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Percutaneous Mitral Valve Repair Techniques

Percutaneous Mitral Valve Repair Techniques
Abstract
This chapter describes established and emerging percutaneous mitral valve repair techniques. The goal of any percutaneous procedure is to achieve a durable correction of mitral disease with clinical efficacy similar to that of well-established open surgical interventions. Knowing which patients will benefit most from percutaneous approach and which approach to apply is exceedingly challenging given the complex and varied pathophysiology and anatomy of mitral valve disease. Surgical risk is often prohibitive given that mitral valve disease is both caused by and develops in parallel to many comorbidities that increase surgical risk. By applying concepts that have made surgical repair successful to the engineering of percutaneous technologies, restoring proper mitral valve function with catheter based techniques can be performed without many of the risks inherent to surgery. Percutaneous therapies therefore represent an expanding toolbox for the modern valvular heart disease center that strives to repair mitral valve disease in patients at all levels of surgical risk. Although catheter based repairs for MR are only approved in patients at prohibitive surgical risk, as more data is collected, percutaneous repair may one day be used as a viable option to surgical candidates who wish to avoid surgery.


Keywords : percutaneous mitral valve repair, mitral stenosis, degenerative mitral regurgitation, functional mitral regurgitation, balloon mitral valvuloplasty, MitraClip, EVEREST trials, COAPT trial, Carillon Mitral Contour System, AMADEUS trials, TITAN trials, AccuCinch Ventriculoplasty System, Cardioband System, IRIS complete annuloplasty ring

Step 1. Surgical Anatomy
·   Percutaneous therapies have changed how the modern cardiothoracic surgeon approaches the treatment of valvular heart disease. Although much of this evolution has come with the advent of transcatheter aortic valve replacement, considerable obstacles inherent to mitral valve disease have been overcome to develop multiple percutaneous technologies.
·    Surgery is often difficult because mitral valve disease is both caused by and develops in parallel to many comorbidities that increase surgical risk. This has been demonstrated by reports that as many as 50% of patients with severe mitral regurgitation (MR) are not candidates for surgery.
·    The challenge of developing effective percutaneous mitral valve repair technology stems from the complexity and variation of both the pathophysiology of mitral valve disease and the anatomy of the mitral valve apparatus.
·  Degenerative MR (DMR; Video 22.1) develops when disease of the valve itself prevents sufficient mitral leaflet coaptation via leaflet or chordal elongation, chordal rupture, or annular deformation, whereas functional MR (FMR) develops when left ventricular dysfunction and deformation prevent sufficient coaptation of anatomically normal leaflets via annular dilation or leaflet tethering.
·  Patients with central, discrete regurgitant jets with relatively narrow bases and single-leaflet prolapse or flail may benefit from percutaneous edge-to-edge repair.
·   Patients with enlarged hearts, annular dilation, minimal tenting, and central jets may benefit from percutaneous annuloplasty.
·    Successful coronary sinus based annuloplasty is more easily achieved in patients with a large coronary sinus and a large great cardiac vein, with minimal tortuosity. Moreover, effective reduction of the septolateral diameter can only be achieved if the coronary sinus and great cardiac vein lie in the same plane as the mitral annulus (Fig. 22.1).


Step 2. Preoperative Considerations
·   The goal of any percutaneous procedure is to achieve a durable correction of mitral disease with clinical efficacy similar to that of well-established open surgical interventions. Most approaches to percutaneous mitral valve repair are modeled after established surgical techniques.
· By applying concepts that have made surgical repair successful to the engineering of percutaneous technologies, restoring proper mitral valve function can be performed without the risks inherent to surgery.

1. Percutaneous Treatment of Mitral Stenosis
·  Worldwide, mitral stenosis (MS) most commonly results from rheumatic valvular disease, typically with fusion of the leaflets at the commissures.
·    Balloon mitral valvuloplasty (BMV) splits the fused commissures, allowing the mitral valve to open more fully, and is the most well-established catheter-based repair of mitral disease since the 1990s.
·    The applicability and efficacy of BMV are limited, with optimal outcomes in patients with a mitral valve that is relatively thin and free of calcification, resulting in greater leaflet mobility when the fused commissures are divided and minimizing the risk of embolic complications.
·  BMV lacks utility when concomitant left atrial clot or more than mild to moderate MR is present. Once either of these is present, mitral valve surgery is preferred unless the patient is at prohibitive surgical risk.
· BMV has limited efficacy in those with senile calcific MS because it is caused not by commissural fusion but by calcification that extends into the leaflets from their origination in the annulus.

2. Percutaneous Treatment of Mitral Regurgitation
Percutaneous Edge-to-Edge Repair
·   Although uncommonly used in conventional surgical repair of MR, the edge-to-edge repair, first described by Alfieri in 1991, has been shown to be effective at decreasing MR without significant risk of MS in selected patients. The MitraClip procedure (Abbott Laboratories, Abbott Park, IL) is a percutaneously delivered device that mimics the sutures placed in an Alfieri repair. Whereas the original Alfieri technique (Fig. 22.2) combined an edge-to-edge suture with annuloplasty, the MitraClip procedure is currently performed in isolation without annuloplasty. Although debated, isolated reports have documented adequate outcomes with surgical edge-to-edge repair without annuloplasty, providing the basis for the use of the MitraClip procedure as a sole therapy.


·    Degenerative and functional MR often necessitate very different treatment approaches but, as an intervention that was hoped to offer benefit to patients with either cause, the MitraClip procedure was initially studied in a heterogeneous population. Surgical mitral repair has provided excellent outcomes for patients with DMR, but the benefit to patients with FMR is controversial. Although there exists a gold standard for treating FMR in nonsurgical patients, no such standard exists for treating DMR. Given the inferior efficacy when compared to surgical repair and the lack of a gold standard for nonsurgical patients with degenerative pathology, the US Food and Drug Administration (FDA) approved the MitraClip procedure in 2013 as an alternative treatment option for symptomatic patients with severe (≥ 3+) DMR at prohibitive surgical risk.
·      Currently, a functional cause of MR is not an approved indication for the MitraClip procedure. Severe FMR certainly worsens heart failure physiology and symptoms by contributing to volume overload and progressive dilation, but it is yet unclear whether correcting the MR actually improves survival. The EVEREST II (Endovascular Valve Edge to Edge Repair Study) trial has shown that FMR is a significant predictor of mortality on multivariable analysis (hazards ratio [HR], 2.7; confidence interval [CI], 1.4–5; p = 0.003),15 so although the repair of MR may improve symptoms, it may not address the causal pathophysiology or affect the clinical trajectory likely determined by the underlying left heart dysfunction. FMR is primarily treated via goal-directed medical therapy aimed at improving underlying left ventricular dysfunction with beta blockade, diuretic use, angiotensin-converting enzyme inhibitors and, if indications are found, cardiac resynchronization. It is therefore recommended to ensure that patients receive maximal medical therapy prior to considering mitral intervention.
·    Patients with DMR must meet many anatomic criteria to have the MitraClip device placed. Although reported to have caused only one case of MS after 5 years of follow-up in the clinical trial, there have been other reports of MS following MitraClip placement. As such, a resting effective orifice area over 4 cm2  is required to minimize this long-term risk of MS.19
·    Considering that the Alfieri technique can only address poor coaptation at one place along the valve orifice, multiple foci of MR preclude the use of the MitraClip. Ideally it should be used when a single primary regurgitant jet is present.
·    Although initial studies excluded patients with excessively calcified leaflet edges out of concern for capture failure, this has often been overcome in subsequent clinical experience with multiple clip placement, with reports of as many as 40% of patients receiving a second clip and some even receiving a third.

Percutaneous Annuloplasty
·      Surgical repair of MR is often accomplished by reducing the septolateral diameter of the mitral annulus, thereby increasing coaptation with the placement of a rigid, undersized annuloplasty ring. Several technologies have been developed to accomplish annuloplasty percutaneously and, because it can halt the progressive dilation of the mitral annulus often responsible for FMR, it may be of greater benefit than MitraClip placement for those with functional pathology. These therapies have been developed either to anchor a device to the annulus directly or indirectly reduce septolateral diameter with a device in close proximity to the annulus.
·     As the only available technology that indirectly reduces mitral annular diameter, the Carillon Mitral Contour System (Cardiac Dimensions, Kirkland, WA) takes advantage of the proximity of the coronary sinus to the mitral annulus.
·     Although the Carillion System obtained CE Mark approval in 2011 for commercial use in the European Union, it continues to be investigational in the United States with the first randomized controlled trial anticipated to begin enrollment in 2017. It is yet to be seen whether this technology will be able to overcome the challenges encountered in initial efficacy studies. Sufficient reduction in MR could not be achieved in many patients because anatomic variability led to device placement in a coronary sinus too far removed from the annulus or above the annular plane in the wall of the left atrium.
·       Furthermore, because as many as 80% of patients have been reported to have a coronary artery course between the coronary sinus and mitral annulus, the device had to be withdrawn in 16% of patients due to impingement of the left circumflex artery or its major branches.
·    Several technologies have emerged to anchor either an annuloplasty ring or plication sutures directly to the mitral annulus via transvenous, transseptal, or retrograde transaortic valve delivery systems.
·   Although the company that developed the only technology available for percutaneous placement of individual suture plication stitches has shifted focus to its application to tricuspid disease, the various technologies that accomplish more complete annuloplasty are in the early stages of development, and the patient populations that will most likely benefit from each have yet to be identified.

Step 3. Operative Steps
1. Percutaneous Treatment of Mitral Stenosis
·   BMV is performed by introducing a long, specially curved, retractable needle in a sheath through the femoral vein into the right atrium and puncturing the atrial septum at the fossa ovalis to gain access to the left atrium (Fig. 22.3A). One or two large, high-pressure balloon catheters are then positioned across the stenotic mitral orifice (see Fig. 22.3B) and inflated until the orifice is stretched or adhesions between leaflets are torn, thus increasing the valve area and decreasing the transvalvular pressure gradient (see Fig. 22.3C).


2. Percutaneous Treatment of Mitral Regurgitation
Percutaneous Edge-to-Edge Repair
·    The MitraClip system (Fig. 22.4) is composed of a steerable guide catheter through which the MitraClip device is delivered and then positioned by a highly maneuverable clip delivery system (CDS).
·    The 24 F guide catheter is advanced into the left atrium over a guidewire that is placed via the right femoral vein across the fossa ovalis under fluoroscopic and echocardiographic guidance. The septum is ideally perforated posteriorly, away from the aortic valve, and at a height of 3.5 to 4 cm (Fig. 22.5; Video 22.2). The height depends on the plane of leaflet coaptation with DMR often necessitating higher placement due to coaptation closer to the annular plane and FMR often necessitating lower placement due to coaptation below the annular placement.
·    Once appropriate positioning has been confirmed, the guidewire is exchanged for a 0.035-inch Amplatz Super Stiff guidewire (Boston Scientific, Marlborough, MA) with a 7-cm floppy tip; systemic heparin is administered for an activated clotting time (ACT) goal of more than 250 seconds before the 24 F guide catheter is advanced into the left atrium.
·    The MitraClip at the tip of the CDS is advanced through the guide catheter into the left atrium, where it is opened to 180 degrees (Fig. 22.6A) to allow for easier orientation perpendicular to the mitral leaflets under three-dimensional echocardiographic guidance (see Fig. 22.6B). The device is then advanced across the mitral valve and closed to 120 degrees to allow for mitral leaflet insertion as the device is slowly withdrawn (Fig. 22.7).


·    The leaflets are captured between cobalt chromium outer grasper and inner gripper arms (see Fig. 22.4B; Video 22.3). Once adequate leaflet insertion has been ensured on multiple two- dimensional transesophageal echocardiography (TEE) views, the previously partially closed arms are fully closed, and the MR reduction is assessed (Fig. 22.8; Video 22.4). If MR reduction is inadequate, the graspers can be released and the device repositioned, or additional devices can be placed.
·    Once MR reduction is satisfactory, the device is deployed, the CDS and guidance catheter are withdrawn, protamine is given until the ACT normalizes, and the femoral sheath is removed.


Percutaneous Annuloplasty
Indirect: Annuloplasty via Device Placement Inside the Coronary Sinus
·    The Carillon Mitral Contour System (Cardiac Dimensions, Kirkland, WA) is delivered via a 9 F catheter placed through the right internal jugular vein and anchored in the coronary sinus near the ostium and anterior commissure.
·  Annular circumference is reduced as the nitinol ribbon connecting the distal and proximal anchors is shortened, allowing for improved leaflet coaptation (Fig. 22.9)


Direct: Anuloplasty via Device Attachment to the Mitral Annulus
·    Two technologies exist for both retrograde-transaortic valve and transvenous-transseptal device delivery.
·    The Mitralign device (Mitralign, Tewksbury, MA) reduces annular dimensions via direct suture plication. Two wires are delivered retrograde up the aorta and across the aortic valve and penetrate the mitral annulus at adjacent points. Under TEE and fluoroscopic guidance, the wires are used to place pledgets on both atrial and ventricular sides of the annulus, and a suture is placed through both pledgeted points and then tightened until the desired plication is achieved before being held in place by a steel lock (Fig. 22.10).
·   The AccuCinch Ventriculoplasty System (Ancora Heart, Santa Clara, CA) provides a near- circumferential plication system delivered retrograde through the aortic valve and anchored to the ventricular side of the annulus. The AccuCinch delivers a series of anchors into the basal ventricle directly beneath the annulus that are connected via a nitinol wire, which is tightened, thereby reducing mitral annular and left ventricular basilar circumference (Fig. 22.11). The developers thought that this system would have a greater impact on ventricular geometry than with other approaches to annuloplasty.
·    The Cardioband System (Edwards Lifesciences, Irvine, CA) is a tubular Dacron band that is anchored every 8 mm as it is extruded from a 24 F sheath around the posterior circumference of the mitral annulus from the posterior to anterior commissure. The internal tension cable connecting each anchor is tightened and adjusted until the desired reduction in mitral dimen- sions has been achieved (Fig. 22.12).
·   The IRIS complete annuloplasty ring (Millipede, Santa Rosa, CA) is also placed above the mitral annulus and delivered transvenously through the atrial septum. Instead of a system that transmits tension between anchors connected by cable, IRIS is a collapsible nitinol ring whose interlaced double-zigzag frame is anchored at every intersection. The distance between each anchor can be adjusted individually via a screw at the apex of each zigzag, allowing for the device to decrease annular dimensions while maintaining the saddle-shaped geometry of the valve.


Step 4. Postoperative Care
1. Percutaneous Treatment of Mitral Stenosis
·  Patients are monitored for the return of MS with serial transesophageal echocardiograms, as well as for symptoms of pulmonary edema and low cardiac output.

2. Percutaneous Treatment of Mitral Regurgitation
Percutaneous Edge-to-Edge Repair
·    Aspirin is started postprocedurally, and patients are observed for 1 to 2 days before discharge.
·    In addition to routine cardiac medical optimization, serial echocardiograms are obtained to evaluate the degree and durability of the reduction of MR.
·   Although there are legitimate concerns that the presence of MitraClip devices impairs the ability to perform subsequent surgical repair, surgical MV reconstruction can be performed in select cases as late as 5 years after the implantation. Unfortunately, the feasibility of surgical repair cannot be predicted at the time of MitraClip insertion should severe MR recur.
Percutaneous Annuloplasty
  Both the feasibility study AMADEUS and the initial safety and efficacy trial TITAN have demonstrated that the Carillon system improves MR and functional status as well as provides favorable LV remodeling up to 2 years after device placement.
  In addition to routine cardiac medical optimization, similar to percutaneous edge-to-edge repair, serial echocardiograms are obtained to evaluate the degree and durability of the reduction of MR.


Step 5. Pearls and Pitfalls
1. Percutaneous Treatment of Mitral Stenosis
·   Although the increase in valve area provided by BMV is occasionally short-lived and usually inferior to the increase provided by surgical repair or replacement, BMV can be repeated multiple times, often allowing surgery to be delayed for decades or avoided altogether.
·  Careful patient selection is necessary because performing BMV on some valves will result in the development of problematic MR or systemic emboli.

2. Percutaneous Treatment of Mitral Regurgitation
Percutaneous Edge-to-Edge Repair
·    After the safety and feasibility of MitraClip was established with the EVEREST I clinical trial, EVEREST II evaluated the safety and efficacy of MitraClip when compared to conventional surgical mitral repair.
·    Although EVEREST II demonstrated the superior safety of MitraClip, with significantly fewer major adverse events at 30 days (15% vs. 48% with surgery; p < 0.001), there was no difference when the main driver, bleeding requiring transfusion (13% vs. 42% with surgery; p < 0.001), was excluded (5% vs. 10% with surgery; p = 0.23).
·    In terms of efficacy, EVEREST II has demonstrated that surgical repair performs better than percutaneous repair with greater combined freedom from death, surgery for mitral valve dysfunction, and the recurrence of 3+ or greater MR both at 12 months (73% vs. 55% with MitraClip; p = 0.007) and 5 years (64% vs. 44% with MitraClip; p = 0.007).
·    The decreased efficacy of MitraClip was driven by the increased rate of recurrence of 3+ or greater MR (12.3% vs. 1.8% with surgery; p = 0.02) and the need for surgery or reoperation for mitral valve dysfunction (27.9% vs. 8.9% with surgery; p = 0.003) with no significant difference in mortality at 5 years of follow-up (21% vs. 27% with surgery; p = 0.4) and treatment strategy not being associated with survival on multivariable analysis (HR, 0.94; 95% CI, 0.51–1.7; p = 0.85).
·    However, investigators identified an early hazard of surgery for mitral valve dysfunction in the percutaneous group, with 78% of surgeries being performed before 6 months, beyond which there was no difference (78% with MitraClip vs. 76% with surgery; p = 0.77). Furthermore, combined efficacy was no different at 5 years in the patient population that was event-free at 1 year, suggesting that the lower efficacy of percutaneous therapy may be minimized as more is learned about optimal patient selection and device placement.
· Despite there being more residual or recurrent severe MR after the MitraClip procedure, percutaneous repair succeeds in providing a durable improvement in left ventricular dimensions, New York Heart Association functional classification, and quality of life measures. These are findings that have been confirmed in multiple studies other than those performed by the EVEREST group.
·    EVEREST II was not able to provide a rationale for approval in patients with FMR because 73% of the study population had degenerative pathology. The EVEREST II high-risk follow-up study has helped address the question of whether the MitraClip procedure can provide clinical benefit to patients with FMR, demonstrating a trend toward increased survival with MitraClip when compared to medical management only (76% vs. 55%; p = 0.05) and a 46% reduction in readmission rate for congestive heart failure exacerbations.
· In combination with the results of many nonrandomized European studies and registries, evidence has mounted to support the claim that the risk of recurrent MR with the MitraClip procedure may outweigh the risks of mitral valve surgery in high-risk patients. In all of these studies, investigators found that despite percutaneous repair being associated with a higher rate of recurrent MR, percutaneous repair provides a substantial proportion of patients with a reduction in MR, as well as lasting symptomatic relief and positive left ventricular remodeling.
·    To determine whether the MitraClip procedure provides benefit beyond that seen with optimal medical therapy more definitively, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) for Heart Failure Patients with FMR trial has been enrolling patients (NCT #01626079). This study, which compares groups randomized to standard medical therapy or MitraClip placement in addition to standard medical therapy, should clarify the appropriate role of the MitraClip procedure in patients with FMR at a high or prohibitive surgical risk.

Percutaneous Annuloplasty
Indirect: Annuloplasty via Device Placement Inside the Coronary Sinus
· Although deemed safe, early generations of the Carillon System were found to have asymptomatic fractures on follow-up imaging; thus, TITAN II was performed to confirm the safety of an updated iteration. The results of TITAN II were consistent with the findings of previous studies, except that only one fracture occurred. The updated Carillon device will soon be evaluated in a randomized, blinded clinical trial (NCT #02325830) in the United States.

Direct: Annuloplasty via Device Attachment to the Mitral Annulus
·    Similar to the limited efficacy of annular plication sutures in open repair, Mitralign has shown modest improvements in MR grade and symptomatic relief at 6 months. The company has therefore abandoned efforts to obtain FDA approval for the use of their technology for mitral annular plication and has instead focused their efforts on applying the Mitralign technology on tricuspid annuloplasty, with the first safety and efficacy study evaluating the newly termed TriAlign technology due to finalize enrollment in 2018.
·   The first study evaluating the safety and efficacy of the AccuCinch system has been actively recruiting participants at multiple centers in Austria and Germany (NCT #00800046), with plans to begin enrollment soon in the United States.
·  Cardioband obtained CE Mark approval in 2015 and has since been shown to be safe and to have provided significant improvement in MR and heart failure symptoms at 6 months.41 A trial in the United States will soon begin, with the goal of obtaining FDA approval.
·    The IRIS complete annuloplasty ring has been placed in multiple patients, with the first study to evaluate the safety and efficacy of the device expected to complete enrollment in 2018 (NCT #02607527).