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June 2007
Current Catheter-Based Treatments of Functional Mitral Regurgitation
Percutaneous approaches for managing mitral valve disease.
Mitral regurgitation is an important clinical entity in which blood regurgitates from the left ventricle to the left atrium during systole. This regurgitant flow results in left-sided volume overload with progressive enlargement of the left atrium and left ventricle (LV). Patients with significant mitral regurgitation may suffer from shortness of breath, symptoms of congestive heart failure, and atrial arrhythmias. Current percutaneous technologies directed at mitral valve repair are as diverse as the underlying mechanisms of mitral regurgitation. The father of surgical mitral valve repair, Alain Carpentier, MD, described a three-tier classification system (types I, II, and III), which incorporates annular size, leaflet mobility, and coaptation, as well as left ventricular and papillary muscle function in determining the structural changes causing mitral regurgitation. This classification remains relevant to the modern-day surgeon and in the new era of percutaneous mitral valve repair (Figure 1).1
The terms functional and ischemic mitral regurgitation are often used interchangeably in clinical medicine, but some relevant differences exist. Functional mitral regurgitation usually occurs when mitral leaflets fail to coapt despite normal leaflet motion (Carpentier type I dysfunction) and can be seen with increased left ventricular sphericity,2,3 papillary muscle tethering from nonischemic LV enlargement,4 or mitral annular dilatation.5 Myocardial infarction, often with regional involvement of the posterolateral left ventricular wall and the posterior papillary muscle, can also result in LV/mitral annular enlargement and so-called ischemic mitral regurgitation. Ischemic mitral regurgitation arises from apical papillary muscle displacement with primarily posterior leaflet tethering and restricted motion during systole (Carpentier type IIIb dysfunction). Apical displacement of both leaflets with restricted motion in systole and diastole, often with associated rheumatic valve disease, results in type IIIa dysfunction.
NEW PERCUTANEOUS TREATMENT MODALITIES
Multiple percutaneous approaches for the treatment of mitral regurgitation are under development. One category of leaflet repair is the edge-to-edge approach for patients with adequate leaflet proximity (and not generally with functional mitral regurgitation/ischemic mitral regurgitation).6 The edge-to-edge percutaneous repair devices (MitraClip, eValve, Redwood City, CA; and Mobius, Edwards Lifesciences, Irvine, CA) are applied primarily to degenerative leaflet pathologies (type II dysfunction, such as leaflet prolapse) and are not covered further in this review. However, it is notable that the MitraClip has been applied successfully to a small cohort of patients with functional mitral regurgitation without significant annular dilation in the EVEREST trials. It is also thought that for patients with mixed mitral regurgitation mechanisms, the edge-to-edge repair technique may be combined with functional repair techniques, although this has not been studied to date.
Pathophysiologic studies have demonstrated that septal-lateral (also known as anterior-posterior) mitral annular enlargement is the final common pathway in the development of functional and ischemic mitral regurgitation, and that shortening this dimension is critical in alleviating mitral regurgitation.7,8 Percutaneous approaches to this problem can be broadly classified into four categories: (1) coronary sinus "annuloplasty" approaches;9-13 (2) direct annular plication simulating a true surgical annuloplasty; (3) left ventricular remodeling using a surgically or percutaneously placed transventricular device; and (4) a transatrial system with anchors in the coronary sinus and interatrial septum. Current technologies under development are summarized in Table 1.
CORONARY SINUS ANNULOPLASTY
It is well known that the coronary sinus travels in close proximity to the mitral annulus, generally superior to the plane of the mitral annulus (Figure 2). Although the distance between the two is variable, it averages between 5 mm and 10 mm.14 By taking advantage of this relationship, several devices are under development that can be placed within the coronary sinus. Through tensioning of these systems by various means, the circumference of the mitral annulus can be decreased, with attendant reduction in the septal-lateral dimension and reduction in mitral regurgitation.
The first-generation Viking device (Edwards Lifesciences) has a distal self-expanding anchor, a middle spring-like "bridge," and a proximal self-expanding anchor. The distal anchor is placed near the anterior interventricular vein and the proximal anchor near the ostium of the coronary sinus. The bridge has shape memory properties that result in shortening forces at body temperature after dissipation of a dissolvable element in the center of the device. As the bridge element shortens and straightens, the posterior annular circumference decreases with reduction in mitral regurgitation. A pilot study in humans with the first-generation Viking device showed some improvement in chronic mitral regurgitation, but one of the five patients could not have the device successfully implanted, and three of the four who did had evidence of bridge separation or fracture during follow-up.13 A second-generation device (Monarc, Edwards Lifesciences) correcting these problems has been created and is currently being tested.
The Carillon device (Cardiac Dimensions, Inc., Kirkland, WA) and the PTMA device (percutaneous catheter-based approach to mitral annuloplasty, Viacor, Inc., Wilmington, MA) are both placed in the coronary sinus and both have shown efficacy in the treatment of mitral regurgitation in an ovine model of ischemic mitral regurgitation.9,10,15 The Carillon device is a second-generation mitral annular constraint device that has been successfully implanted in humans, with promising early results including improved exercise tolerance. The PTMA device has also undergone human implantation with encouraging early results. Finally, St. Jude Medical (St. Paul, MN) is developing a device with percutaneously placed anchors in the coronary sinus and right atrium with directed coronary sinus annuloplasty mostly surrounding the P2/P3 and A3 portions of the mitral annulus.
Although all of these devices are based on sound concepts, future challenges include the potential for device erosion or embolization, the inconsistent relationship between the coronary sinus and mitral annulus, risk of perforation, the presence of mitral annular calcification, and the often intimate crossing of the circumflex coronary artery over or under the coronary sinus up to 68% of the time.16 This relationship puts the circumflex coronary artery at risk for compression during coronary sinus device placement. Finally, these devices can be bulky and, with competition for the coronary sinus by electrophysiologists becoming prevalent, they may pose future obstacles to interventional therapy.
DIRECT ANNULAR PLICATION
The direct annular plication approach is modeled directly after surgically implanted annular rings and seeks to replicate the direct annuloplasty achieved by surgeons. Direct annular plication devices are being developed by QuantumCor, Inc. (Q-Care, Lake Forest, CA), Mitralign, Inc. (Tewksbury, MA), and Guided Delivery Systems, Inc. (AccuCinch system, Santa Clara, CA). The Mitralign and Guided Delivery System devices attempt to mimic a true surgical annuloplasty by placing multiple interrelated anchors within the mitral annulus and then using these anchors to change the geometry of the mitral apparatus, hence reducing mitral regurgitation. The QuantumCor technology applies thermal energy to the mitral annulus to heat and contract the collagen fibers, thereby reducing mitral annular circumference. All of these devices remain in the preclinical phase of development.
LEFT VENTRICULAR SHAPE CHANGE RESULTING IN SEPTAL-LATERAL SHORTENING
The Coapsys system (Myocor, Inc., Maple Grove, MN) reshapes the left ventricle by means of a surgically placed system. The analogous percutaneous i-Coapsys system is currently under development. Anchoring devices are placed on the outer left ventricular surfaces in an anterior-posterior configuration and are connected by a tethering or anchoring suture that passes horizontally through the left ventricle. By applying tension to the anchoring suture, the geometry of the ventricle is changed. Likewise, the orientation of the mitral annulus is affected, ideally resulting in proper leaflet coaptation. Surgical results have been promising, with sustained reduction in mitral regurgitation.17
TRANSATRIAL SHAPE CHANGE RESULTING IN SEPTAL-LATERAL SHORTENING
The Percutaneous Septal Sinus Shortening System (PS3 System, Ample Medical, Inc., Foster City, CA) uses magnetic catheters to allow accurate placement of a "bridge," which connects anchors in the coronary sinus and the interatrial septum. Once this connection is made between the coronary sinus and the interatrial septum, tension can be applied to the bridge element, effectively shortening the septal-lateral dimension. Using an ovine model, the investigators found that device implantation with an average 24% septal-lateral diameter reduction resulted in acute and chronic mitral regurgitation reduction.18 This approach has shown early promise, and temporary devices were recently implanted in a first-in-human study, confirming efficacy and significantly reducing mitral regurgitation.19
CONCLUSIONS
It is likely that in the near future, with further refinements in existing percutaneous approaches and improved intraprocedural imaging, we will see the advent of a new era in the management of mitral valve disease. The challenges for all these devices will be to demonstrate safety, and either equivalent or superior efficacy to traditional management strategies, whether medical or surgical. Patience, collaboration, and vision will be needed to allow the promise of these percutaneous methods to be fully realized.
Jeffrey A. Southard, MD, is an interventional cardiology fellow at University of California, Davis Medical Center, Division of Cardiovascular Medicine, in Sacramento, California. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Southard may be reached at jeffrey.southard@ucdmc.ucdavis.edu.
Jason H. Rogers, MD, is Director, Cardiovascular Research Unit, Division of Cardiovascular Medicine, University of California, Davis Medical Center, Sacramento, California. He has disclosed that he is a paid consultant to Ample Medical. Dr. Rogers may be reached at (916) 734-3764; jason.rogers@ucdmc.ucdavis.edu.
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