PercutaneousTechniques for theTreatment of Patientswith Functional MitralValve Regurgitation

Rodrigo M. Lago, MD, Roberto J. Cubeddu, MD,Igor F. Palacios, MD*

KEYWORDS

� Mitral Valve � Regurgitation � Valvular insufficiency� Percutaneous device

m

SCOPE OF THE PROBLEM

Mitral regurgitation (MR) is the most commontype of valvular insufficiency. It is estimated thatapproximately 5 million people in the United Statesand more than 20 million worldwide suffer fromcongestive heart failure, often associated withdilated ventricles and coexisting MR. Ischemiccardiomyopathy is the most common cause ofheart failure in the United States.1 This diseaseis marked by diffuse myocardial damage, leftventricular remodeling, and often functionalischemic MR.2 Although surgery can be effectivein treating MR, it is frequently associated withhigh operative morbidity, disease recurrence,and increased mortality.3–5 Currently, potentialpercutaneous options for the treatment of mitralregurgitation are in different stages of develop-ment, either in the early phases of clinical use orbeing preclinically tested. These techniques areas follows:

� Leaflet coupling with edge-to-edge repair(Evalve MitraClip, Edwards Stitch)

� Coronary sinus reshaping (MONARCdevice, Carillon device, Miltralife ev3,Cardiac Dimensions, Viacor)

Massachusetts General Hospital, Harvard Medical School* Corresponding author.E-mail address: ipalacios@partners.org

Intervent Cardiol Clin 1 (2012) 85–99doi:10.1016/j.iccl.2011.10.0012211-7458/12/$ – see front matter � 2012 Published by E

� Annular plication with posterior annulusreshaping (Mitralign, Guided DeliverySystems)

� Left ventricular remodeling (Myocor,Ample PS3 [percutaneous septal sinusshortening]).

This article discusses current options and futuredirections for the percutaneous treatment of mitralvalve regurgitation.

MITRAL VALVE STRUCTURE AND FUNCTION

It is important to understand the anatomic andfunctional substrate underlying the developmentof MR. The mitral valve is a complex anatomicstructure and its proper function depends on thestructural and functional integrity of its individualcomponents (Fig. 1). Abnormalities in 1 or moreof its components can result in stenosis or regurgi-tant valvular dysfunction.

The distinction between primary and secondary(functional) MR is important for the potential role ofpercutaneous device therapies for MR (Box 1).In primary organic MR, there is an abnormalityof the mitral valve components, whereas insecondary functional MR, the mitral valve itself is

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Fig. 1. Anatomy of the mitral valve.

Lago et al86

usually unaffected. However, previous damage ofthe left ventricle (LV) by coronary artery diseaseor by dilated cardiomyopathy can cause malcoap-tation of anatomically normal mitral leaflets in thesetting of geometric distortion of the LV, withdisplacement of papillary muscles and/or annulardilatation with subsequent MR.Functional MR has been associated with an

adverse prognosis among patients with dilatedand ischemic cardiomyopathy.6,7 Althoughsurgical intervention is associated with improvedsymptoms of heart failure and reverse remodelingof the LV, surgical treatment of functional MR hasnot been shown to improve survival.8 Mitral valverepair with reduction annuloplasty rather thanreplacement is currently favored for the treatmentof functional MR.9,10 Lessons from surgical

Box 1Primary and secondary (functional) MR

Primary organic MR

� Abnormality of the mitral valve components

Secondary functional MR

� Mitral valve usually unaffected

� Previous damage of the LV (by coronaryartery disease or by dilated cardiomyopathy)can cause malcoaptation of anatomicallynormal mitral leaflets in the setting ofgeometric distortion of the LV, with displace-ment of papillary muscles and/or annular dila-tation with subsequent MR

experience showed that mitral valve repair caneffectively treat many, but not all, patients withfunctional MR.Potential factors that can predict the recurrence

of MR after mitral repair include the following:

� Annular ring geometry� Chordae tendineae repositioning� Concomitant reshaping of the LV during

repair� The need for a complete (D-shaped) annu-

loplasty ring rather than a partial (C-shaped)ring.11,12

Until recently, available treatment options forfunctional MR were limited to open surgical repairor replacement, an option that is often challengedand associated with high operative morbidity,disease recurrence, and increased mortality.3–5

The most common form of mitral valve repairinvolves annuloplasty, the placement of a ringaround the mitral annulus to reduce the mitralvalve orifice by decreasing the distance betweenthe septal and lateral dimensions of the mitralvalve, thereby bringing the leaflet edges closertogether. Annuloplasty is used as an adjunctivetherapy in most forms of mitral valve repairincluding functional MR. A less commonly usedsurgical leaflet repair approach pioneered by Al-fieri and colleagues13 is the edge-to-edge repairthat creates a double-orifice mitral valve bysuturing the free edges of the mitral leafletstogether to form a double orifice. Although the iso-lated use of this surgical technique has beencontroversial because of the concomitant use ofannuloplasty with most leaflet repairs, follow-up

Mitral Valve Regurgitation 87

for as long as 12 years in patients who have under-gone isolated surgical edge-to-edge repair withoutannuloplasty has shown durable clinical outcomewith this surgical technique.13,14 In the pastdecade, potential percutaneous catheter-basedtreatment strategies for valvular heart diseasehave emerged as an attractive option. Percuta-neous therapies for MR try to emulate surgicalapproaches that have been in use for many years.

PERCUTANEOUS TREATMENT OF MITRALVALVE REGURGITATION

In general, there are 4 groups of strategies fortranscatheter treatment of MR:

1. Leaflet coupling with edge-to-edge repair tosimulate the Alfieri stitch procedure15–17

2. Coronary sinus reshaping devices (indirectannuloplasty)

3. Annular plication with posterior annulus re-shaping (direct annuloplasty)

4. Left ventricular remodeling devices (Table 1).

PERCUTANEOUS EDGE-TO-EDGE REPAIR

The Alfieri surgical technique to treat degenerativeand functional MR was introduced in the early1990s by Alfieri and colleagues.13 Although initiallypoorly accepted, the Alfieri stitch or edge-to-edgetechnique gained popularity.18 The technique con-sisted of suturing the free edges of the middleanterior (A2) and posterior (P2) mitral leaflets andcreating a double-orifice inlet valve. The techniquewas intended to improve leaflet coaptation andtherefore decrease MR. Long-term results fromthis technique were reported for both degenerativeand functional MRwith 5-year freedom from recur-rent MR more than 21 and reoperation rates as

Table 1Current status of percutaneous mitral valve repair p

Approach Dev

Edge-to-edge leaflet repair MitrMOB

Indirect annuloplasty CariPTMMitrMON

Direct annuloplasty MitrAccuQua

Ventricular remodeling iCoa

Atrial/coronary sinus remodeling PS3PMV

high as 90%.19 The development of transcathetermitral valve edge-to-edge repair techniques wasbased on the surgical technique. Two mitral valvepercutaneous techniques and devices have beendeveloped to emulate the double-orifice strategyusing a catheter-based approach: the EvalveMitraClip (Evalve Inc., Menlo Park, CA, USA) andthe MOBIUS system (Edwards LifesciencesCorp., Irvine, CA, USA).

The Evalve MitraClip

The Evalve MitraClip (Fig. 2) is a device that usesa guide catheter that is placed using transseptalpuncture, a delivery catheter, and an implantable4-mm-wide cobalt-chromium implant clip with 2arms covered with polyester fabric (see Fig. 2).The device uses a triaxial catheter system todeliver its clip fixation device and create adouble-orifice mitral valve.

After the initial encouraging results in animalmodels, this transcatheter technique was firstused in humans in 2003. During 2-year follow-upafter MitraClip implantation, a 56-year-old womanwith heart failure and severe 41 MR remainedasymptomatic with less than 21 MR.20,21

The safety and feasibility of the MitraClip systemwere tested in the EVEREST (Endovascular ValveEdge-to-Edge Repair Study) phase I and phase IIstudies.22 Results from the 107 patients (55 fromEVEREST I; 52 from EVEREST II) with eitherdegenerative (79%) or functional (21%) MR wereencouraging. On an intent-to-treat basis, implantsuccess occurred in 90% of patients, in whomacute success (MR grade �21) was reported in84% of the cases. Among these patients, improve-ment in New York Heart Association (NYHA)functional class was reported in 73% at 1-year

rocedures

ice Manufacturer

aClip EvalveIUS Edwards Lifesciences

llon Cardiac DimensionsA ViacoraLife ev3ARC Edwards Lifesciences

align Mitraligncinch Guided Delivery SystemsntumCor QuantumCor

psys Myocor

Ample MedicalR St Jude Medical

Fig. 2. Evalve MitraClip.

Lago et al88

follow-up. Partial clip detachment occurred in 9%of the initial cohort and was the most importantmechanical problem with the procedure. Thiscomplication was often detected at the protocol-mandated 30-day echocardiogram. These partialdetachments were generally not associated withsymptoms, and most were treated either withsurgery or second clip placement.Midterm durability of the MitraClip in the EVER-

EST study has recently been reported and showedlow rates of morbidity and mortality and acute MRreduction to less than or equal to 21 in mostpatients.23 The initial 107 patients were analyzed.Nine percent had a major adverse event, including1 death not related to the procedure. There wereno clip embolizations. Partial clip detachmentoccurred in 9% of patients. Overall, 74% of thepatients achieved acute procedural success, and64% were discharged with MR of less than orequal to 11. During the 3.2 years after MitraClipimplantations, 30% of the patients underwentmitral valve surgery. When surgical mitral valverepair was planned, 84% (21 of 25 patients) weresuccessful. Thus, surgical options were preserved.A total of 66% of the successfully treated patientswere free from death, mitral valve surgery, or MRgreater than or equal to 21 at 12 months, whichwas the primary efficacy end point of the study.Freedom from death was 95.9%, 94.0%, and90.1%, and freedom from surgery was 88.5%,83.2%, and 76.3% at 1, 2, and 3 years, respec-tively. Similar acute results and durability were

observed among the 23 patients with functionalMR enrolled in the study.A recently reported hemodynamic substudy of

EVEREST showed that successful mitral valverepair with the MitraClip system resulted in animmediate and significant improvement in thefollowing:

� Forward stroke volume� Cardiac output� Left ventricular loading conditions.

There was no evidence of a low cardiac outputstate following MitraClip treatment of MR,a complication occasionally observed aftersurgical mitral valve repair for severe MR.24

The EVEREST II trial, a prospective, random-ized, phase II, multicenter study between theUnited States and Canada comparing MitraClipwith either surgical valve repair or replacement in279 patients randomized in a 2-to-1 fashion.Twelve-month follow-up showed that, despitebeing driven by a higher incidence of blood trans-fusions in the surgical group, safety end pointswere reached in about 50% of surgery patientsand 15% of MitraClip patients, showing superiorityof safety for the percutaneous approach by inten-tion to treat. The 1-year efficacy end point of thecombined incidence of death, mitral valve surgery,or reoperation for mitral valve dysfunction wasmore frequent in the surgery patients than inthe MitraClip patients, meeting the noninferiority

Mitral Valve Regurgitation 89

hypothesis for efficacy. Similar reductions in leftventricular volumes and dimensions, and improve-ments in NYHA functional class, were achieved inboth groups after 1 year.

Careful evaluation and patient selection is crit-ical for the success of the procedure. Patientswith degenerative or functional MR are candidatesfor the procedure. Patient selection criteria areshown in Box 2.

Technically, the procedure is performed withgeneral anesthesia, using fluoroscopy and transe-sophageal echocardiography (TEE). Transseptalaccess is used to place a guide catheter into theleft atrium. The Evalve MitraClip guide catheter is24 Fr proximally and tapers to 22 Fr distally atthe level of the atrial septum. It is inserted fromthe femoral vein and advanced above the mitralvalve following a transseptal puncture. The steer-ing knob at the end of the guide allows flexionand lateral movement of the distal tip so that theclip is positioned orthogonally over the 3 planesof the mitral valve and the origin of the regurgitantjet. The delivery catheter passes coaxially throughthe guide, and has the MitraClip attached to itsdistal end. The clip arms are opened and closedby a knob on the delivery catheter handle. Theopened span of the clip is approximately 2 cmand the width is 4 mm. Through the guide catheter,the delivery system is maneuvered to center theclip over the mitral orifice, and the clip is partiallyopened and passed across the leaflets into theLV. The open clip is then pulled back to graspthe mitral leaflets and the clip is closed. Thedegree of MR is assessed by TEE. If necessary,the clip is reopened, the mitral leaflets released,and the clip repositioned. If needed, a secondclip is placed. Once optimal reduction of MR isachieved, the clip is released from the deliverysystem and both the delivery system and guidecatheter are withdrawn. Repeat hemodynamic,

Box 2Patient selection criteria for Evalve MitraClipimplantation

� Coaptation length of at least 2 mm

� With a flail mitral leaflet, a flail gap less thanor equal to 10 mm or a flail width on short-axis estimation less than15 mm

� MR jet must arise from the central two-thirdsof the line of coaptation as seen on short-axiscolor Doppler examination

� Baseline mitral valve area should be greaterthan 4 cm2 to avoid the creation of mitralstenosis

angiographic, and echocardiographic assess-ments are routinely performed. Heparin is routinelyused during the procedure and administered toachieve an activated clotting time of 250 secondsor more. Aspirin 325 mg and clopidogrel 75 mgdaily are ordinarily recommended following theprocedure for 6 months and 30 days respectively.Clip failure is well tolerated and does not precludesurgical mitral valve repair or replacement.

The MOBIUS Leaflet Repair System

The MOBIUS leaflet repair system (Edwards Life-sciences Inc., Irvine, CA, USA), also called MilanoStitch, (Fig. 3) was introduced by Buchbinder andcolleagues as a similar catheter-based edge-to-edge technique. In contrast with the Evalve Mitra-Clip, this strategy uses a small guiding catheter tostitch the free edges of the anterior and the poste-rior mitral leaflets, thus creating a double-orificeinlet valve. An innovative suction catheter is usedto bring the leaflets together and facilitate stitchplacement under fluoroscopic and echocardio-graphic guidance.25

After the successful animal model experience,the first in-human case was performed in Milan,Italy, in a 67-year-old woman with NYHA functionalclass III and severe (grade 41) MR secondary toa prolapsed posterior leaflet. Subsequently, thepercutaneous Alfieri-like stitch was tested ina feasibility trial of 15 patients with either degener-ative or functional MR. In this phase I study, acuteprocedure success occurred in 9 of 15 patients. Ofthese, 3 patients required a single stitch, 5required 2 stitches, and 1 patient required 3stitches. At 30-day follow-up, only 66% of thepatients (6 of 9) had a successful stitch in placewith at least 1 grade improvement in MR reduc-tion. The patients with acute failure (6 of 15) allunderwent subsequent successful surgical repair.However, the study’s intermediate result hasprompted the investigators to abandon furtherevaluation for this indication.

PERCUTANEOUS ANNULOPLASTY

Annuloplasty is the mainstay of surgery in patientswith functional MR. Annular dilation caused bydilation of the LV and geometric distortion of themitral apparatus is the mechanism of MR in thisgroup of patients. Surgical mitral annuloplastytypically involves a complete ring to reshape themitral annulus. Partial annuloplasty is thoughtto be ineffective. Percutaneous annuloplasty ap-proaches are either direct or indirect (Box 3).

Indirect approaches use the coronary sinus asa route to deliver a device to partially wrap themitral annulus parallel to the posterior mitral valve

Fig. 3. Milano Stitch/MOBIUS device.

Lago et al90

leaflet and create tension that is transmitted tothe mitral annulus. The rationale is that any confor-mation change of the coronary sinus may beused advantageously to reduce the septal-lateralannular dimensions and improveMR severity. Indi-rect annuloplasty approaches include the CardiacDimensions Carillon system (Cardiac Dimen-sions, Kirkland, WA, USA), the Edwards MONARCsystem (Edwards Lifesciences, Irvine, CA, USA),the MitraLife/ev3 device, and the Viacor PTMA(percutaneous transvenous mitral annuloplasty)system (Viacor, Wilmington, MA, USA).Direct annuloplasty approaches involve direct

implantation of a device into the mitral annulus,which more closely mimics surgical annuloplasty.

Box 3Percutaneous annuloplasty approaches

Indirect annuloplasty approaches

Cardiac Dimensions Carillon system (CardiacDimensions, Kirkland, WA, USA)

Edwards MONARC system (Edwards Lifescien-ces, Irvine, CA, USA)

MitraLife/ev3 device

Viacor PTMA (percutaneous transvenous mitralannuloplasty) system (Viacor, Wilmington, MA,USA)

Direct annuloplasty devices

Mitralign system (Mitralign, Tewksbury, MA,USA)

Guided Delivery Systems device (GuidedDelivery Systems, Santa Clara, CA, USA)

Direct annuloplasty devices include the Mitralignsystem (Mitralign, Tewksbury, MA, USA) andthe Guided Delivery Systems device (GuidedDelivery Systems, Santa Clara, CA, USA).

Indirect Annuloplasty Techniques

Cardiac dimensions carillon deviceThe Cardiac Dimensions Carillon device (CardiacDimensions, Kirkland, WA, USA) (Fig. 4) sys-tem combines an implantable device and deliverysystem. The device consists of 2 anchors con-nected by a nitinol bridge.Via jugular access under fluoroscopic guidance,

a 9-Fr guide catheter is delivered into the distalcoronary sinus. A distal anchor is placed in thegreat cardiac vein and a proximal anchor is placednear the ostium of the coronary sinus. Once thedistal anchor is deployed into the great cardiacvein, tension is applied to the system resulting inimmediate decrease in the diameter of the mitralannulus, by moving the posterior leaflet more ante-riorly. Then, the proximal anchor is released.Simultaneous TEE allows for direct visualizationof MR improvement.The Carillon Mitral Contour System is simple,

quick, and easy to use. It is adjustable and canapply varying degrees of tension to a system. Itis compatible, because it fits contours of variousanatomies, allowing for optimal and safe deliveryto occur. A major advantage of this device is thatit is retrievable if positioning is not optimal. Its intu-itive delivery system comes in sizes of 60 mm inlength with a distal anchor height of 7 to 14 mmand proximal anchor height of 12 to 20 mm (1.5–2.0 ratios). The issue with the first generation ofthe device, in which there was a difficulty in

Fig. 4. The Carillon system consists of a nitinol bridge connecting a distal anchor that is placed at the greatercardiac vein and a proximal anchor placed in the proximal coronary sinus. (A) Delivery system in the CS; (B)Deployment of the Carillon system into the CS around the mitral valve annulus; (C) Carilon system deployed inposition into the CS. CS, coronary sinus; GCV, great cardiac vein.

Mitral Valve Regurgitation 91

anchoring, was corrected with improvements inengineering (Carillon XE).

Initial experiments in animals showed thatplacement of the Carillon system in 6 dogs withdilated cardiomyopathy resulted in both a meandecrease in mitral annulus diameter from 2.7 (�0.2) cm to 2.3 (�0.1) cm (P<.05), and a meandecrease in MR/left atrial area ratio from 16 (�4)to 4 (�1) (P 5 .052).26 The first in-human implan-tation of the Carillon device was performed byDr Schofer in Hamburg, Germany.

Recently, the AMADEUS (Carillon Mitral Annu-loplasty Device European Union Study) trial, aprospective, single-arm, multicenter safety andefficacy trial of the Carillon system, was reported.The primary end point of the study was safety ofdeployment and implantation of the device in thecoronary sinus and the great cardiac vein. Thesecondary end point included long-term safetyand effect of the device on hemodynamic param-eters and subject function.

The study enrolled 48 patients with follow-up atintervals of 1, 3, and 6 months. Candidate patientswith CHF, MR (�21), and decreased left ventric-ular systolic function (ejection fraction <40%)for the trial underwent a standardized 6-minutewalking test, a TEE, a treadmill test, and a multi-slice computed tomography scan to determinethe anatomic relationship between the coronarysinus, the mitral annulus ring, and the left circum-flex coronary artery. Angiographic examination ofthe coronary sinus and the coronary arterieswere acquired before device implantation. Thestudy initially enrolled 4 patients between July2005 and March 2006, and showed successfulpermanent device implantation in only 1 patient.This patient had successful reductions in MR

severity and improvement in functional statusthat persisted at 6 months’ follow-up. In the re-maining 3 patients, the device moved becausethe distal anchor was unable to consistently main-tain its shape during device tensioning before finaldeployment. Nevertheless, the devices were re-captured and removed safely. Successful implan-tation occurred in 70% of the patients, andresulted in improved functional class and MRseverity of at least 11 in 80% of the cases. Thosewho benefited most had evidence of congestiveheart failure and greater than or equal to 21centric MR secondary to mitral annulus dilatation.Acute MR reduction (grade 3.0 � 0.6 to 2.0 � 0.8,P<.0001) and permanent implantation wereachieved in 30 of 43 patients in whom an attemptwas made. Additional measurements in 20patients with implants showed reductions in thevena contracta (0.69 � 0.29–0.46 � 0.26 cm,P<.0001), effective regurgitant orifice area (0.33 �0.17–0.19 � 0.08 cm2, P<.0001), regurgitantvolume (40 � 20–24 � 11 mL, P 5 .0005), and jetarea/left atrial area (45% � 13%–32% � 12%,P<.0001) (Fig. 5). The coronary arteries werecrossed in 36 patients (84%) (see Fig. 5).

One major limitation of this device is the poten-tial obstruction of left circumflex coronary arteryflow during device deployment. In 84% of thepatients, the device crossed the left circumflexcoronary artery, in which compromise of bloodflow occurred in 14%, and in whom the devicewas immediately retrieved. Overall, the AMADEUSstudy achieved its safety end point with an accept-able adverse event profile. MR was reduced by27% out to 6 months and the patients had signifi-cant improvements in functional parameters out to6 months.27

MR Grade Vena Contracta

0

0.5

1

1.5

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3.5

NOLLIRRACENILESAB

0

0.1

0.2

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NOLLIRRACENILESAB

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NOLLIRRACENILESAB

0

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NOLLIRRACENILESAB

Effective RegurgitantOrifice

Regurgitant Volume

3.0

2.0

0.69

0.46

0.33

0.19

40

24

P = 0.0005

P<.0001

P<.0001P<.0001

Fig. 5. Amadeus trial results. (Data from Siminiak T, Hoppe UC, Schofer J, et al. Effectiveness and safety of percu-taneous coronary sinus-based mitral valve repair in patients with dilated cardiomyopathy (from the AMADEUStrial). Am J Cardiol 2009;104(4):565–70.)

Lago et al92

Edwards MONARC systemThe Edwards MONARC system (Edwards Life-sciences, Irvine, CA, USA) is percutaneously im-planted in the coronary sinus after cannulationwith a guide catheter. The device is designed toimprove MR severity over an estimated period of

Fig. 6. MONARC device.

3 to 6 weeks, remodeling the mitral annulus by im-planting a bioabsorbable springlike bridge that isconnected between 2 self-expanding proximaland distal nitinol stents (Fig. 6).The procedure is performed under local anes-

thesia via a 12-Fr right transjugular approach.

Mitral Valve Regurgitation 93

The stent anchors provide force that brings theproximal coronary sinus and distal great cardiacvein together while the interconnecting bridgetenses and foreshortens with time. The conforma-tional changes invoked over the posterior annularsegment presumably shorten the septal-lateraldimensions to reduce MR severity.

The first human experience with the MONARCsystem was reported by Webb and colleagues28

in 2006 and included 5 patients with chronicsevere ischemic MR. Implantation was successfulin 4 of the 5 patients, and resulted in a meandecrease in MR grade from 31 to 11. Loss of effi-cacy was later seen in 3 of the patients, causedby asymptomatic separation and fracture of thebridging segment.

Following device modification and reinforce-ment of the bridging segment, the EVOLUTION(Clinical Evaluation of the Edwards LifesciencesPercutaneous Mitral Annuloplasty System for theTreatment of Mitral Regurgitation) phase I studywas conducted. In this study, successful implanta-tion was achieved in 59 of the 72 patients (82%)with functional MR and heart failure. Freedomfrom death, MI, and cardiac tamponade at 30days was 91%. Left circumflex coronary arterycompression occurred in 30% of patients. Majoradverse events at 18-months included 1 death, 3myocardial infarctions, 2 coronary sinus perfora-tions, 1 anchor displacement, and 4 anchor sepa-rations. This study showed that implantation ofthe MONARC system was feasible, and, althoughefficacy data are encouraging, coronary compres-sion and anchor separations remain importantconcerns and limitations. The effect of theEdwards MONARC device cannot be assessedat the time of placement, therefore there is no indi-cation regarding the efficacy outcome until thespring has shortened several weeks later. The

Fig. 7. The Viacor PTMA system consists of a catheter withdistal part of the coronary sinus (A) to apply pressure at t

EVOLUTION II trial study of the MONARC devicehas been stopped by the sponsor because ofslow enrollment.

Viacor PTMA systemThe Viacor PTMA system (Fig. 7) consists of a pol-ytetrafluoroethylene catheter in which rods ofdifferent stiffness are introduced into the distalpart of the coronary sinus via subclavian or jugularvenous puncture. A trilumen plastic cannula isdelivered into the coronary sinus and nitinol rodsare passed through the lumens of the catheter toapply pressure to the posterior annulus in thecentral part of the posterior mitral valve leaflet(P2) and compress the septolateral dimension.Following the identification of the optimal amountof compression of the posterior annulus to resultin a reduction in MR, permanent implantation isperformed. The device can be retrieved in casesof absence of reduction in MR or left coronarycircumflex cinching.29–31 Preliminary studies insheep models were highly encouraging and re-sulted in decreased MR severity from between 13and 14 to between 10 and 11 (P<.03), and asso-ciated with significant reductions in septal-lateralmitral annular dimensions (from 30 � 2.1 mm to24 � 1.7 mm; P<.03).32 The first in-human feasi-bility and safety study was reported in 2007 andincluded 4 patients with ischemic MR and NYHAclass II or III, MR greater than or equal to 21,type I and/or IIIB Carpentier MR functional classrequiring surgical mitral annuloplasty, and showedcontinued reduction of the mitral orifice for as longas 1 year after initial implantation. In this study, thedevice was temporarily implanted, adjusted, andsubsequently removed. The investigators reportsubstantial reductions in regurgitant volumes(45.5 � 24.4 to 13.3 � 7.3 mL) caused by the me-chanically induced anterior-posterior diameter

nitinol rods of different stiffness introduced into thehe posterior mitral valve annulus (B).

Lago et al94

reduction (40.75 � 4.3 to 35.2 � 1.6 mm) in 3patients. In 1 patient, the device could not be de-ployed because of extreme angulated anatomy.30

Recently, the Canadian and European phase IPTOLEMY (Percutaneous Transvenous Mitral An-nuloplasty) trial has been reported. This studyincluded 27 patients with NYHA functional classII or III, and moderate to severe functional MR.33

Successful implantation was performed in 19 ofthe 27 patients. The remainder were excludedbecause of unsuitable coronary sinus anatomy.Of those who underwent successful implantation,13 had a reduction in MR severity and, in 6, thedevice was ineffective. Device removal wasrequired in 4 patients because of fracture, devicemigration, or diminished efficacy. Long-termsuccess in MR reduction was seen in only 18.5%of the patients. An attractive feature of this deviceis the ability to regain venous access at a later dateto remove rods if the reduction of MR is dimin-ished. In that case, stiffer rods may be used toreplace the initial implanted rods. The phase IIPTOLEMY trial has been presented and showed2.8% 30-day cardiac event rates and greaterthan 90% procedural success. However, thecompany has stopped further development andmanufacturing of the device.Despite the effectiveness and ease of use of the

coronary sinus devices approach, they all havelimitations. Metal fatigue and the risk of devicefracture caused by mechanical stress in thecoronary sinus created by torsional forces onthese devices is an important issue. Reengineeringof all of these devices has improved outcomes. Asecond limitation common to this class of deviceis the potential for compression of the leftcircumflex coronary artery. Cardiac computedtomography to assess the relationship of thecoronary sinus and the coronary arteries beforedevice implantation is an important step in theevaluation of these patients before annular deviceimplantation.

MitraLife deviceThe MitraLife device (ev3/Edwards Lifesciences,Irvine, CA, USA) is one of the first annuloplastydevices tested in humans. It consists of a percuta-neous delivery system that is preloaded with theMitraLife device and is permanently implantedin the coronary sinus via the internal jugularapproach. The device is designed to reduce mitralannular size and restore valve leaflet closure.Durability and feasibility results in canine animalmodels have thus far been promising, and havebeen associated with significant reduction in MR.To date, only a handful of human temporary place-ments have occurred outside the Unites States.

Initial reports of the MitraLife device have beenpresented of 7 patients (5 men and 2 women),aged 22 to 66 years, with functional MR. Allpatients had severe MR and NYHC III and IV,and the mean ejection fraction was 27%. Signifi-cant reductions in mitral annulus and MR weredescribed; however, a clinical trial is pending.

Direct Annuloplasty Techniques

Mitralign systemThe Mitralign system (Mitralign, Tewksbury, MA,USA) involves placement of the guide catheterunder the middle scallop of the posterior mitralleaflet. The device consists of a deflectable cath-eter that is manipulated and advanced in a retro-grade fashion across the aortic valve througha 14-Fr femoral sheath into the subvalvular mitralvalve space. A steerable catheter with a deflect-able 2-arm (bident) catheter end is delivered viaa 12.5-Fr guide catheter between the papillarymuscles facing the posterior mitral annulus.Once properly aligned, anchor pledgets are deliv-ered from the LV to the left atrium across thecircumferential mitral valve annulus and pulledtogether with a guidewire to decrease the annulusseptal-lateral dimension. The feasibility and dura-bility of this technique has been confirmed in earlyanimal studies in which significant reductions inMR were shown.34 Currently, the technique isbeing tested in a safety and feasibility phase I clin-ical study; however, preliminary results have yet tobe released and clinical outcome data are ex-pected in the future.

Accucinch deviceThe Accucinch device (Guided Delivery Systems,Santa Clara, CA, USA) is another promisingstrategy. A small adjustable ring of anchors inter-linked with a cable is implanted percutaneouslyinto the muscle below the mitral valve. The cinch-ing effect improves the ability of the mitral valve toclose properly and reduces the mitral regurgita-tion. After access to the annulus, a series of asmany as 12 nitinol anchors are placed in the mitralannulus. These anchors are connected with a cordthat is tensioned to draw the anchors together.This device has been implanted surgically, andfirst-in-human experience has shown the technicalfeasibility of percutaneous use. The Accucinchsystem has been successfully tested during openheart surgery in 2 patients with 21 MR and coro-nary arterial disease undergoing routine coronaryartery bypass grafting. The surgically implanteddevice resulted in sustained and successful reduc-tions in MR severity at 6-month and 12-monthfollow-up. The first in-human percutaneousimplantation of the Accucinch system for mitral

Mitral Valve Regurgitation 95

valve repair was reported in 2009. The procedurewas performed by Dr Schofer in Hamburg, Ger-many, and the Accucinch system significantlyreduced the patient’s mitral regurgitation.

Although arterial access as the delivery routeadds morbidity to the procedure compared withthe simplicity and ease of use of the transvenouscoronary sinus approach, direct annuloplasty hasthe advantage of avoiding coronary compression,and the potential for greater efficacy in reductionof MR through the direct approach is highly attrac-tive. Direct annuloplasty technologies are in earlydevelopment, and more human experience isexpected.

QuantumCor systemThe QuantumCor system (QuantumCor Inc., LakeForest, CA, USA) (Fig. 8) represents a uniqueand different concept that has yet to be tested inhumans. This technology is based on thermalremodeling of collagen (TRC), which uses thehigh collagen content of the mitral valve annulusin which high-frequency energy is deliveredthrough an electrode to denature collagen fibers,causing them to shrink and consequently remodel-ing the annulus. The end-loop catheter electrodesystem device is positioned on the dilated valveannulus where a precise subablative radiofre-quency energy protocol is delivered. This protocolreleases the hydrogen bonds in the collagen fibersof the mitral annulus, causing them to shrink. Theposterior annulus is treated in 4 quadrants fromtrigone to trigone, achieving segmental shrinkagein each quadrant. Segmental shrinkage in all 4quadrants results in a remodeling of the valveannulus, a reduction of the anteroposterior dimen-sion of the valve, and improved coaptation of thevalve leaflets. When the procedure is complete,the catheter device is removed and no hardwareis left in the heart or vascular system. The tech-nique has been tested in acute and chronic sheepmodels in which up to 20% reductions inseptal-lateral annular dimensions have been

Fig. 8. QuantumCor device.

reported.35 Histopathologic examination hasshown no evidence of undesirable injury torelated structures.

REMODELING OF THE LEFT VENTRICULAR/LEFT ATRIAL MITRAL VALVULAR COMPLEX

This group of transcatheter devices is currentlybeing developed to improve the paravalvulargeometric distortion that is encountered inpatients with functional MR.

PS3

The PS3 system (Ample Medical, Inc.) (Fig. 9) isa transcatheter atrial/mitral annulus remodelingdevice that integrates several concepts andconsists of an atrial septal occluder, an intercon-necting cinching wire, and a permanent smallcoronary sinus T-bar element that is positionedbehind P2. The interatrial occluder serves asa pivotal anchor and allows cinching to occurfrom the posterior annulus to the superior medialinteratrial septum. The concept was based onprevious animal studies that showed increase inposterior wall to interatrial septum dimensions infunctional MR. The initial experience with thePS3 device was first reported in 23 sheep withdilated cardiomyopathy and functional MR. Imme-diate and midterm results at 30 days revealedimportant reductions in septal to lateral dimen-sions and MR severity.36 Coronary arterialimpingement was not observed, and the greatcardiac vein was patent in all animals duringfollow-up histopathologic examination. Significanthemodynamic improvements and a reduction inbrain natriuretic peptide levels were observed.The feasibility and safety of this technique was firstconfirmed in 2 patients undergoing temporaryimplantation of the PS3 system before mitral valverepair surgery.37 In the first patient, the PS3 re-sulted in a relative change of 29% in septal-lateral dimension and was associated with a 11decrease in MR severity. The MR severity in the

Fig. 9. (A) The PS3 device consists of a septal anchor, a bridge, and a coronary sinus anchor. (B) PS3 device in place.

Lago et al96

second patient decreased from13 to11 followinga 31% relative change in septal-lateral dimension.No procedural complications were reported. Theongoing CAFE trial is a phase I safety and feasi-bility study of long-term PS3 implantation in hu-mans with heart failure and severe functional MR.

The iCoapsys Left Ventricular ReshapingDevice

The iCoapsys (Myocor Inc., Maple Grove, MN,USA) left ventricular reshaping device was, untilrecently, a promising alternative percutaneousstrategy developed to treat functional MR

Fig. 10. The iCoapsys transventricular device and its mechational mitral regurgitation. AML, anterior mitral valve lemitral valve leaflet; PPM, posterior papillary muscle, S-LLV,annulus, (before [1] and after [2] device implantation).

(Fig. 10). Although no longer in use, the strategyrepresents an important concept. The iCoapsystransventricular system consists of an anteriorand posterior epicardial pad tethered together bya subvalvular transventricular chord that travelsthrough the LV and between the papillary muscles.After its implantation via subxyphoid pericardialapproach, the chord length can be reduced andadjusted to establish optimal septal-lateral LVand annular dimensions. Conformational changesare intended to reorient the papillary musclesand reduce LV geometric distortion, resulting ina decrease in regurgitant orifice and MRseverity. Promising results were reported from

nical reconfiguration of the left ventricle to treat func-aflet, APL, anterior papillary muscle, PML, posteriorseptal-lateral left ventricle; S-LMA, septal-lateral mitral

Mitral Valve Regurgitation 97

the early animal experience.38 Unfortunately, theVIVID (Valvular and Ventricular Improvement ViaiCoapsys Delivery) feasibility study in humanswas prematurely discontinued because of tech-nical difficulties during device implantation andsuboptimal patient applicability.

PERIVALVULAR PROSTHETIC MITRALREGURGITATION

Percutaneous repair of perivalvular prostheticmitral regurgitation has evolved to become anotherimportant and attractive alternative to surgicalcorrection. Paravalvular mitral regurgitation isa serious complication seen in up to 7%of patientsfollowing prosthetic heart valve surgery.39,40 In thisgroup of patients, redo-operations are commonlyassociated with increased procedural mortality.41

More recently, percutaneous endovasculardevices have been evaluated with promisingresults.42–44 The Amplatzer Vascular Plug, theSeptal Occluder, and Duct Occluder (AGAMedicalInc., Golden Valley, MN, USA) are used to sealthe paravalvular regurgitation. The AmplatzerDuct Occluder is the most commonly used device.Implantation of 2 or more devices may be

Fig. 11. Doppler and 3D echocardiographic imaging of asuccessful transcatheter closure using 2 Amplatzer Occlud

necessary. In our experience, simultaneous three-dimensional (3D) TEE imaging should be encour-aged for all cases, because it provides optimalinformation during device implantation (Fig. 11).45

SUMMARY AND FUTURE DIRECTIONS

Percutaneous approaches to MR remain largelyinvestigational. However, in the last decade, novelpercutaneous strategies have opened new optionsin the treatment of valvular heart disease. Animaland early human studies indicate that many ofthese techniques are safe and feasible. Severalimportant clinical studies are currently underwayto determine the benefits of transcatheter mitralvalve repair therapy. Given the complexity of themitral valve apparatus and its subvalvular struc-ture, a single device to treat all forms of mitralregurgitation is unlikely to be effective in everypatient. However, the encouraging results of theMitraClip suggests that this technique may even-tually play an important role in the treatment oforganic MR. In contrast, the role for isolated coro-nary sinus devices remains uncertain. The role oftranscatheter left ventricular remodeling devicesto treat functional MR is at the beginning of its

mitral paravalvular leak before (A, B) and after (C, D)er PDA devices.

Lago et al98

development. Transcatheter chordal proceduresare being developed, including chordal cuttingand chordal implantatation.46,47 Transcathetervalve implantation in the mitral position might offera desirable alternative in selected patients and hasbeen accomplished in a compassionate fashion onrare occasions in patients who are not candidatesfor surgical valve repair or replacement.

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