Chapter 45. Percutaneous Catheter-Based Mitral Valve Repair

There has been intense interest over the past decade in developing percutaneous catheter-based techniques to manage valvular heart disease.1–4 Although the success has been rapid to the point of being disruptive in catheter treatment of aortic stenosis, progress has been much more modest in correcting mitral regurgitation (MR) percutaneously.5 The success of catheter-based treatment of aortic stenosis can be attributed to a singular pathophysiology of the disease and the successful development of delivery systems and techniques to treat this disorder using conventional imaging techniques. The field of percutaneous mitral valve repair, however, has not progressed nearly as rapidly for a host of reasons. These include the complex pathophysiology of MR with diverse causes as well as challenging imaging and complex delivery issues. These obstacles have led to slower than anticipated clinical adoption of catheter-based approaches for the treatment of MR. To understand the potential for successful therapy, it is first instructive to examine the pathophysiology of the various mechanisms of the disease.

Pathophysiology of Mitral Regurgitation

The mitral valve is a complex structure composed of two leaflets, a fibrous annulus with varying degrees of continuity and integrity, and a subvalvular apparatus consisting of chordae tendinea and papillary muscles attached to the wall of the left ventricle (LV). The causes of mitral regurgitation range from intrinsic disease of the leaflets mainly owing to degenerative disease or fibroelastic deficiency in patients with mitral valve prolapse, although connective tissue diseases, including Barlow's syndrome, also occur, to functional mitral regurgitation (FMR) in which the valve is anatomically normal but stretched because of tethering and annular dilatation.6 Although the mitral regurgitation in intrinsic disease occurs initially as leaflet disease, secondary annular dilatation occurs in the large majority of patients by the time they present for treatment. The larger proportion of patients with mitral regurgitation, however, are those without intrinsic disease of the leaflets, or FMR. FMR is not a primary valvular pathology but a secondary one caused by ventricular dilation, which leads to apical and lateral distraction of the papillary muscles tethering the mitral leaflets causing central regurgitation owing to failure of coaptation during systole of the anatomically normal leaflets7 (Fig. 45-1). The causes and prognosis are inherently different from intrinsic disease. Although annular dilatation also occurs in this disease, it also is a secondary phenomenon. Surgical correction of FMR is based upon overcorrection of the annular dilatation component by performing an undersized annuloplasty to restore leaflet coaptation.

Transcatheter Approaches to the Treatment of Mitral Regurgitation

There is a wide spectrum of ingenious devices and creative approaches to manage MR from a percutaneous or transcatheter approach8 (Table 45-1). Most of these are based on techniques that have been developed and proved to be effective in open surgical mitral valve surgery. Examples include the edge-to-edge techniques, annular remodeling, and placement of artificial chords. However, the challenges in adapting these techniques to catheter-based treatment are significant and center mainly on device delivery and imaging. In addition, totally new concepts have also been developed, including a “mitral spacer” to augment leaflet coaptation and use of external devices and energy sources to remodel the mitral annulus. Although some devices such as the Evalve MitraClip (Abbott Vascular, Irvine, CA) have been employed to treat both intrinsic disease as well as FMR, most of the devices have been designed to treat only one, with the majority devoted to FMR because of the larger clinical unmet need as well as the existence of excellent surgical repair techniques for intrinsic disease. This chapter reviews the procedures and devices for the management of degenerative mitral disease.

Percutaneous Techniques for Degenerative Disease of the Mitral Leaflets

Percutaneous Edge‐to-Edge Repair

Two devices have been developed based on the surgical edge-to-edge repair technique of Alfieri (Fig. 45-2).9 The Evalve MitraClip and the Mobius Mitral leaflet repair system (Edwards Lifesciences, Irvine, CA) both simulate the Alfieri surgical edge-to-edge repair technique; the former by placement of a clip between the free edges of the anterior and posterior leaflets, and the latter by employing a suture-based system.10,11 The Mobius device underwent an early clinical feasibility trial in 15 patients, and because of disappointing results and arduous delivery and placement, further development of this device was abandoned. Modification of this device to create artificial chords attached to the free edge of the leaflet is now being developed.

The Evalve MitraClip system is a catheter-based device designed to perform endovascular reconstruction of the regurgitant mitral valve while the heart is beating. It includes a clip device (MitraClip) and a delivery system that is a steerable guide catheter that enables placement of the clip on the free edges of the mitral valve leaflets, resulting in permanent leaflet approximate approximation and a double orifice mitral valve (Fig. 45-3). The procedure is performed percutaneously via the femoral vein in a cardiac catheterization laboratory with echocardiographic guidance under general anesthesia. The addition of three-dimensional echocardiography has significantly facilitated the procedure (Fig. 45-4). Following the procedure, patients are treated with dual antiplatelet therapy and hospital discharge is usually the day after the procedure.

The potential benefit associated with the use of the MitraClip includes repairing MR while eliminating the need for open chest surgery, cardiopulmonary bypass, and cardiac arrest. The potential risks include those associated with cardiac catheterization and transseptal puncture. The major concern regarding this technique centers on the efficacy of a procedure with a less complete correction of the MR than is usually accomplished surgically. Whether partial reduction of MR is sufficient to translate to ventricular remodeling and more importantly clinical benefit remains to be determined. Additional concerns have been raised regarding the potential impairment of the ability to perform a subsequent surgical valve repair should that prove necessary.12

Evalve MitraClip has undergone significant clinical testing over the past 7 years. As of early 2010 a total of 1316 patients had been entered into the various clinical trials and registries.13–15 In the initial clinical feasibility trial (Everest I), 55 patients were enrolled with safety and efficacy of the device demonstrated. Subsequent high-risk, European, and continued access registries have enrolled approximately 1000 additional patients, the majority of whom (~80%) have FMR. The pivotal trial of this system, the Everest II trial, has recently been completed and results presented.16 This trial is a multicenter randomized controlled trial to evaluate the benefits and risks of mitral valve repair using the MitraClip device compared with open mitral valve surgery in patients with moderate or severe mitral regurgitation. Patients were randomized in a 2 to 1 ratio of device versus mitral valve surgery. Enrollment was 279 patients at 37 sites with 184 patients receiving the device and 95 patients receiving surgical repair or replacement. There were very specific anatomical criteria, including moderate or severe MR defined as 3 to 4+, with the primary regurgitant jet originating from between the A2 and P2 scallops. Important exclusion criteria included ejection fraction less than 25% and left ventricular and systolic dimension greater than 55 mm. The width of the flail segment could not be greater than 15 mm nor was the flail gap greater than 10 mm. If leaflet tethering was present, a coaptation depth of greater than 11 mm or a vertical co-optation length less than 2 mm would be excluded. Severe mitral annular calcification, calcification of the leaflets, a significant cleft in the A2 or P2 scallops, and bileaflet flail or severe bileaflet prolapse were also excluded.

There were both safety and efficacy primary end points in the randomized trial. The primary safety end point was major adverse event rate at 30 days on a per-protocol analysis based upon a superiority hypothesis. Predefined major adverse events included death, major stroke, reoperation of the mitral valve, urgent or emergent cardiovascular surgery, myocardial infarction, renal failure, wound infection, prolonged ventilation, new onset atrial fibrillation, and transfusion of greater than or equal to two units of blood. The major adverse events in the surgical control arm were 657% at 30 days compared with 9.6% in the device arm for an observed absolute difference of 47.4%. Although transfusion was the major component of the composite safety end point in the surgical arm, the device still met noninferiority hypothesis criteria even if transfusion was eliminated.

The primary effectiveness end point was based on the clinical success rate defined as freedom from the combined outcome of death, mitral valve surgery or reoperation, or greater than 2+ mitral regurgitation at 12 months. It also was a per-protocol analysis, but on a noninferiority hypothesis. The trial also met the noninferiority hypothesis of clinical success rate at 12 months. The clinical success rate in the control group was 87.8% compared with 72.4% in the device group. The absolute observed difference of 15.4% met the prespecified margin of 31%, satisfying the noninferiority hypothesis.

Patient benefit was also demonstrated in the trial as defined by improved left ventricular ejection function, improved NYHA functional class, and improved quality of life. For the most part surgery remained a viable option after a MitraClip procedure was performed.

Experience with this device is ongoing in a continued access protocol, which will allow enrollment until the results of this trial are presented to the Food and Drug Administration expert panel expected to be late 2010. Approximately 70% of the patients currently being enrolled in the continued access protocol are those with functional mitral regurgitation, as opposed to the randomized trial, in which only 20% of the enrollees had FMR. The ultimate role of this device in the management of both patients with intrinsic and functional disease remains presently unclear.17

Leaflet Repair Using Artificial Chords

Another unique concept for repair of the prolapsing or flail mitral leaflet percutaneously is placement of artificial chords by a transapical approach. The access for this procedure is a left minithoracotomy through which a pursestring is placed at the apex of the heart. A delivery device that contains an infrared sensor grasps the edge of the prolapsing leaflet. Using the device a suture is passed through the grasped free edge. The two ends of the suture that are passed through the edge of the leaflet are then brought through the apex of the heart and tied on the epicardial surface (Fig. 45-5). Proper chordal length is determined by adjustment under echocardiographic guidance. The chords can be either lengthened or shortened based on the color jet seen on echo. Early clinical feasibility testing with this device is currently under way in Europe with eight patients enrolled in a 30-patient feasibility trial.

Functional Mitral Regurgitation

Functional mitral regurgitation when treated surgically is most commonly managed by reduction in the septal lateral diameter of the dilated mitral annulus by an undersized, complete, and rigid annuloplasty ring. Although there is dilatation of the whole mitral annulus in patients with FMR, the greatest degree of dilation is in the posterior annulus and the greatest increase in dimension is in the septal lateral (or anterior posterior) diameter.18,19 A key element of this surgical repair includes anchoring a complete ring to the central fibrous skeleton of the heart at the fibrous trigones. Anchoring the ring away from the mitral annulus in the atrial wall or in the leaflet tissue leads to less effective reduction in annular dimensions. Similarly, it has been well proved in the surgical arena that a partial posterior annuloplasty is less effective in annular reduction and treating mitral regurgitation.20–22 Correction of the septal lateral diameter by as little as 5 to 8 mm has been demonstrated to reconstitute leaflet coaptation and improve MR. Transcatheter approaches to FMR are based on this concept of remodeling the mitral annulus with the goal of decreasing the septal lateral diameter. There is no shortage of ingenious strategies to accomplish this goal23–28 (see Table 45-1). Some devices take advantage of the anatomical relationship between the coronary sinus and posterior mitral annulus. Other devices take a direct approach to plicating the posterior annulus; still others rely on distraction of the left ventricle or left atrial walls to decrease the septal lateral diameter.

Coronary Sinus Annuloplasty

The close proximity of the coronary sinus to the posterior mitral annulus has served as an attractive entrée for placement of devices to remodel the mitral valve29–33 (Fig. 45-6). The easy access by a transvenous route led to great early optimism. However, the variability in the relationship of the coronary sinus to the mitral annulus has been problematic in obtaining consistent decrease in annular dimensions. Although most commonly the coronary sinus is located adjacent to the posterior annulus, it is frequently located along the free wall of the left atrium and superior to the mitral annulus.34,35 The smallest separation between the coronary sinus in the mitral annulus is usually at the entry to the sinus. Separation of the coronary sinus from the mitral annulus is maximal at the posterolateral commissure, as demonstrated in an anatomical study by Miselli of coronary sinus anatomy in 61 human cadaver hearts.36 The distances between the inferior border of the coronary sinus and the mitral annulus at the P2 and P3 mitral segments averaged 9.7 mm. It is important to note that in patients with severe MR, the distance between the coronary sinus and the mitral annulus is usually much greater compared with patients without severe regurgitation. In addition, the relationship between the circumflex coronary artery or its branches intervening between the coronary sinus and mitral annulus is of significant concern. The left circumflex artery or major branches has been reported to course between the coronary sinus and the mitral annulus in up to 80% of patients37 (Fig. 45-7).

There now is clinical experience with at least three devices that access the coronary sinus for deployment of devices for posterior annular remodeling.38–42 Experience with the Edwards Lifesciences Monarc device in the Evolution Trial has been reported in 72 patients with FMR. The device was successfully implanted in 59 (82%) patients. The 1-year cumulative event-free rate was 81%, with a modest improvement in the degree of MR. Coronary artery compression has occurred in 30% of the implanted cases. A second device Cardiac Dimensions (Cardiac Dimensions, Kirkland, WA) Carillon System is a fixed-length device designed for plication of the coronary sinus between deployable anchors placed via internal jugular access. In two trials, Amadeus and Titan trials, a total of 113 patients with FMR have been attempted. Implant success rate is 58% (66/113).39,40 The primary end point was 30-day major adverse events, and secondary end points included decrease MR severity. At 30 days the major adverse event rate was 13% and there was reduction in only two of the four parameters used to measure degree of MR. There was a modest improvement on patients' 6-minute walk tests. Coronary artery compression occurred in 12% of cases. Although the study was declared successful by the investigators, the accompanying editorial expressed a much more modest interpretation of the results.39,40

The third device is the Viacor (Viacor, Inc., Wilmington, MA) PTMA system, in which a distributed anatomical bending with variable diameter nitinol rods are delivered through subclavian access.41,42 This has been tested in 27 patients with FMR in the Ptolemy Trial. The device was successfully implanted in 13 (48%) patients attempted.

Direct Mitral Annular Remodeling

There are a number of devices designed to remodel the mitral annulus by direct plication The Mitralign system (Mitralign, Inc., Tewksbury, MA), which is placed retrograde through the aortic valve on the ventricular side of the mitral annulus performs suture-based placation of the posterior annulus. Two sutures are placed in two locations placating P1-P2 and P2-P3 (Fig. 45-8). The GDS Accucinch (Guided Delivery Systems, Santa Clara, CA) selectively places a tensioning wire directly into the posterior mitral annulus. Another device, the Valtech Cardioband (Valtech, Inc., Tel Aviv, Israel) places a tensioning member anchored by screws placed into the mitral annulus. The tensioning band is then adjusted under echocardiographic guidance until the regurgitant jet disappears. Other systems include the Mitral Solutions (Fort Lauderdale, FL) Cordis DPA, and MiCardia for direct annular plication.

Another interesting concept that is still in the preclinical proof of concept stage is the QuantumCor (QuantumCor, Inc., Lake Forest, CA) device. This concept is designed to remodel the posterior mitral annulus by delivery of radiofrequency energy directly to the posterior annulus causing shrinkage. A similar concept uses radiofrequency energy to shrink the mitral leaflet and/or chords.43

Indirect Mitral Annuloplasty

Another concept is that of indirect annuloplasty. This conception relies on compression of either the left ventricle or the left atrium to distract the mitral annulus and decrease the septal lateral diameter and thus the degree of mitral regurgitation.44–50 Both of the devices pursuing this concept, i-Coapsys for the ventricle and Ample Medical for the atrium, have been shelved after early human feasibility studies.

Other Concepts

Other intriguing concepts include cinching devices placed in an extracardiac location to compress the anteroposterior diameter of the mitral annulus. The devices are placed by a thoracoscopic transpericardial approach and placed on the atrioventricular groove causing compression of the annulus. These C-shaped devices have undergone animal proof of concept testing and early human trials in open surgical settings during concomitant CABG.

Another unique concept is the placement of a prosthetic “spacer” into the mitral valve orifice (Fig. 45-9). With this concept, a prosthetic device anchored in the apex of the left ventricle fills the regurgitant space in the mitral valve orifice. Rather than repairing the mitral regurgitation by leaflet-to-leaflet coaptation, leaflet-to-device-to-leaflet coaptation is the mechanism of intended correction.

Percutaneous Mitral Valve Replacement

The last and perhaps most intriguing concept for the percutaneous treatment of functional mitral regurgitation is mitral valve replacement (Fig. 45-10). One of the issues with surgical annuloplasty for the treatment of FMR is the subsequent recurrence of regurgitation as the left ventricle continues to dilate. Although the annuloplasty performed by either a surgical or percutaneous approach completely corrected the regurgitation at the time of the index procedure, the ongoing ventricular disease process causes further dilation, causing further tethering of the papillary muscles and free edges of the leaflets, causing a recurrence of the regurgitation. The concept of mitral valve replacement rather than repair would theoretically prevent recurrence of mitral regurgitation if further left ventricular dilation occurs. This concept of surgical mitral valve replacement with preservation of the mitral leaflets and subvalvular apparatus compared with ring annuloplasty is the current subject of a National Institutes of Health Cardiothoracic Surgery Network randomized trial.

Two devices, Endovalve (Endovalve, Inc., Princeton, NJ) and CardiAQ (CardiAQ, Inc., Irvine, CA) have been developed to perform percutaneous valve sparing mitral valve replacement. In both of these concepts a delivery system placed from the femoral vein across the interatrial septum under fluoroscopic and echocardiographic guidance positions a valve in the mitral annulus. A nitinol-based anchoring system is deployed to keep the valve in place. Both of these devices have undergone proof of concept animal testing. Numerous issues exist, including the complexity of the delivery system, mechanisms of anchoring, and then translation of these concepts into the clinical arena.

In summary, there are a host of unique and intriguing concepts for the transcatheter treatment of mitral regurgitation. Although progress in the transcatheter treatment of aortic stenosis has rapid and promising, progress with mitral regurgitation has been much slower. There are a host of reasons for this, including complex valvular anatomy, variable pathology, the necessity for complex delivery systems, limited early success in clinical trials, and the existence of effective established therapy. In addition, trial design has proved problematic, with the ability to demonstrate clinical benefit a significant challenge. However, the clinical unmet need is huge and with a host of unique concepts significant progress can be expected. However, the timeline will be a long one and none of these devices will have a significant clinical impact on the management of patients with mitral regurgitation in the near future.