Mitral regurgitation (MR) is the most prevalent form of valvular heart disease. Its major causes are primary mitral leaflet abnormalities (valve prolapse, healed endocarditis, or rheumatic disease), primary myocardial disease (functional MR), and ischemic disease. Even with severe MR, affected individuals may remain asymptomatic for long periods of time.1 The early, compensated state of MR is characterized by atrial and ventricular remodeling into larger, more compliant chambers; initially, this avoids pulmonary artery hypertension and maintains normal cardiac output. At a histological/biochemical level, this process has been characterized in canine models by increased myocardial matrix metalloproteinase activation with significant degradation of the extracellular matrix.2,3 With disease progression, clinical heart failure develops as a result of volume overload of the left ventricle, eventually leading to irreversible myocardial dysfunction and death unless the valve is repaired or replaced.4,5
Surgical correction of MR is recommended for asymptomatic patients before significant left ventricular dilatation or left ventricular systolic dysfunction occur, and is also recommended for patients after symptoms have developed.6 Current operative strategies include annuloplasty, leaflet repair (reshaping, edge-to-edge approximation, pericardial patch), leaflet mobilization, or chordal repair and valve replacement.7 In an effort to develop less invasive treatment options and to circumvent the necessity of cardiopulmonary bypass for mitral valve repair/replacement, efforts have recently focused on the development of transcatheter techniques that mimic these surgical approaches.
Catheter-based Edge-to-edge Repair
Edge-to-edge—or Alfieri—surgical repair for the treatment of MR initially consists of suturing the middle scallop (A2) of the anterior leaflet to the middle scallop (P2) of the posterior leaflet, creating a ‘double-orifice’ mitral valve.8–11 This technique offers a simple solution to the common problem of mitral valve prolapse, and has served as the basis for edge-to-edge transcatheter MR repair. Using a trans-septal approach with a guiding catheter and a smaller delivery catheter within it, a mitral clip (MitraClip, Evalve, Menlo Park, CA) is delivered to the ventricular surface of the mitral valve in the open position. The clip is then withdrawn, grasping the central anterior and posterior leaflets, and closed; this approximates the A2 and P2 scallops (see Figure 1).
Ideal candidates for this procedure are those with primary or ‘degenerative’ MR with A2–P2 malcoaptation. Some patients with functional MR without significant annular dilation are also candidates. The phase I Endovascular Valve Edge-to-Edge Repair Study (EVEREST) feasibility trial showed that this strategy for mitral valve repair was safe and effective.12 MR was reduced to 2+ or less in 74% of patients in that trial combined with the run-in patients in EVEREST II.13 Among those who underwent successful clip implantations, 75% had significant symptomatic improvement. The randomized EVEREST II trial is now under way, comparing this percutaneous technique with surgical mitral valve repair.
Percutaneous Mitral Annular Reduction Techniques
Surgical placement of an annuloplasty ring to reduce mitral annular dilation is a common accompaniment to any operative mitral valve repair. In functional MR, surgical correction is often achieved by placement of an annuloplasty ring alone, which reduces annular size and re-establishes the mitral coaptation line. Despite the potentially beneficial effects of reducing MR in those with depressed left ventricular function,14 surgical intervention in this patient group is frequently limited by high operative mortality rates.15 Thus, a transcatheter annuloplasty strategy in this group of patients would be ideal. The goal of this technology is to reduce the posterior annulus and shorten the septolateral annular dimension. There are a number of these devices, examples of which are described below.
Posterior Coronary Sinus Devices
Posterior coronary sinus devices take advantage of the anatomical proximity of the coronary sinus to the posterior mitral annulus.16 In one type of procedure using these devices, two anchors are placed: one in the distal coronary sinus/great cardiac vein and one in the proximal coronary sinus (near the ostium). The two anchors are tethered by a spring-like or movable bridge that, under tension, cinches the posterior annulus, moving the posterior leaflet toward the anterior leaflet (see Figure 2). Animal implantation has been successful,17–19 and initial human experience is encouraging.20 Cumulative data from two device studies—the MONARC system (Edwards LifeSciences) and the CARILLON Mitral Contour System (Cardiac Dimensions)—indicate a 70–75% success rate for implantation, with no procedure-related deaths and rare cardiovascular complications. Improvement in MR severity of approximately one grade occurs in ~50% of patients who received implants.21,22 However, the number of patients in these trials is small and long-term data are still pending.
Conceptually similar to the coronary sinus devices mentioned above is the Viacor device (Viacor, Inc., Wilmington, MA). Progressively stiffer straightening rods are introduced into a guiding catheter percutaneously placed from the internal jugular or subclavian vein into the coronary sinus. This device changes the conformation of the posterior annulus such that it is displaced toward the anterior annulus, reducing the annular septolateral dimension. While animal studies and temporary implantation of such devices in humans have been promising, data regarding permanent implantation in humans are not yet available.23,24
While these conceptually reasonable techniques have been validated in animal models and, more recently, in limited human studies, there are restrictions to their application. First, the location of the coronary sinus to the mitral annulus is variable, sometimes coursing adjacent to the posterior wall of the left atrium and at other times directly overlying the annulus itself. Furthermore, the left circumflex can be interposed between the coronary sinus and the mitral annulus, limiting the use of these devices because of potential circumflex artery compression.25,26 Non-invasive imaging has demonstrated that the coronary sinus courses are superior to the mitral annulus in many patients, and that the circumflex courses are situated between the coronary sinus and the mitral annulus in about two-thirds of patients.27 The minimal distance between the coronary sinus and the mitral annulus is larger in patients with heart failure (the population for whom the technology would seem most applicable), and severe mitral regurgitation occurs due to rotation of the annulus as it grows. Non-invasive imaging modalities pre-implantation will be important in selecting patients for this technology.
Transatrial Devices
Another device permitting a percutaneous septal sinus shortening procedure also depends on the proximity of the coronary sinus to the posterior mitral annulus.28 Magnet-tipped catheters—one introduced into the coronary sinus, the other introduced trans-septally into the left atrium—are linked, and the coronary sinus is punctured by the left atrial catheter. Subsequently, a T-bar anchor is placed in the coronary sinus via the internal jugular vein and tethered to an interatrial septal anchor (Amplatzer PFO Occluder) (see Figure 3A). The feasibility of this novel device (PS3 System, Ample Medical, Foster City, CA), now validated in animal models and in limited human experience, has resulted in significant reductions in the septal–lateral annulus dimension and a reduction in MR severity.28,29 The potential limitations of this device are similar to the other posterior coronary sinus devices.
An additional theoretical concern is the possibility of atrial tissue or annular tissue remodeling after device placement resulting in laxity of the transatrial connecting bridge with recurrent mitral regurgitation. Again, careful patient selection by non-invasive imaging is of paramount importance for successful implantation.
Transmyocardial Devices
Repair of ischemic MR, a subcategory of functional MR, remains a challenge for cardiac surgeons. The MR is the consequence of regional ventricular dysfunction at sites of active ischemia or prior infarction and/or ventricular enlargement in a remodeled ventricle.30 These changes result in loss of coaptation of the valve leaflets secondary to dilation of the mitral annulus, displacement of the papillary muscles with chordal tethering, or both.31 Although annuloplasty and operative repair of the chordal/papillary muscle abnormalities is usually performed, there is frequently recurrence of MR in long-term follow-up.32,33 With this in mind, the surgically implanted Coapsys device (Myocor, Maple Grove, Minnesota) was developed. This device consists of posterior and anterior epicardial pads that are connected by an adjustable subvalvular/transpapillary muscle chord. The anterior pad is positioned halfway down the longitudinal axis of the left ventricle, on the right ventricular side of the interventricular groove. The posterior pad is positioned behind the left ventricle, between the papillary muscles, approximately 2cm below the insertion of the posterior leaflet (see Figure 3B).34,35 Shortening of the adjustable chord moves the posterior annulus toward the anterior annulus, allowing improved leaflet coaptation in addition to repositioning and stabilizing the papillary muscles.36 One-year data from the first 11 patients in whom the device was placed at the time of concomitant coronary bypass grafting in the phase I trial were encouraging, with no deaths, device failures, or valve re-operations. MR was reduced from 3+ to 1+.37 This device is currently being evaluated in the Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve (RESTOR-MV) pivotal trial comparing the Coapsys device with traditional surgical mitral valve repair in patients undergoing coronary bypass surgery.
Recently, a percutaneous application of this transmyocardial device has been developed. The iCoapsys Device (Myocor) is intended to provide another non-surgical option for mitral valve repair by implanting the device in the pericardium via a percutaneous subxiphoid technique. The same epicardial pads (anterior and posterior) are positioned using a combination of intracardiac and transesophageal ultrasound. Variable tension on the tethering chord exerts support on the posterior annulus and papillary muscles reshaping the annulus to promote improved leaflet coaptation. Human feasibility data are not yet available, although animal models have demonstrated a decrease in intra-procedural MR.
Other Annuloplasty Devices
Other transcatheter annuloplasty devices are being developed that will involve direct reduction of the annulus via a left atrial or left ventricular approach. Early animal experience with the Mitralign system (Salem, New Hampshire) demonstrates the ability to place three implants into the posterior annulus and exert tension via suture lines, thereby cinching the annulus from the left ventricular side (see Figure 4).
Conclusions and Future Directions
Clinically significant MR is a common valvular abnormality that can lead to disabling symptoms or need for early surgical correction. Beyond medical therapy and biventricular pacing in the setting of functional MR, there is a need for other non-surgical options. Transcatheter therapy is a developing future direction for treatment of MR. Perhaps a combination of transcatheter repair techniques or even transcatheter valve replacement will become a viable first option for patients seeking a less invasive approach.