Journal of the American College of Cardiology Vol. 53, No. 20, 2009 © 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2008.12.067

FOCUS ISSUE: VALVULAR DISEASE

Transcatheter Mitral and Pulmonary Valve Therapy

Nicolo Piazza, MD,* Anita Asgar, MD,† Reda Ibrahim, MD,‡ Raoul Bonan, MD‡ Rotterdam, the Netherlands; London, United Kingdom; and Montreal, Quebec, Canada

As the percentage of seniors continues to rise in many populations around the world, the already challenging burden of will become even greater. Unfortunately, a significant proportion of patients with moderate-to-severe valve disease are refused or denied valve based on age and/or accompanying comorbidities. Furthermore, because of advances in pediatric cardiology, the number of adult patients with con- genital heart disease is on the rise and over time, these patients will likely require repeat high-risk surgical pro- cedures. The aim of transcatheter valve therapies is to provide a minimally invasive treatment that is at least as effective as conventional valve surgery and is associated with less morbidity and mortality. The objective of this review was to provide an update on the clinical status, applicability, and limitations of transcatheter mitral and pulmonary valve therapies. (J Am Coll Cardiol 2009;53:1837–51) © 2009 by the American College of Cardiology Foundation

The prevalence of moderate-to-severe valvular heart disease ing prevalence of adults with congenital heart disease. It is is highly age-dependent, ranging from an estimated 0.7% in safe to assume that some of these patients will require 18- to 44-year-olds in the U.S. to 13.3% among those 75 high-risk surgical valve procedures in the future (2). In an years of age or older (1). Given the aging population in effort to address the challenges ahead, researchers have been many developed countries, the percentage of seniors with developing new options for a rapidly growing pool of significant disease is projected to rise substan- patients in whom heart or repair may be tially in coming years. Moreover, an increasing number of beneficial, but for whom surgical intervention is considered adult patients with congenital heart disease will contribute too high risk. The goal of transcatheter valve therapy is to further to the growing number of patients who will require provide a treatment modality that is less invasive, associated high-risk surgical procedures in the future (2). with equal or greater efficacy compared with standard Although surgical or replacement re- surgery, and is potentially safer than more invasive mains the standard of care for patients with hemodynami- procedures. cally significant valvular heart disease, the European Heart Conceptualization of a catheter-mounted heart valve Survey demonstrated that up to one-third of patients with emerged 3 decades ago (6,7). In 1992, investigators pro- symptomatic severe valve disease are denied surgery (3). posed transcatheter deployment of a stent-mounted porcine This includes about one-half of patients with severe symp- bioprosthetic valve in an animal model (8). In 2000, tomatic mitral regurgitation (MR) and one-third of elderly Bonhoeffer et al. (9) reported the first percutaneous implan- patients with severe, symptomatic aortic who are tation of a stent-mounted bovine jugular vein valve in the denied or refused surgery (4,5). Compared with those who pulmonary position. Soon thereafter, Cribier et al. (10) underwent surgery, these patients were typically older, had described the first-in-man percutaneous im- moderate impairment of ejection fraction (31% to 60%), and plantation and subsequently, the first percutaneous mitral had more noncardiac comorbidities than did patients un- dergoing valve surgery. Whether denying surgery in these valve repair was performed. patients was justified or not, the challenges of managing Historically, randomized controlled trials are not required these patients will only increase in the coming years as the by the U.S. Food and Drug Administration for the approval number of patients considered for surgery continues to rise. of surgical heart valve prostheses. Instead, objective perfor- Finally, the situation is further complicated by the increas- mance criteria, established by large retrospective observa- tional studies, have been used to assess the safety and efficacy of surgical valve prostheses (11). The Food and Drug Administration, however, views percutaneous valve From the Interventional Cardiology Departments, *Erasmus Medical Center, Tho- raxcenter, Rotterdam, the Netherlands; †Royal Brompton Hospital, London, United technology as enough of a departure from the current Kingdom; and the ‡Montreal Heart Institute, Montreal, Quebec, Canada. Dr. Bonan standard of clinical care that randomized controlled is a consultant for Medtronic Vascular and CoreValve. Manuscript received June 12, 2008; revised manuscript received December 16, clinical trials will be required to evaluate safety and 2008, accepted December 23, 2008. effectiveness. 1838 Piazza et al. JACC Vol. 53, No. 20, 2009 Transcatheter Mitral and Pulmonary Therapies May 19, 2009:1837–51

Abbreviations Generally speaking, a trial . This produces a double orifice mitral valve. The and Acronyms comparing transcatheter valve procedure can be used to treat degenerative or functional therapy to surgical therapy will MR. Like leaflet repair, the Alfieri procedure requires left ؍ LV /ventricular require superiority assessment for concomitant annuloplasty to avoid repair failure (18,19). myocardial infarction safety and noninferiority or even This concept, however, has been challenged by Maisano et ؍ MI superiority assessment for effi- al. (20), who reported that isolated surgical edge-to-edge myocardial ؍ MR regurgitation cacy. On the other hand, a trial repair performed intentionally without annuloplasty has right ventricular comparing transcatheter valve acceptable midterm results for degenerative and functional ؍ RVOT outflow tract therapy with medical therapy in mitral regurgitation (5-year freedom from recurrent MR Ͼ ϩ Ϯ right nonoperable patients will require grade 2 and reoperation 90 5%). The results support ؍ RV ventricle/ventricular proof of superiority for both the use of an isolated transcatheter edge-to-edge repair safety and efficacy. technique. After mitral valve surgery, 15% to 30% of The objective of this review patients have persistent/recurrent MR Ն2ϩ (17,21–24), yet was to provide a comprehensive update on the current a significant proportion of these patients remains asymp- clinical status, applicability, and limitations of transcatheter tomatic and does not require reoperation (93% to 96% mitral and pulmonary valve therapies. freedom from reoperation at 10 years) (16,25). Strategies for transcatheter (reviewed Transcatheter Mitral Valve Repair in Table 1) include: 1) creation of a double orifice mitral valve using percutaneous edge-to-edge techniques with a One of the most common forms of valvular heart disease clip device (e.g., MitraClip [Evalve, Inc., Menlo Park, (1,3), MR affects an estimated 9.3% of the population age California]) or stitch (e.g., MOBIUS [Edwards Lifesciences Ն75 years (1). Furthermore, 15% to 20% of patients with Corp., Irvine, California]); 2) remodeling of the annulus of heart failure and 12% of patients 30 days after myocardial the mitral valve by suture-based techniques (e.g., Percuta- infarction (MI) have moderate to severe MR (12,13). Even neous Suture Annuloplasty [Mitralign, Inc., Tewksbury, mild-to-moderate degrees of MR that occur after an acute Massachusetts], AccuCinch [Guided Delivery Systems, MI will adversely affect 5-year survival, yet the potential Santa Clara, California]), or application of radiofrequency benefits of surgically or percutaneously treating mild or energy (e.g., QuantumCor Endovascular Device [Quantum- moderate degrees of MR are unknown. Cor, San Clemente, California]); 3) remodeling of the Proper functioning of the mitral valvular complex de- mitral valvular complex by transventricular (e.g., iCoapsys pends on the structural and functional integrity of its [Myocor, Maple Grove, Minnesota]) or transatrial (e.g., individual components (i.e., the mitral annulus, leaflets, Percutaneous Septal Sinus Shortening [PS3] system [Am- chordae tendineae, papillary muscles, left atrial and left ple Medical, Foster City, California]) devices; and ventricular [LV] walls in continuity with the leaflets, and 4) remodeling of the annulus of the mitral valve by devices papillary muscles, respectively). MR can be classified as implanted in the coronary sinus (e.g., Percutaneous Mitral primary, that is, an abnormality of the mitral valve apparatus Annuloplasty [PTMA] device [Viacor, Wilmington, Mas- (e.g., degenerative mitral valve disease), or secondary (or sachusetts]; CARILLON Mitral Contour System [Cardiac functional), as a result of an ischemic or nonischemic dilated Dimensions Inc., Kirkland, Washington]; and MONARC cardiomyopathy in the setting of anatomically normal mitral System [Edwards Lifesciences Corp.]). valvular leaflets and chords. It is axiomatic that a thorough There are 2 important points. First, unlike pulmonic understanding of the mechanisms of MR and its surgical valve disease, treatment of MR has the potential to have an treatment are essential to the conceptualization, develop- extraordinary impact on clinical practice due to the higher ment, and understanding of transcatheter mitral valve tech- prevalence of the disease. Second, as opposed to the endolu- niques. Despite the superior long-term outcomes associated minal treatment of aortic valve disease, significant and with mitral valve repair rather than robust clinical results from transcatheter mitral valve ther- (14), mitral valve repair is performed in only one-third of apies cannot be expected in the short term, due both to the patients undergoing mitral valve surgery (15). complexities of the anatomy and the pathophysiology of Annuloplasty is the cornerstone of mitral valve repair and is MR. In addition, as with conventional surgery, a combina- essential for the surgical correction of functional MR. For tion of more than 1 transcatheter mitral valve technique may repair of degenerative mitral valve disease, failure to perform a be required to achieve satisfactory results. concomitant annuloplasty procedure adversely affects the long- term durability of the repair (16,17). Annuloplasty may be used Edge-to-Edge Techniques concomitantly with leaflet repair (resection, sliding annulo- plasty) or chordal reconstruction (transposition, artificial Mitraclip. The Mitraclip (Evalve, Inc.) uses a tri-axial chords). catheter system with a clip device at its distal tip (Figs. 1A The Alfieri procedure involves suturing the free edges of and 1B). The goal of the procedure is to create a double- the middle anterior (A2) and posterior (P2) leaflets of the orifice mitral valve similar to the Alfieri surgical technique JACC Vol. 53, No. 20, 2009 Piazza et al. 1839 May 19, 2009:1837–51 Transcatheter Mitral and Pulmonary Therapies

Overview of Transcatheter Mitral Valve Therapies Table 1 Overview of Transcatheter Mitral Valve Therapies

Technical Aspects

Dependency on Technology Study Technical Coronary Artery Imaging for (Manufacturer) General Approach Indication Vascular Access Phase Demand* Compromise† Implantation Mitraclip (Evalve) Edge-to-edge repair Degenerative or Standard transseptal Phase II (ϩϩϩ)(Ϫ) Ͼ (“percutaneous functional MR fluoroscopy Alfieri stitch”) MOBIUS Leaflet Edge-to-edge repair Degenerative or Standard transseptal Phase I (ϩϩϩ)(Ϫ) Echocardiography Ͼ Repair System (“percutaneous functional MR fluoroscopy (Edwards) Alfieri stitch”) Mitralign “Suture” Degenerative or FA (retrograde access Phase I (ϩϩϩ)(Ϫ) Echocardiography ϭ (Accelerated annuloplasty functional MR to LV) fluoroscopy Technologies) AccuCinch (Guided “Suture” Functional MR RIJ vein (access to CS) Pre-clinical Not available (Ϫ) Echocardiography ϭ Delivery Systems) annuloplasty and FA (retrograde fluoroscopy access to LV) QuantumCor “Radiofrequency” Functional MR Under investigation Pre-clinical Not available (Ϫ) Under investigation radiofrequency annuloplasty technology iCoapsys (Myocor) Transventricular Functional MR Subxiphoid pericardial Phase I (ϩϩϩ)(ϩϩ) Echocardiography ϭ remodeling approach fluoroscopy Percutaneous Septal Transatrial Functional MR RIJ vein (access to CS) Phase I (ϩϩϩ)(Ϫ) Fluoroscopy Ͼ Sinus Shortening remodeling and standard echocardiography Device (Ample transseptal Medical) MONARC System Coronary sinus Functional MR RIJ vein (access to CS) Phase II (ϩϩ)(ϩϩϩ) Fluoroscopy Ͼ (Edwards) device echocardiography Percutaneous Mitral Coronary sinus Functional MR RIJ vein (access to CS) Phase II (ϩϩ)(ϩϩϩ) Fluoroscopy Ͼ Annuloplasty device echocardiography (PTMA) device (Viacor) The CARILLON Mitral Coronary sinus Functinal MR RIJ vein (access to CS) Phase I (ϩϩ)(ϩϩϩ) Fluoroscopy Ͼ Contour System device echocardiography (Cardiac Dimensions)

*The number of ϩ symbols indicates the relative technical demands of the procedure; 3 ϩ symbols indicate the most demanding and 1 ϩ symbol indicates the least demanding. †The number of ϩ symbols indicates the potential for coronary artery occlusion with the device; 3ϩ symbols indicates the greatest risk and a Ϫ symbol indicates no risk. CS ϭ coronary sinus; FA ϭ femoral artery; LV ϭ left ventricle; MR ϭ mitral regurgitation; RIJ ϭ right internal jugular.

(Fig. 1C). The guide catheter is 24-F at its proximal end, valve disease and 23 patients (21%) had functional MR. tapering to 22-F at its distal end. The system is delivered via One or more clips were implanted in 96 patients (90%) a standard transseptal approach into the left . The (65 patients, 1 clip; 31 patients, 2 clips). Acute procedural 2-armed clip is a polyester-covered device. Each clip arm success, defined by clip placement and MR grade Յ2ϩ, opposes against a multipronged friction element that allows was observed in 81 of 96 patients (84%) (Table 2). There up to 8 mm of mitral valve leaflet to be grasped securely on was 1 in-hospital death (0.9%) unrelated to the clip each side. Once clip placement and real-time echocardiog- device. At 30 days, 97 patients (91%) were free from raphy confirm adequate reduction of MR (grade Յ2ϩ), the major adverse events. Ten patients (9%) experienced clip device is detached from the delivery catheter. Use of partial clip detachment and 9 of these occurred within 30 standardized echocardiographic protocols can greatly im- days, but without any major adverse events. Length of prove procedural times and ease of clip placement (26). hospital stay averaged 3.2 days, and 104 patients (97%) The safety and feasibility of the Mitraclip in a porcine were discharged without the need for home care. After a model has been reported (27,28). The EVEREST (En- median follow-up of 386 days, 75 patients (70%) did not have dovascular Valve Edge-to-Edge Repair Study) phase I to resort to surgery for device failure. Among patients with clinical study is completed and EVEREST phase II is acute procedural success, 73% of patients had improvement in currently enrolling patients with degenerative or func- New York Heart Association functional class at 12 months. tional MR (moderate-severe [3ϩ] or severe [4ϩ]). Pa- The 2-year follow-up of the first patient showed a sustained tients are being randomized to Mitraclip versus mitral decrease in the severity of mitral regurgitation (reduced from valve surgery (2:1). Preliminary results from the initial grade 4 to 1) and favorable positive remodeling indexes after 107 patients—55 patients from the EVEREST I and 52 Mitraclip implantation (29). patients from the ongoing EVEREST II study— To date, approximately 400 patients (EVEREST I and indicated that 84 patients (79%) had degenerative mitral II) have been implanted with the Mitraclip. Initial results 1840 Piazza et al. JACC Vol. 53, No. 20, 2009 Transcatheter Mitral and Pulmonary Therapies May 19, 2009:1837–51

are encouraging, but they remain inferior to surgical results. Importantly, clip failure is well tolerated and does not preclude surgical mitral valve repair. In rare instances, excessive fibrous reaction around the clip device may pro- hibit mitral valve repair and lead to the necessity for mitral valve replacement. MOBIUS Leaflet Repair system. Although similar in concept to the Mitraclip device, the Edwards MOBIUS Leaflet Repair system (Edwards Lifesciences Corp.) uses a “percutaneous” stitch to create a double-orifice mitral valve (Fig. 2). The procedure is performed under intracardiac echocardiography and fluoroscopy (30). A standard trans- septal approach is used to access the left atrium with a 10-F catheter. The therapy catheter is used to vacuum, capture, and deliver a 4-0 polypropylene suture to the free edges of the mitral valve. Finally, a 7-F fastener catheter deploys a nitinol suture clip and cuts the excess suture. In case of inadequate results, it is possible to remove the suture before deploying the clip. Feasibility studies in animals provided encouraging re- sults (31). Outcomes from the initial 15 patients treated with the MOBIUS Leaflet Repair system demonstrated acute procedural success in about two-thirds (9 of 15) of patients, with the remainder undergoing successful mitral valve surgery (Table 2). The degree of MR improved from a mean grade of 4ϩ to 2ϩ at discharge. At 30-day follow-up, fewer than one-half of the total patients enrolled (6 of 15) had a successful stitch in place. Of the 6 stitch responders, 3, 2, and 1 patients had a 1ϩ,2ϩ, and 3ϩ reduction in the severity of MR, respectively. The poor intermediate durability results led investigators to suspend further experimentation with the device for this particular indication.

Direct Annuloplasty Techniques

The gold standard for surgical annuloplasty is to implant an undersized, rigid, and complete prosthetic ring (21), but both semi-rigid and flexible rings abolish normal annular dynamics and freeze the posterior mitral leaflet in the semi-open position. Surgical suture annuloplasty was devel- oped to reduce the size of the annulus while maintaining physiological annular and leaflet motion. Evidence suggests that a 20% relative reduction of the septal-lateral dimen- sions of the mitral annulus can significantly reduce the severity of regurgitation (32). This approach has acceptable 7-year durability results, including an 82% rate of freedom from significant MR, a 95% rate for freedom from reopera- tion, and an actuarial survival rate of 87.2% at 6.4 years (33). Mitralign. In an effort to imitate a surgical suture annulo- Figure 1 The Evalve Mitraclip (Evalve, Inc.) plasty procedure, the Mitralign system (Mitralign, Inc.) (A) Clip device on distal tip of tri-axial catheter delivery system. (B) Illustrated relies on a single 14-F femoral arterial access whereby a components of clip device grasping mitral valve leaflet. (C) Animal pathology therapy catheter with a deflectable end is inserted retrograde specimen of the mitral valve with clip resulting in a double-orifice mitral valve. across the aortic valve into the LV and positioned in a subvalvular mitral position (Fig. 3A). The deflectable cath- eter helps direct guidewires and anchors pledgets across the JACC Vol. 53, No. 20, 2009 Piazza et al. 1841 May 19, 2009:1837–51 Transcatheter Mitral and Pulmonary Therapies

Clinical Results Table 2 Clinical Results

Procedural % of Patients With Procedural Success Technology Study Phase Success and Reduction in Severity of MR Clinical Improvement 30-Day Outcomes Evalve Mitraclip Phase II (n ϭ 107) 84% Յ grade 2 MR: 84% (immediate) 73% of patients had at least 91% free of major 1 grade improvement in adverse events NYHA functional class MOBIUS Leaflet Repair System Phase I (n ϭ 15) 60% Յ grade 2 MR: 83% (immediate) and Not available Not available 50% (30 days) Edwards MONARC System Phase I (n ϭ 79) 82% Not available Not available 90% free of death, MI, and tamponade Viacor Percutaneous Mitral Phase I (n ϭ 19) 68% Ն1 grade reduction in MR: 68% Not available Not available Annuloplasty device (immediate) CARILLON Cardiac Dimensions Phase I (n ϭ 43) 70% Ն1 grade reduction in MR: 80% 75% of patients had at least Not available Coronary Sinus (immediate) 1 grade improvement in Annuloplasty Device NYHA functional class

MI ϭ myocardial infarction; MR ϭ myocardial regurgitation; NYHA ϭ New York Heart Association. mitral annulus from the LV to the left atrium. The anchors implant study in humans was recently initiated in the last are tethered and put into tension to decrease the septal- quarter of 2008. lateral dimensions of the mitral annulus (Figs. 3B and 3C). AccuCinch. The AccuCinch device (Guided Delivery Sys- Outside of the U.S., a small number of patients have tems) uses a commercially available catheter with a propri- undergone preliminary studies examining only catheter etary design allowing retrograde access to the subannular positioning and wire placement. A European-based pilot space of the mitral valve. The goal is to deliver anchors

Figure 2 The MOBIUS Leaflet Repair Suture Delivery System (Edwards Lifesciences Corp.)

(A) A 17-F guide catheter, (B) a 10-F therapy catheter, and (C) a 7-F fastener catheter designed to deploy the suture clip and cut the suture. (D) Animal pathology speci- men of the mitral valve with suture clip resulting in a double-orifice mitral valve. (E) Zoomed view of the end of therapy catheter showing an orifice (white arrow) that is used to suction the mitral leaflet and deliver the suture. (F) Nitinol suture-clip that is delivered over the suture before the suture is cut above the suture-clip. The * and ** denote the anterior and posterior mitral valve leaflets, respectively. 1842 Piazza et al. JACC Vol. 53, No. 20, 2009 Transcatheter Mitral and Pulmonary Therapies May 19, 2009:1837–51

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. Acute and chronic animal studies of the AccuCinch device have shown no evidence of acute trauma to the leaflets of the mitral valve or LV outflow tract obstruction. Histological studies observed normal tissue healing sur- rounding the site of implantation of the device. Two surgical patients treated with the device so far have shown sustained reductions in MR severity (2ϩ to 0) at 6- and 12-month follow-up. In both cases, the surgery was adjunc- tive to primary coronary artery bypass surgery. The company is performing human cineangiographic studies with its guide catheter to understand the shapes, angles, and views. First-in-man studies of the AccuCinch device are planned for 2009. QuantumCor. The QuantumCor device (QuantumCor) uses subablative radiofrequency energy to induce heating and shrinkage of the collagen of the mitral annulus. This results in remodeling and reduction of the septal-lateral dimensions of the mitral annulus. The initial prototype of the QuantumCor device involves a catheter with an end- loop diameter of 40 mm that has 7 electrodes along with 14 thermocouples measuring 3 mm in length with 2-mm spacing (Fig. 4). Acute and chronic studies in sheep have shown relative reductions in septal-lateral dimensions of up to one-fifth (34). Acute histopathology specimens have documented no injury to the mitral leaflets or coronary sinus. First in-man studies are planned.

Indirect Annuloplasty Techniques Coapsys. The Coapsys or iCoapsys (Myocor) LV reshap- ing device was designed to be delivered surgically via an open-chest procedure (Coapsys) or percutaneously through a subxiphoid pericardial approach (iCoapsys). (Editor’s note: On October 30, 2008, Myocor sold its intellectual property to Edwards Lifesciences Corp., which, according to news reports, has no plans to continue trials of the Coapsys surgical system. However, the devices represented an important concept and are included in this discussion.) The Coapsys surgical system consists of an externally placed epicardial posterior pad and an anterior pad bridged by a cord that is covered with polytretrafluoreth- ylene (Fig. 5). The posterior pad has 2 heads, 1 posi- tioned at the level of the mitral annulus and 1 at the level Figure 3 The Mitralign System (Mitralign, Inc.) of the papillary muscles. The Myocor device results in: 1) reshaping of the LV and reduction in the dimensions of (A) Illustration depicting the therapy catheter with a deflectable end inserted retrograde across the aortic valve into the left ventricle and posi- the septal-lateral dimensions of the mitral annulus; and tioned in a subvalvar mitral position. (B and C) Tethering and tension on 2) superior displacement of the papillary muscles in a the system brings the anchors in closer proximity, resulting in a reduction more subvalvular position. These changes address the 2 in the septal-lateral dimensions of the mitral annulus. main pathophysiological mechanisms of functional MR: annular dilatation and LV remodeling associated with JACC Vol. 53, No. 20, 2009 Piazza et al. 1843 May 19, 2009:1837–51 Transcatheter Mitral and Pulmonary Therapies

includes reduction in MR severity and change in indices of LV remodeling. To date, 138 patients have undergone randomization, and preliminary acute results have shown similar improvements in MR grade (3ϩ to 1ϩ) and reductions in anteroposterior dimensions of the mitral annulus (3.45 Ϯ 0.39 cm to 2.34 Ϯ 0.37 cm vs. 3.40 Ϯ 0.27 cm to 2.85 Ϯ 0.34 cm) with either approach. The iCoapsys system is delivered through a subxiphoid pericardial approach under fluoroscopic and angiographic guidance. A specifically designed needle, guidewire, and sheath are used to obtain controlled access into the pericar- dial space. A needle is passed transventricularly to allow passage of a flexible wire and eventually, a transventricular cord is passed and exteriorized. Once implantation is complete, the sizing cord is used to alter the geometry of the LV until the desired reduction in mitral regurgitation is achieved (36). A prospective, nonrandomized, single-arm feasibility evalu- ation of the iCoapsys System (the VIVID [Valvular and Ventricular Improvement Via iCoapsys Delivery] study) was initiated in 2008 for patients with functional MR. Percutaneous septal sinus shortening. This device, also known as PS3 (Ample Medical), consists of an atrial septal occluder device and T-bar element that act as anchors in the interatrial septum and coronary sinus, respectively (Fig. 6A). A bridging element traversing the left atrium connects the 2 anchors (Fig. 6B). Specialized catheters, known as Magn- ecaths, incorporate corresponding shaped magnets at their distal tip; these are placed in the coronary sinus and left atrium. After magnetic linking of both Magnecaths, a crossing catheter is advanced from the left atrial catheter into the coronary sinus catheter. The T-bar element is advanced into the coronary sinus and the bridging element, attached to the T-bar, is pulled back across the transseptal puncture. Finally, the atrial septal occluder device is de- Figure 4 QuantumCor Device (QuantumCor, Inc.) ployed over the bridging element and tension is applied to displace the coronary sinus toward the atrial septum. This Early prototype of end-loop catheter used in open-chested animal models. A percutaneous system is under development. papillary muscle displacement, leaflet tethering, and leaf- let malcoaptation. A prospective, nonrandomized feasibility study in hu- mans with functional ischemic MR (TRACE study [TRAndolapril Cardiac Evaluation]) has been completed, demonstrating significant acute and midterm reductions in MR grade (3ϩ to 1ϩ) and improved LV remodeling indices at 1-year follow-up (35). RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) is a Figure 5 The iCoapsys Device (Myocor) prospective, multicenter, pivotal U.S. Food and Drug Ad- ministration trial randomizing patients with coronary artery The device (no longer in development) consists of an externally placed epicar- disease and functional MR to surgical revascularization and dial posterior pad and an anterior pad bridged by a cord covered with poly- tretrafluorethylene (PTFE). Tension on the cord decreases the septal-lateral reduction annuloplasty or surgical revascularization and dimensions of the mitral annulus. Coapsys annuloplasty. The primary end point at 1 year 1844 Piazza et al. JACC Vol. 53, No. 20, 2009 Transcatheter Mitral and Pulmonary Therapies May 19, 2009:1837–51

Figure 6 The Percutaneous Septal Sinus Shortening (PS3) Device (Ample Medical)

(A) The device consists of an atrial septal occluder device and T-bar element that act as anchors in the interatrial septum and coronary sinus, respectively. (B) A bridging element traversing the left atrium connects the 2 anchors. results in reduction of the septal-lateral dimensions of the direct contact with the posterior left atrial wall (40–42). valve annulus. The smallest and largest separation distance between the Studies using the PS3 in a sheep model of functional MR coronary sinus and mitral annulus is usually located near the demonstrated acute and chronic reductions in septal-lateral anterolateral commissure (i.e., distal coronary sinus) and dimensions of the mitral annulus by up to one-quarter and anteromedial commissure (i.e., proximal coronary sinus), reductions in MR from 2ϩ to 1ϩ (37). Subsequently, 2 respectively (40–44). The crossover frequency between the patients have undergone temporary implantation of the PS3 left circumflex coronary artery and coronary sinus can range device before clinically indicated mitral valve repair surgery from 63.9% to 80.8%. Thus, the coronary sinus device can (38). In the first patient, with severe aortic insufficiency and potentially compress and limit flow in the coronary artery ϩ moderate functional MR, a reduction in MR grade from 2 (41,42,45). It is important to note, however, that crossing of ϩ to 1 and a decrease in septal-lateral dimensions from 38 to the coronary arteries does not necessarily result in compro- 27 mm (29% relative change) were observed. The second mised coronary atrial flow. Last, variability exists in the patient, who had severe functional MR and multivessel branching points of the coronary venous tree. Although not , also experienced significant reduc- ϩ ϩ yet confirmed, these subtleties can result in suboptimal tions in MR grade from 3 to 1 and a decrease in deformation of the mitral annulus and inadequate reduc- septal-lateral dimensions of the mitral annulus from 36 to tions in MR. 25 mm (31% relative change). In both patients, no proce- MONARC. The Edwards MONARC device (Edwards dural complications were observed and removal of the device Lifesciences Corp.) is implanted in the coronary sinus via at surgery was uneventful. The final generation device has the right internal jugular vein. The support frame is con- been tested in animals and the company plans to initiate structed of nitinol. Intervening between the proximal and phase I clinical trials in late 2008 and early 2009. distal stent anchors is a spring-like bridging segment that contains biodegradable material (Fig. 7). A few weeks after Transcatheter Coronary Sinus Techniques implantation, resorption of the biodegradable material Transcatheter coronary sinus techniques use a reshaping causes shortening of this bridging segment, bringing the device implanted in the coronary sinus to reduce the proximal and distal anchors closer together and displacing septal-lateral dimensions of the mitral annulus. The spatial the posterior mitral annulus more anteriorly. The net effect relationship between the coronary sinus and mitral valve is a reduction in the septal-lateral dimension of the mitral annulus plays a crucial role in these procedures (39). valve annulus. Several aspects of the coronary sinus-mitral valve annulus Human experience with the first-generation Viking an- are of note. In the majority of cases, the coronary sinus is nuloplasty device (Viking Systems, La Jolla, California) was located superior to the level of the mitral annulus, often in reported by Webb et al. (46); 4 of 5 patients with chronic JACC Vol. 53, No. 20, 2009 Piazza et al. 1845 May 19, 2009:1837–51 Transcatheter Mitral and Pulmonary Therapies

the P2 segment and a decrease in the septal-lateral dimen- sions of the mitral annulus. The PTMA device has been tested in animal models of ischemic MR (48,49), with evidence of significant reduc- tions in the septal-lateral dimensions of the mitral annulus, mitral valve tenting area, and mitral regurgitation. In a temporary implant study of 4 patients with ischemic car- diomyopathy and MR, successful device implantation was achieved in 3 patients (50). There was a reduction in the effective regurgitant orifice area (0.25 Ϯ 0.06 cm2 to 0.07 Ϯ 0.03 cm2), regurgitant volume (45.5 Ϯ 24.4 ml to 13.3 Ϯ Figure 7 MONARC System (Edwards Lifesciences Corp.) 7.3 ml), and septal-lateral dimensions of the mitral annulus The support frame is constructed of nitinol. Intervening between the proximal (40.75 Ϯ 4.3 mm to 35.2 Ϯ 1.6 mm). and distal stent anchors is a spring-like bridging segment with memory charac- The phase I PTOLEMY (Percutaneous TransvenOus teristics and biodegradable material. Mitral AnnuloplastY) trial enrolled 27 patients with heart failure (New York Heart Association functional class II to ischemic MR Ն2ϩ underwent successful implantation and IV) and moderate to severe functional mitral regurgitation 1 patient had perforation of the anterior interventricular from 5 centers in Europe and Canada (51). Eight patients vein. In those with a functioning device at last follow-up, were excluded before implantation because of unsuitable mean MR grade decreased from 3.0 Ϯ 0.7 to 1.6 Ϯ 1.1. coronary sinus anatomy. Of the 19 patients who underwent Three patients had separation of the nitinol bridge segment implantation, 13 had a reduction in MR severity and in 6, at 22, 28, and 81 days post-implantation. the device was ineffective (Table 2). Four patients subse- The now completed EVOLUTION phase I study en- quently required removal of the device: 1 patient at day 7 for rolled patients with functional MR and heart failure. The device fracture and 3 patients referred to surgery because of MONARC device used in this study was designed with a device migration and/or diminished efficacy. Five patients reinforced bridging segment. Implantation success was (18.5%) had long-term implants with reductions in MR achieved in 59 of 72 patients (82%) (47). Freedom from severity. Following the completion of the phase I studies death, MI, and cardiac tamponade at 30 days was 91% (n ϭ and the ensuing device iterations, the PTOLEMY II trial is 57). At 90 days, freedom from death, MI, cardiac tampon- currently underway and will treat up to 60 patients at ade, coronary sinus thrombosis, device migration, device investigational sites in Europe, Canada, and the U.S. embolization, or pulmonary embolus was 86%. Of note, Patients with moderate to severe mitral regurgitation, 3-month follow-up angiography revealed coronary artery NYHA functional class II to IV, and LV dysfunction (LV compression in 15 of 50 patients (30%); 3 patients experi- ejection fraction 25% to 50%) will be included. enced an MI resulting in 1 death. Major adverse events at CARILLON. The CARILLON Mitral Contour System 18-month follow-up included 1 death, 3 MIs, 2 coronary (Cardiac Dimensions) consists of a proximal and distal sinus perforations, 1 anchor displacement, and 4 anchor helical anchor connected by a curved nitinol bridge that is separations. implanted in the coronary sinus (Fig. 9). The right internal Based on the evidence, the MONARC system is feasible jugular vein is cannulated with a 9-F catheter to access the to implant. Although efficacy data are encouraging, coro- coronary sinus. After deployment of the distal anchor in the nary compression and anchor separation are important great cardiac vein, tension is applied by pulling on the safety concerns. Screening of patients and design iterations system, resulting in cinching of the mitral annulus. After the may solve these problems. A nonrandomized, multicenter, desired effect is achieved, the proximal anchor is deployed prospective safety and efficacy study (EVOLUTION phase and the device is uncoupled from the delivery catheter II) is planned for the near future. system. The proximal and distal anchors may be deployed PTMA device. The Percutaneous Mitral Annuloplasty and subsequently recaptured in the event of malpositioning device (PTMA) (Viacor) consists of a 7-F multilumen or inadequate efficacy. delivery catheter that is placed in the coronary sinus. Up to Animal safety and feasibility studies demonstrated acute 3 rods of varying stiffness, length, and tapers can be inserted and chronic reductions in the diameter of the mitral annulus into the parallel lumens of the delivery catheter to vary the and reductions in the ratio of MR to left atrial area (16 Ϯ tension of the delivery catheter (Fig. 8). In contrast to the 4to4Ϯ 1) (52–54). MONARC system and CARILLON Cardiac Mitral Con- In the European phase I AMADEUS (CARILLON tour system (see the following text), this device exerts an Mitral Annuloplasty Device European Union Study) trial outward force at its proximal and distal segments (i.e., (55), implantation success was achieved in 30 of 43 patients commissural points) resulting in anterior displacement of (70%) and 80% of patients had at least a 1-grade reduction 1846 Piazza et al. JACC Vol. 53, No. 20, 2009 Transcatheter Mitral and Pulmonary Therapies May 19, 2009:1837–51

Figure 8 The PTMA Device (Viacor)

(A) Proximal component and (B) distal components. Up to 3 rods of varying stiffness, length, and tapers can be inserted into the parallel lumens of the delivery catheter to vary the tension in the catheter and on the mitral annulus. PTFE ϭ polytetrafluorethylene; PTMA ϭ percutaneous mitral annuloplasty. in MR severity (Table 2). Major adverse events at 1-month complications. Of note, not all crossed coronary arteries follow-up included 1 death, 2 MIs, 2 coronary sinus resulted in compromised coronary artery flow. perforations, 1 dissection, 1 anchor displacement, and 1 contrast nephropathy. Coronary arteries were crossed in 36 A Glimpse Into the Future patients (84%). Arterial compromise contributed to lack of implantation in 6 patients (14%). All unsuccessful implants A number of transcatheter mitral valve therapies are cur- were recaptured and removed in these patients without rently in developmental stages: transcatheter mitral valve

Figure 9 The CARILLON Mitral Contour System (Cardiac Dimensions)

Device consists of a proximal and distal helical anchor connected by a curved nitinol bridge that is implanted into the coronary sinus. JACC Vol. 53, No. 20, 2009 Piazza et al. 1847 May 19, 2009:1837–51 Transcatheter Mitral and Pulmonary Therapies replacement (e.g., Endovalve Hermann or Lutter mitral tions, demonstrating that percutaneous pulmonary valve im- valve), percutaneous neochordal implantation (56), and plantation was possible in animals and perhaps humans (57). hybrid surgical-transcatheter strategies (e.g., a surgically The first implantation of a pulmonary valve in a human implanted prosthetic annular ring that can, in case of future was carried out by Bonhoeffer et al. (58) in 2000. The need, be adjusted mechanically in the catheterization labo- patient was a 12-year-old boy with a history of congenital ratory percutaneously). heart disease and a previous RV-to- con- duit that had become stenotic with moderate insufficiency Pulmonary Valve Therapies leading to moderate RV dilation. The procedure, performed under general anesthesia, used hemodynamic and angio- The pulmonary valve, often thought to be the least impor- graphic evaluation of the conduit was used to determine the tant valve in the heart, has long been ignored in the adult severity and location of stenosis. A right coronary catheter population. Disease of this valve was believed to have little was placed in a distal branch pulmonary artery, and a impact on patient morbidity and mortality. This is, in fact, super-stiff exchange guidewire (Amplatz, Meditech, Water- not the case, particularly in the subset of patients with town, Massachusetts) was positioned in the distal pulmo- congenital heart disease. Tetralogy of Fallot accounts for nary artery. The valve assembly, composed of the valved-stent approximately 10% of all forms of congenital heart disease and balloon-in-balloon catheter, was then passed over the and is associated with varying degrees of pulmonary ob- guidewire and advanced into the pulmonary artery. Once in an struction ranging from pulmonary atresia to right ventricu- acceptable position, the sheath was withdrawn to expose the lar outflow tract (RVOT) obstruction. Reparative options in stent crimped on the balloon. The inner balloon was initially these patients have focused on increasing pulmonary blood inflated followed by the outer balloon, thus deploying the flow using various surgical techniques including homograft valved stent. The inner and the outer balloons were then conduits and transannular patches. rapidly deflated and the balloon catheter was removed, Unfortunately, long-term follow-up suggests that these leaving the guidewire in place (Fig. 10). The procedure was techniques are associated with serious complications once uncomplicated and the patient was discharged home the thought to be benign. Severe pulmonary insufficiency, for following day. On follow-up, the child was asymptomatic example, results in right ventricular (RV) volume over- with complete relief of conduit insufficiency and mild load, dilation, and failure, thereby increasing the risk of residual stenosis secondary to severe conduit calcification. arrhythmias and sudden death. In addition, homograft After this initial successful implant in a human being, pulmonary valve stenosis is associated with the develop- Bonhoeffer et al. (59) reported the first series of percutane- ment of RV hypertension and arrhythmias. These com- ous pulmonary valve implantations in 8 patients with plications often require further surgical intervention that surgically repaired congenital heart disease and resultant comes at the cost of additional morbidity and mortality. conduit pulmonary valve disease. All patients were symp- In this group of young patients, multiple additional tomatic with effort intolerance and breathlessness, and procedures may be required during their lifetimes, which needed conduit replacement because of significant stenosis has led to interest in developing a nonsurgical technique for percutaneous placement of a biological valve in the pulmonary position. Early work. Development of a percutaneous pulmonary valve was pioneered by Bonhoeffer and his group’s work with lambs. They used a biological valve harvested from the jugular veins of fresh bovine cadavers. These valves were bicuspid or tricuspid, with extremely thin leaflets. The valves were prepared by trimming the venous wall to eliminate any extraneous tissue and reduce the valve profile. These valves were then sutured to a vascular stent composed of platinum and iridium. For implantation the valve was hand-crimped onto a balloon catheter ranging from 18 to 22 mm in length. The balloon catheter was chosen to approx- imate the size of the pulmonary artery as measured on angiography. The position of the valved stent was easily visualized using fluoroscopy and the stent was then balloon- expanded and deployed in the native pulmonary valve of the lamb to fix the device on the pulmonary wall. The balloon Figure 10 The Melody Pulmonary Valve (Medtronic) was subsequently deflated and the catheter removed, leaving Angiogram (lateral projection) of the main the replacement valve in the desired position. The procedure pulmonary artery after implantation of the Melody valve. was carried out successfully in 5 animals with no complica- 1848 Piazza et al. JACC Vol. 53, No. 20, 2009 Transcatheter Mitral and Pulmonary Therapies May 19, 2009:1837–51 and/or pulmonary regurgitation. The procedures were per- weight 56 kg (range 25 to 110 kg); 36 patients (61%) had formed in the manner discussed previously with the excep- variants of tetralogy of Fallot, the majority of whom had tion that manual inflation of a balloon (Zmed II 1 8ϫ4, pulmonary atresia (n ϭ 18), 3 with absent pulmonary valve Numed Inc., Nicholville, New York) was performed in the syndrome, and the rest with severe pulmonary stenosis. RVOT to determine whether there was sufficient room to Most patients had a homograft conduit after surgery to the implant a pulmonary valve without creating additional RVOT (46 of 59, 78%). Three patients had a “native” obstruction in the conduit. RVOT that had been augmented with a pericardial or The valved stent was successfully implanted in all 8 homograft patch. patients. After implantation, angiographic evaluation con- Pulmonary valve implantation was successful in 58 of 59 firmed competence of the newly implanted valve in 6 patients. There were 3 significant early complications. In 2 patients. Two patients had suboptimal valve placement patients, the stent dislodged over the guidewire, and both had resulting in an insignificant paraprosthetic leak. Hemody- successful surgical homograft implantation. There was 1 life- namic improvement was seen in 5 of 8 patients, with partial threatening bleed due to dissection of the homograft that relief of obstruction in 3 patients. There were no major required emergent surgical intervention. Minor complications procedural complications and all patients were discharged included minor dissection of the homograft (n ϭ 1, treated between 1 and 5 days after the procedure. Echocardio- conservatively), detachment of the distal tip of delivery system graphic follow-up at a mean of 10 months demonstrated (n ϭ 2) into the branch pulmonary artery (snared successfully good valve function, with improvement in RV size and and retrieved), and local bleeding (n ϭ 4). function as well as clinical improvement based on relief of Mean follow-up was 9.8 Ϯ 1.4 months and there was no symptoms and improved functional capacity in those with reported mortality. Follow-up echocardiography demon- complete relief of obstruction. strated sustained hemodynamic improvements in all pa- This study demonstrated the feasibility and safety of the tients with a history of stenosis. The improvement in percutaneous approach for replacement of the pulmonary regurgitation also was sustained, with only 1 patient having valve and, in this group of patients, demonstrated that relief moderate regurgitation because of endocarditis of the valve. of pulmonary insufficiency was associated with improve- Magnetic resonance imaging showed significant reduction ments in RV function, perhaps leading to subsequent in pulmonary regurgitant fraction and in RV end-diastolic beneficial effects on arrhythmia reduction. volume as well as a significant increase in LV end-diastolic Certain limitations remain; in particular, the procedure volume and effective RV stroke volume. may not provide adequate relief of obstruction in patients There were device-related problems during follow-up in with severely calcified or small conduits. In addition, for 14 patients. In-stent stenosis was observed in 7 patients those with large or aneurysmal conduits, there may be an because of a problem with valve apposition within the stent. upper limit of size for which this procedure will be suitable. The problem may have been secondary to failure to suture The longevity of such valves is also unclear and will require the valve to the entire length of stent in the initial design long-term follow-up studies. of the device. This led to device explantation in 3 patients; Congenital heart disease. This successful initial series however, with further experience, these patients were later prompted further study of percutaneous pulmonary valve treated with a second percutaneous valve implantation. replacement in congenital patients with a history of RVOT. Stent fracture was observed in 7 patients at a median of 9 A larger series of 59 patients with pulmonary regurgitation months after the procedure, but this was associated with with or without stenosis after repair of congenital heart only 2 clinical events. There was 1 incident of late stent disease followed in 2005 (60). Patients were considered for embolization to the right pulmonary artery 9 months after participation if they had previously undergone RVOT the procedure. surgery during repair of congenital heart disease and had Recently published data on the previous cohort, now symptoms or RVOT dysfunction of a sufficient degree to expanded to 155 congenital heart disease patients, illus- warrant surgical intervention on the basis of conventional trated the impact of changing technology and operator indications: RV hypertension (two-thirds of systemic blood learning curve on the success of this procedure (61). Be- pressure or greater) with outflow tract obstruction, signifi- tween 2000 and 2007, 163 patients were evaluated for cant pulmonary insufficiency, RV dilation, or RV failure. percutaneous pulmonary valve replacement, with 155 pa- Exclusion criteria included patients Ͻ5 years of age or tients eventually undergoing the procedure. Median age of weighing Ͻ20 kg, pregnancy, occluded central veins, active the cohort was 21.2 years (range 7 to 71 years); 37% of infection, and outflow tracts with RVOT diameter Ͼ22 mm patients were Ͻ16 years old, and 42% were female. The on angiography, or conduits Ͻ16 mm in diameter at majority of patients had a diagnosis of tetralogy of Fallot surgical insertion. (61%) and the anatomic substrate was an RV-pulmonary Fifty-nine patients were recruited for percutaneous pul- artery conduit in 92% of patients. monary valve implantation with the Melody bovine jugular All patients were assessed using transthoracic echocardi- vein valve (Medtronic, Minneapolis, Minnesota). The me- ography, magnetic resonance imaging, or angiography. In dian age was 16 years (range 9 to 43 years) and median some cases simultaneous coronary angiography was per- JACC Vol. 53, No. 20, 2009 Piazza et al. 1849 May 19, 2009:1837–51 Transcatheter Mitral and Pulmonary Therapies formed at the time of balloon sizing of the conduit to phy after valve implantation. Research has identified the evaluate the risk of coronary compression by percutaneous following factors associated with a higher risk of stent fracture: valve implantation. implantation into a “native” RVOT, the absence of calcifica- Results of the cohort were divided into 2 groups (the first tion along the RVOT, and recoil of the percutaneously 50 patients and the remaining 105 patients) in order to implanted pulmonary valve after deployment (62). demonstrate a difference in the learning curve and improved Finally, the question of valve longevity remains. Current technology. The first 50 patients were believed to represent data confirm that the bovine jugular valve functions well at the learning curve because many design and protocol a median of 29 months, yet this valve will likely suffer from changes took place with this initial group of patients. The the same degenerative processes that affect other biological procedure was successful in the majority of these early valves. Until longer-term data are available, patients will patients; however, there were 7 major complications includ- have to be closely monitored for signs of valve failure. ing homograft rupture, coronary compression, device dis- Overall, these initial results in percutaneous pulmonary valve lodgment, and embolization with obstruction of the right replacement are encouraging for the field of transcatheter pulmonary artery. None of these complications resulted in intervention, but long-term follow-up is essential to under- mortality, although 5 patients required surgical intervention stand the overall impact of this technology on patients. of the RVOT. Median follow-up was 28.5 months (range 0 to 83.7 Conclusions months) and data were available on all patients with respect Transcatheter valve therapy provides a minimally invasive to mortality, reoperation, and repeat transcatheter interven- approach compared with existing alternatives, with the tion. Four of 155 patients who underwent percutaneous ability to address a significant number of patients and have pulmonary valve implantation died, and survival at 83 a positive impact on their lives. However, many questions, months was 96.6%. Freedom from transcatheter reinterven- remain: What are the indications/contraindications for tion decreased from 95 Ϯ 2% at 10 months to 73 Ϯ 6% at these procedures? What are the patient selection criteria? 70 months. Repeat interventions included balloon dilatation What are the short- and long-term complications (safety)? and placement of a second valve within a valve. Reasons for What are the short- and long-term benefits (efficacy)? What reintervention included stent fracture, residual gradient, and are the cost implications? What type of pivotal study designs valve restenosis. Follow-up echocardiography demonstrated are needed to adequately evaluate these therapies? good valve function with, at worst, mild regurgitation and One thing is certain: The widespread implementation of predominantly trivial or absent pulmonary regurgitation in transcatheter technology will require a heart team approach more than 100 patients. (i.e., interventional cardiologists and cardiac surgeons) to Analysis of the data with respect to the impact of the understand where these new therapies will fit into the learning curve suggested improved patient selection, lower management of valvular heart disease. Fortunately, both the occurrence of a residual gradient due to aggressive post- knowledge and limitations of the cardiac surgeon and dilatation of the device after deployment, and treatment of interventional cardiologist are complementary; conse- device failures with a second device as opposed to reopera- quently, when they perform as a team, it is the patient who tion. The incidence of procedural complications also de- ultimately benefits the most. creased, from 6% in the earliest group of patients to 2.9% in the second (3 of 50 patients vs. 3 of 105 patients). However, there was no difference in transcatheter reintervention Reprint requests and correspondence: Dr. Raoul Bonan, Institut between the 2 groups. This was attributed to the require- de Cardiologie de Montreal, 5000 East Belanger, Montreal, H1T 1C8 Quebec, Canada. E-mail: [email protected]. ment of additional interventions due to stent fracture, a complication not related to the learning curve of the REFERENCES procedure. These studies illustrate the success of percutane- ous valve implantation in patients with both stenotic and 1. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, regurgitant lesions, as well as the problems that can be Enriquez-Sarano M. Burden of valvular heart diseases: a population- based study. 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