Catheter-based interventions for mitral regurgitation are currently under clinical evaluation. They represent the natural evolution of surgical treatment, which has been characterised by a progressive decline of invasiveness from the traditional open-heart and open-chest procedures to minimally invasive video-assisted procedures (including robotic technology), with closed-heart solutions using the catheter-based approach being the last stage of this process. The new devices are pushing transcatheter intervention beyond the limit of balloon valvuloplasty for rheumatic mitral stenosis. As happened several years ago during the pioneering phase of balloon mitral dilatation, transcatheter mitral repair is encountering numerous challenges, although an entire world of opportunities can be foreseen.
Is There a Need for New Mitral Valve Treatment Solutions?
The need for less invasive solutions to treat mitral regurgitation arises from a recent report from the EuroHeart survey revealing that a significant proportion of patients with severe mitral regurgitation are currently not referred for surgical treatment.1 Elderly patients, particularly those with co-morbidities and with low ejection fraction, are the most likely to be refused surgery. Transcatheter interventions could be a solution for these challenging patients, and may increase the proportion of patients undergoing mitral valve treatment. At the opposite end of the spectrum, less invasive solutions may be more acceptable for younger patients who are referred for early treatment.
What Can We Expect in the Future? Learning from the Experience of Balloon Valvuloplasty
Mitral balloon valvuloplasty was introduced about 25 years ago by the surgeon Kanji Inoue.2 The concept of balloon dilatation was derived via the surgical closed commissurotomy, and the specific indications still reflect this lineage. The initial clinical experience in the late 1980s was characterised by a substantial incidence of procedural complications. Contemporary surgical literature includes many case reports of life-saving emergency operations required to treat acute mitral regurgitation due to balloon lacerations.3 As more experience was accumulated, indications were identified, and patient selection has been perfected. Today, acute complications of mitral balloon valvuloplasty are rare, and surgery for pure mitral stenosis is reserved for patients with more advanced disease and with more calcified valves.4 The history of mitral balloon valvuloplasty suggests that similar issues should be expected for the upcoming mitral repair transcatheter techniques. Although catheter-based mitral repair has been surrounded by scepticism, the development of more reliable and simpler techniques and the narrowing of indications will probably allow transcatheter interventions to compete with surgery.
Techniques and Devices
Several technologies and techniques, mostly derived from surgical procedures, are currently being evaluated in pre-clinical research and clinical trials. Two main families of techniques are available: mitral valve annuloplasty and leaflet repair (using the Alfieri technique5).
The device with the largest amount of clinical experience is the e-valve Mitraclip™, which is in a phase II US Food and Drug Administration (FDA) clinical trial – Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) II. Since its first in-man case in 2003, approximately 150 patients have received mitral repair with this device. The Mitraclip is a clip device that is intended to replicate surgical edge-to-edge repair in an endovascular fashion. Leaflet approximation is obtained with either one or two clips. The procedure is completed by a combination of fluoro and echo guidance. Imaging is the most challenging issue during this procedure. While fluoroscopic imaging is irreplaceable during the initial steps of the procedure (guidewire manipulations, transeptal puncture and positioning of the delivery system in the left atrium), echocardiography is used to guide leaflet capture and to confirm the efficacy of the clip position before the final delivery. The initial results of the EVEREST trial show that isolated transcatheter edge-to-edge using the Mitraclip device is feasible, and that in selected patients mitral regurgitation can be eliminated or largely reduced. In addition, the procedure seems to be particularly safe, with the incidence of peri-operative morbidity and mortality below the average in surgical data.6 It must be clarified, however, that patients undergoing isolated transcatheter edge-to-edge are highly selected. Surgical experience has demonstrated that isolated edge-to-edge without annuloplasty carries a higher risk of late recurrence of mitral regurgitation and need for further interventions.7 The only exception is those few patients who are referred to surgery with minimal annular dilatation.8 Annular dilatation has never been a selection criterion for repair in surgical series. Surgery is usually carried out with the routine addition of annuloplasty, regardless of annular dimensions and function. In the endovascular scenario, assessment of annular function and dimensions will play a major role in the selection process for the different procedures.9
In the field of annuloplasty, the device with the largest amount of experience is the MONARC™ device (Edwards Lifesciences LLC, Irvine, CA, US), which has been used in over 50 implants. The MONARC device is a coronary sinus device. The rationale of such devices is to remodel the mitral annulus by implanting a device inside the coronary sinus, which has anatomically close relations to the posterior aspect of the mitral annulus.
The MONARC device is composed of two nitinol stents: a small distal stent that is placed in the anterior cardiac vein, and a distal stent that is placed at the coronary sinus ostium. The two stents are connected by a nitinol bridge designed to shorten over a period of a few weeks. The foreshortening of the bridge provokes a pushing effect on the mitral annulus, reducing its dimensions. The MONARC device is currently under clinical investigation in the EVOLUTION trial in Europe. Initial results have been presented at EUROPCR07, showing a limited efficacy: most patients respond to the therapy, but in some cases there is only limited reduction of the degree of mitral regurgitation. On the other hand, the procedure has been safe and easy to perform. The identification of the criteria to predict clinical response to the procedure is the next step towards the recognition of the role of coronary sinus annuloplasty in the field of transcatheter mitral repair.
To overcome the limitation of coronary sinus annuloplasty, other devices more closely resemble surgical procedures. A good example is Mitralign, a device designed to closely reproduce suture-based annuloplasty. This technology adopts a sophisticated delivery system to implant transventricular anchors in the mitral annulus, connected by sutures that can be tethered to approximate the anchors and reduce annular size. The challenges related to this procedure are mainly related to the safety of releasing the transventricular anchors in the mitral annulus and to the echo guidance during the delivery. Another interesting device is the PS3™ (Ample Medical), which is a combination of a coronary sinus bar, an Amplatzer™ septal occlude and a connecting bridge. The shortening of the bridge reduces the distance between the coronary sinus and the septum. As a result, the posterior leaflet is pushed towards the anterior leaflet to selectively reduce the septo-lateral distance of the annulus. This device could be particularly useful in the treatment of functional mitral regurgitation, where the increase of septolateral dimensions plays a major role in the mechanism of regurgitation. Another interesting chapter in the field of transcatheter mitral repair may be related to a new class of hybrid devices: annuloplasty rings, which are implanted using a traditional surgical approach. However, the construction of the rings is such that their shape and size can be modified with a transcatheter intervention on a second step. This could be particularly helpful in challenging mitral repairs to optimise the amount of coaptation by titrating the septolateral dimension of the annuloplasty ring at various delays from initial surgical intervention.
Any new approach introduces new challenges. The main challenge is usually adaptation of medical professionals to the new environment. For example, in order to complete an endovascular mitral repair using the Mitraclip device, a combination of skills is required, including advanced catheter skills (transeptal puncture and navigation of a large delivery system into the circulation), advanced imaging skills (visualisation of the mitral valve ad of the device, guidance of the procedure, assessment of the results, etc.) and surgical expertise (patient selection and decision-making). At present, the only way to combine all of these skills is to perform the procedures with a team approach. In the future, it is possible that a new profession incorporating all of the above-mentioned skills will evolve.10
At present, collaboration and a team approach is also the only way to overcome another possible challenge: competition between surgeons and interventionalists. However, as demonstrated by the EuroHeart survey, there is room for both approaches. A substantial number of patients do not receive an intervention because surgery is considered either too risky or too invasive for their disease stage. On the other hand, classical surgical intervention will play a role in the majority of patients, since, with the current technology, only a few selected patients can be considered candidates for the transcatheter procedures. Another possible challenge is the growth of a new iatrogenic disease: the failed valve after transcatheter intervention. Such a condition will require advanced interventions to treat complex disease, where the native lesions will be complicated by the procedural lesions and by the eventual presence of devices. Recently, the experience of surgical repair of failed Mitraclip procedures has been reported. In most occasions, the clip has been safely removed and the mitral valve has been repaired.11 The consequences of the long-term presence of the device, with fibrous tissue ingrowth into the mitral leaflets, have yet to be determined.
For any given degree of efficacy of a procedure, minimisation of invasiveness should be the goal of any intervention. Minimising the invasiveness of mitral repair will allow high-risk patients to be treated more safely, and will also increase acceptance of the prophylactic procedures for asymptomatic patients with mitral regurgitation. A recent publication from Olmsted county reports a 10% prevalence of mitral valve disease in the population over 75 years of age.12
In this age-group, co-morbidities often dominate the clinical scenario, and the risk of conventional surgery could be prohibitive. The option of endovascular solutions could also be adopted in a staged approach. This refers to patients in whom either the clinical decision is doubtful or the risk of a combined procedure is too high. For example, the need for mitral repair in patients undergoing coronary bypass grafting with intermediate degrees of ischaemic mitral regurgitation is frequently debated. Combination of a surgical and interventional approach could be useful to guide decision-making and reduce the risk of combined surgery. The final opportunity, related to the limited risk involved with the transcatheter procedures, is to treat patients at an even earlier stage than today, treating the lesion before any haemodynamic consequence occurs. This will be possible only when the risk of the procedure is zero and the procedure will re-establish the normal function of the mitral valve. When this happens, the prediction of Alain Carpentier, the father of modern surgical mitral repair, will become reality.13