Mitral regurgitation (MR) is a complex haemodynamic abnormality of various aetiologies that may lead to heart failure and sudden cardiac death.1–3 The prevalence of MR in unselected populations increases with age, from less than 10% among individuals under 40 years of age to approximately 33% among those over 70 years of age.2,4 Most instances of MR found in the general middle-aged population are mild; however, in ageing populations the prevalence of MR is 13%, and is projected to rise substantially in the years to come.3 Mitral valve prolapse, usually resulting from myxomatous connective tissue degeneration, has been estimated to be present in 4% of the normal population and has replaced rheumatic heart disease as the leading cause of mitral valve regurgitation. Rheumatic fever is now uncommon in the western world, but remains an important aetiology in developing countries.5 Ischaemic heart disease is the cause of functional MR (FMR) in one-third to half of all cases.
Functional Mitral Regurgitation
FMR occurs without any alteration of the structure of the mitral valve leaflets and is secondary to myocardial dysfunction due to coronary artery disease and myocardial infarction (MI) or dilated cardiomyopathy.6,7 FMR can be found in 84% of patients with congestive heart failure (CHF), and in 65% of them the degree of regurgitation is moderate or severe. Several studies have documented the strong impact of FMR on early and late survival after acute MI.1,2,8,9 In the Survival And Ventricular Enlargement (SAVE) trial, patients with MR were more likely than those without MR to experience cardiovascular mortality (29 versus 12%; p<0.001) or severe heart failure (24 versus 16%; p=0.0153).2 In a sub-group analysis in the Thrombolysis in Myocardial Infarction (TIMI) trial, MR was associated with a seven-fold increased risk of mortality.10 Even mild MR was an independent predictor of cardiac death.1
The mechanisms of FMR are complex. Left ventricular (LV) systolic dysfunction and remodelling can result in annular dilatation and papillary muscle displacement with consequent tethering of the mitral leaflets.6,11 The papillary muscles are normally aligned directly under the mitral annular area so that they exert a perpendicular force on the leaflets, producing normal coaptation. The final position of the mitral leaflets is determined by the balance of the forces acting on them, including the tethering forces of the annular and papillary muscles and LV-generated closing forces.
With LV remodelling and papillary muscle displacement, the muscles exert forces in an oblique direction, resulting in increased tethering and ineffective coaptation.12 This tethering produces a leak in the mitral valve by both causing a lack of coaptation due to the restricted leaflet motion and creating a change in the geometry of the posterior leaflets with a consequent interscallop malcoaptation.13 Once tethering is increased, leaflet closure is further impaired when less LV contractile force is available to oppose tethering.14 The direction and degree of tethering are critically important for the development of FMR.14 The posterior–lateral with apical displacement of the papillary muscles, seen more frequently in inferior rather than anterior MI, seems to create the major leaflet tension.14–16 This explains the higher incidence of FMR following inferior (38%) rather than antero-septal MI (10%).16 Tethering degree can be assessed echocardiographically by tent height and tent area.17 In controls, tent height and area are <0.5cm and close to zero, respectively, whereas in patients with FMR they are usually >1cm and >1.7cm2, respectively.18 In a multivariate analysis, the tent area is the best predictor of MR severity.
Mitral annulus dilation is another aetiology for FMR.7 Annular dilation can significantly increase the degree of MR in the presence of leaflet tethering and is considered an important modulating factor.13,19 The mitral annulus constitutes the anatomical junction between the ventricle and the left atrium, and serves as an insertion site for the leaflet tissue. The mitral annulus is saddle-shaped, and during systole the commissural areas move apically while annular contraction also narrows the circumference. Both processes aid in achieving leaflet coaptation, and may be affected by processes such as annular dilatation and calcification. Compared with normal controls, patients with FMR present with dilated and flattened annulus with loss of saddle configuration.20–22 The annulus is often divided according to the site of leaflet insertion (anterior or posterior annulus). The posterior mitral annulus is less well developed at the insertion site of the posterior leaflet. This segment is not attached to any fibrous structures, and the fibrous skeleton in this region is discontinuous. This posterior portion of the annulus is prone to increasing its circumference in the setting of MR in association with LV dilation.23 Correction of the annular dimension to normal is therefore an essential part of the treatment of FMR.24
Mitral Annuloplasty for the Treatment of Functional Mitral Regurgitation
FMR is a mechanical problem that can be corrected by a mechanical method. Treatment of FMR is based on the principle of correcting leaflet malcoaptation by decreasing the size of the mitral annulus. Surgical suture annuloplasty was first developed to reduce the size of and re-shape the annulus in patients with FMR. In some patients, annuloplasty alone is sufficient to restore normal mitral valve function, but most often it is combined with partial leaflet resection or chordal remodelling. The gold standard for treatment of FMR is surgical annuloplasty with an undersized, rigid complete prosthetic ring.24,25 Both methods can reduce the septal–lateral dimensions. Evidence suggests that a 20% relative reduction of the septal–lateral dimensions of the mitral annulus can significantly reduce the severity of regurgitation.26,27 Even as little as 5–8mm reduction in the septal–lateral dimension can reconstitute leaflet coaptation and correct FMR. Mitral valve annuloplasty can be performed with low mortality (2%) and morbidity.13 Surgical ring annuloplasty has demonstrated long-term durability, with 82 and 71% freedom from significant MR and 95% freedom from re-operation.26 Although valve surgery can have low operative mortality, co-morbidities usually associated with dilated cardiomyopathy or coronary artery disease are significant risk factors for adverse events.25 In addition, only 45% of patients in the US and Europe who require surgery for MR receive mitral valve repair.28,29 Given the shortcomings of cardiac surgery, the relatively high prevalence of FMR and the recent recommendation for earlier treatment of MR, the development of less invasive methods to repair the mitral valve is of vast importance. Currently, a number of new concepts for percutaneous mitral annuloplasty are under development to address FMR, and are at different stages of evaluation.30
Percutaneous approaches for FMR rely on the surgical concept of diminishing the annular circumference and, thus, the septal–lateral dimension. A number of devices have been developed to address this clinical condition.31–33 Two basic types of mitral annulus intervention are being developed. One group of interventions is indirect and utilises the close proximity of the mitral annulus to the coronary sinus. By inserting devices in the coronary sinus to alter its shape, the mitral annulus can be cinched and mitral competence might be improved. The second group of interventions reduces posterior annulus directly and in turn restores the valve closure.34–36
Coronary Sinus Devices
Transcatheter coronary sinus techniques use a re-shaping device implanted in the coronary sinus to reduce the septal–lateral dimensions of the mitral annulus. They have been developed due to easy accessibility of the coronary sinus and its vicinity to the mitral annulus. However, there are several anatomical issues that may influence the clinical utilisation of the coronary sinus devices. In the majority of cases, the coronary sinus is located superior to the level of the mitral annulus and is immediately adjacent to the left atrium, with an average distance between the coronary sinus and the mitral annulus of 8–14mm at the ostium, 13–20mm in the middle of the coronary sinus and 7–14mm at the level of the great coronary vein.37,38 This relation may result in mitral annulus deformation through secondary tension from the left atrial wall and a suboptimal effect on the mitral annulus. In addition, cross-over frequency between the left circumflex coronary artery and coronary sinus can range from 64 to 81%.38–40 Thus, the coronary sinus device can potentially compress and limit flow in the coronary artery and may cause MI, especially in patients with a dominant circumflex artery.41,42 In addition, there are risks of coronary sinus dissection, perforation or thrombosis due to the device, which may also conflict with other therapies, such as ablation, cardiac resynchronisation and retrograde cardioplegia.35 Despite these serious anatomical concerns, several devices have been developed over the past five years.
The Edwards MONARC device (Edwards Lifesciences Corp.) consists of a proximal and a distal stent connected by a spring-like bridge element that is held open by a biodegradable material (see Figure 1A).33,43 Resorption of the biodegradable material causes shortening of the bridging element over six weeks, which brings the proximal and distal anchors closer together and displaces the posterior mitral annulus more anteriorly. The final effect is a reduction in the septal–lateral dimension of the mitral valve annulus. However, the delayed cinching of the mitral annulus does not allow any intraprocedural adjustments and may cause late MI due to delayed compression of the left circumflex artery. The first-in-man studies revealed device fractures.43 The re-designed MONARC was studied in EVOLUTION I, a phase I feasibility study.44 The device was implanted in 59 out of 72 patients (82%);44 however, seven patients were sent to surgery. At three-month follow-up, there were 52 patients (72%) with the implanted device.
Serious adverse events (death, MI, cardiac tamponade, coronary sinus thrombosis, device migration, device embolisation or pulmonary embolus) occurred in 13% of patients and coronary angiography revealed coronary artery compression in 30% (15/50) of patients, leading to MI in three patients and death in one.45 At one-year follow up, MR severity decreased by 0.9 degrees from 2.7 to 1.8. Limited efficacy and important safety concerns (coronary compression, anchor separation and displacement, coronary sinus perforations) could be solved by robust patient screening and design improvement. A non-randomised, multicentre, prospective safety and efficacy study (EVOLUTION phase II) is planned.
Similarly to Monarc, the Carillon device (Cardiac Dimensions) consists of a proximal and a distal anchor connected by a curved bridge that is implanted in the coronary sinus to force the mitral annulus to shrink (see Figure 1B).41,46–48 Both anchors may be deployed and subsequently recaptured, thus allowing significant adjustment during the procedure in case of malpositioning, safety concerns or inadequate efficacy. In the European phase I AMADEUS (Carillon Mitral Annuloplasty Device European Union Study) trial, implantation success was achieved in 30 of 43 patients (70%), and 80% of patients had at least a one-grade reduction in MR severity.49 Major adverse events at one-month follow-up included one death, two MIs, two coronary sinus perforations, one dissection, one anchor displacement and one contrast nephropathy. Coronary arteries were crossed in 36 patients (84%). Arterial compromise contributed to lack of implantation in six patients (14%). All unsuccessful implants were recaptured and removed in these patients without complications.
The Percutaneous Mitral Annuloplasty device (PTMA) (Viacor) is quite different from the other coronary sinus devices (see Figure 1C). It consists of a 7F multilumen delivery catheter that is placed in the coronary sinus.50,51 Up to three straight and rigid rods of varying stiffness, length and taper can be inserted into the parallel lumens of the delivery catheter in order to obtain the desired tension and graded conformational changes in the mitral annulus. In contrast to other mitral annuloplasty coronary sinus devices, this device exerts an outward force at its proximal and distal segments (i.e. commissural points), resulting in anterior displacement of the P2 segment and a decrease in the septal–lateral dimensions of the mitral annulus. This straightening rather than cinching of the mitral annulus reduces the risk of circumflex artery compression, which is considered a significant safety advantage.52
However, the implantation success rate is low and the effectiveness is limited. The phase I Percutaneous TransvenOus Mitral AnnuloplastY (PTOLEMY) trial enrolled 27 patients with heart failure (New York Heart Association [NYHA] II to IV) and moderate to severe FMR.52 Eight patients were excluded because of unsuitable anatomy. Thirteen out of 19 patients implanted with the device had a reduction in MR, whereas in six patients there was no change in MR severity. In addition, four patients subsequently required removal of the device due to device fracture, migration or diminished efficacy. Finally, only five patients (18.5%) had long-term implants with sustained reduction in MR severity.52 Following the phase I studies, the PTOLEMY II trial is currently under way and will treat up to 60 patients at investigational sites in Europe, Canada and the US.
It is difficult to predict who may benefit from the coronary sinus interventions and who will not.53 Coronary venous anatomy is highly variable, and some patients respond well to the coronary sinus interventions whereas others do not show any improvement whatsoever. Identifying patients with the best chance of success with these procedures will be critically important in the future.
Direct Mitral Annuloplasty
The anatomical issues with coronary sinus have been circumvented by devices that perform percutaneous direct mitral annuloplasty. Mitralign, Inc. (Tewksbury, MA, US) has developed a proprietary mitral valve repair system (Mitralign Percutaneous Annuloplasty System) that attempts to mimic surgical suture annuloplasty. The Mitralign system is designed for femoral access (14Fr) and approaches the posterior mitral annulus via the left ventricle. A steerable catheter with a deflectable end is delivered via a 12.5Fr guide catheter between the papillary muscles facing the posterior mitral annulus. The steerable catheter and a two-arm (bident) catheter help to place two pairs of wires through the mitral annulus at P1 and P3 (see Figure 2A). Once the wire pair is placed at one location, surgical pledgets are delivered over the wires and anchored across the posterior mitral annulus from the left atrium to the left ventricle (see Figure 2B). The surgical pledgets are tethered and put into tension to decrease the annulus circumference, and the achieved mitral annulus plication is locked in place. Once the entire procedure is completed at one location, the next wire pair is then placed at the other scallop location (P1 or P3) (see Figure 2C) and the implant process is completed (see Figure 2D).
This procedure aims to reduce mitral annulus circumference and the septal–lateral dimension of the mitral valve, thereby significantly reducing MR severity. There is limited experience with a previous version of the Mitralign system (trident) utilising three pledgets at P2 (see Figure 3). A European first-in- man study (Germany and Brazil) with the new bident system is expected to start in 2009.
Two additional percutaneous devices approaching the mitral annulus directly are in early pre-clinical development. The AccuCinch device (Guided Delivery Systems) is another device delivered to the subannular space of the mitral valve. The goal is to deliver anchors across the mitral annulus and use a cinching cable to reduce the septal–lateral dimensions of the mitral annulus. The investigational strategy has been to demonstrate efficacy in humans using a surgical approach before developing fully a percutaneous delivery system. First-in-man studies of the AccuCinch device are planned for 2009. The QuantumCor device (QuantumCor) uses subablative radiofrequency energy to induce heating and shrinkage of the collagen of the mitral annulus.53 Acute and chronic studies in sheep have shown relative reductions in septal–lateral dimensions of up to one-fifth.53 First in-man studies are planned.
FMR affects a large number of patients with CHF due to MI or dilated cardiomyopathy. FMR is associated with increased morbidity and mortality. Surgery is a standard of care for symptomatic patients with moderate or severe FMR; however, a large number of patients are refused surgery. Several percutaneous approaches have been developed to address the need for less invasive treatment of mitral annulus dilatation. Devices using coronary sinus to cinch the mitral annulus are relatively easy to use; however, a number of factors may limit their clinical application, such as a suboptimal anatomical relationship between the coronary sinus and the mitral annulus, the risk of coronary artery compression, the large variability in the coronary venous anatomy and conflict with other therapies such as ablation or cardiac resynchronisation. Direct mitral annuloplasty is anticipated to be more effective than the coronary sinus approaches; however, it has to demonstrate its safety and efficacy in carefully designed clinical trials. The best candidates and best timing for each percutaneous mitral annuloplasty therapy, whether direct or indirect, have yet to be identified.