiography are of minimal utility as they cannot visualizethe mitral leaflets. Therefore, the procedure is guided bysimultaneous 3D trans-esophageal echocardiography (TEE).The introduction of 3D real-time imaging is mandatory for allthese type of procedure. We can obtain a real surgical view ofthe mitral valve from the atrium or from the ventricle, and withthe X-plane function, we can precisely position our device inthe desired position. The transseptal puncture is also guidedby 3D-TEE. The transseptal puncture, for every specific de-vice should be in a different point. For Mitraclip, this locationis usually superior and mid-posterior; it needs to be over the

Table 5 Mitral valve implantation devices for transcatheter delivery device

Approach Description Status

CardiAQ Transeptal Self-positioning, self-anchoring and self-conforming in three dimensions; fixation does notinvolve the use of radial force.

First-in-manperformed in 2012[67]

“Lutterprosthesis”

Transapical Nitinol structure featuring an atrial fixation, a tubular intrannular segment and a ventricularchordal fixation system.

Preclinical [68]

CardioValve Transeptal Two-stage implant: atrial skirt assuring adequate fixation and landing zone onto which theprosthesis is deployed.

Preclinical [69]

Tiara Transapical D-shaped atrial frame to respect LVOT and aorta; anchoring structures to fibrous trigonesand posterior leaflet

Preclinical [70]

MedtronicMitralProgram

Transeptal Wide atrial inflow and short profile ventricular outflow; uses gripper to leaflet capture. Preclinical [71]

EndoValve Trans-septal Tripod-shaped nitinol and stainless steel frame leverages claw-like gripping features forfixation and a support ring for bioprosthetic leaflets.

Preclinical

“von Segesserprosthesis”

Minithoracotomy Porcine valve sutured into a Dacron conduit, onto which two nitinol Z-stents were suturedto form two self-expanding crowns for fixation, ventricular and atrial.

Preclinical


line of coaptation of the mitral valve, which is generally aposterior point, higher in patient with FMR and lower inpatients with DMR. Using TEE bicaval (view 100°–110° onthe multiplane), we can reach the height of the puncture. Theshort axis at the base view (which is usually ∼45° on themultiplane) allows determination of the anterior/posterior re-lationship and the distance from the aortic valve; in Mitraclipprocedure, the optimal location is generally mid-posterior.Finally, in the four-chamber view, we evaluate both the pointof transseptal puncture and the mitral valve. For example, inMitraclip procedure, it must be positioned ∼4 cm above thepoint of mitral coaptation line; for the Cardioband, an inferiorpuncture is preferable. Proper location of the transeptal punc-ture is critical to provide a smooth procedure. The transeptalpuncture may be particularly challenging in case of thickseptum (as in case of post cardiotomy patients), large left orright atrium, in presence of bulging septum and in presence ofintracardiac pacing leads. In Mitraclip therapy, possible com-plications due to suboptimal puncture are aortic hugging (tooanterior puncture), inability to cross the mitral valve (too highpuncture), inability to pull back the clip and tether theleaflets (too low puncture), and perforation (too posteri-or puncture). Three-dimensional trans-esophageal echo-cardiography is also mandatory during all the proce-dures in order to evaluate the exact positioning of anydevice in relation to cardiac structure and to assess the successof the procedure in terms of reduction of MR. Newer probesand 3D softwares with better spatial and temporal-resolutionare under evaluation.

Another interesting future application could be the ICE (IntraCardiac Echocardiography). The ICE device is an 8/10Fr. probeinserted via an introducer into the human vessel. With ultra-sound and echo Doppler technology, it provides meaningful,real-time anatomic information occurring within the structuresof the heart (Fig. 9). Nowadays, ICE is already adopted inElectrophysiology Laboratories for ablation procedures or dur-ing the implant of coronary sinus leads (procedure similar tosinoplasty). Thus, the introduction of ICE could open the way to

a totally percutaneous mitral valve plasty without the need ofTEE and therefore the absence of intubation.

Ultimately, cardiac-gated computed tomographic (CT)scan is increasingly playing a relevant role during decisionmaking and to plan the strategy for transcatheter mitral inter-vention. It is fundamental not only to identify any coronarydisease, but also to calculate the exact distance between them(coronary artery and CS) and to evaluate the structure andrelation of the mitral annulus with the surrounding tissues inorder to prevent damage with a specific device, to define thediameter and the EF of the ventricles and to determine accu-rately the anatomy of vessels and to plan the possible accessroute (trans-femoral or transapical).

Currently, during the procedure, the fluoroscopy tool withpre-operative CT scan and the TEE images are complementa-ry modalities and are visualized in separate coordinate sys-tems and on separate monitors creating a challenging clinicalworkflow. Thus, different companies are working on fusionimaging that allows superimposing on fluoroscopic screen thesoft tissue images obtained by echocardiographyinterconnecting them with previously collected CT images.

All these new improvements in technology, especially thedevelopment of fusion imaging, will help us to be more

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

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

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


precise, to speed up the procedures, and to be more appropri-ate in patient selection.

Conclusion

A relevant number of patients in need of MR reduction do notundergo surgery because of a high perioperative risk. Giventhe technological progress of the present day, transcathetervalve technologies represent the natural evolution of minimal-ly invasive surgery, aiming to reduce the procedural risk andinvasiveness. To date, MitraClip therapy has proved excellentsafety results and good efficacy in high-risk patients and isalready a real and valid option in such a population.

In particular, the lack of a reliable annuloplasty device isprobably the most important limitation to the expansion of thepercutaneous mitral valve intervention field either in degen-erative and in functional disease. For all these reasons, severaldevices, addressing many different anatomical and patho-physiological concepts (from annuloplasty to chordal implan-tation or LV remodeling), are under development to improveoutcomes and expand patients’ indications. Finally, transcath-eter mitral valve implantation will be considered in the nextfuture to complete the therapeutic portfolio.

Imaging is fundamental for pre-operative planning andintra-procedural guidance and relies on 3D trans-esophagealechocardiography, 3D coronary CT scan, fluoroscopy, andfusion imaging techniques.

The patient-centered care and the Heart-Team approachesare fundamental to obtain procedural success and, more im-portantly, patient health.

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Devices for Mitral Valve Repair