New Aortic Valves on the Horizon

Introduction

Catheter therapy as an alternative to surgical cardiovascular therapy has had a long and steady development process beginning in the 1960s. When Charles Dotter first described opening a superficial femoral artery with a sequence of rigid dilators, he recognized many possibilities for percutaneous approaches as alternatives to traditional surgical operations. Remarkably, he spoke of percutaneous valve replacement, even at that early juncture, at the birth of catheter therapy for cardiovascular disease. The subsequent development of alternatives to traditional surgical approaches has been one of steady development punctuated by occasional remarkable leaps in concept and technology. The introduction of balloon angioplasty represents the most striking and critical such leap. The recent adoption of percutaneous valve replacement is probably the second leap of this magnitude. The idea took hold with early devices such as those described by Andersen in the early 1990s.^1,2 The development of the procedure and application in humans by Bonhoeffer in the pulmonic valve^3,4 and then Cribier^5,6 in the aortic position has brought the field to where it is today. Other sections in this text characterize the details of the state of the art of percutaneous aortic valve replacement. The first two devices to have wide application in human clinical use, the Edwards-SAPIEN (Edwards Lifesciences, Irvine, California)^7–12 and the Medtronic CoreValve prosthesis (Medtronic, Inc., Minneapolis, Minnesota),^13–18 have had remarkable success. These devices are highly successful first-generation technologies. They have come to the point of much more than proof of concept.^19,20 The rapid adoption of both of these prostheses with their approval in the international market is a testimony to their utility. They are certainly more than first-generation devices, but represent the first generation in practice. These first-generation devices, despite their rapid adoption and early success, have several limitations. The large caliber of the devices, especially the first generation of the Sapien device, have excluded a substantial number of people in the target population, the elderly with aortic valve stenosis, due to the high frequency of concomitant peripheral vascular disease. As many as three-quarters of patients are not suitable for the first-generation sheaths associated with the Sapien device. The lack of repositionability and retrievability of these devices has a tremendous impact on patient selection, the conduct of the procedure and certainly the mind-set of the operator. The Edwards valve is positioned, and the force of balloon expansion necessarily imparts a high degree of energy to the device as it opens, with resultant movement of the prosthesis as it is being deployed. The potential for malposition exists with 100% of procedures, even though the actual frequency of this complication is low. The CoreValve device is similarly challenging to position and, especially because of its length, may be placed low in the outflow tract with impingement on the mitral valve, or high in the aortic root with resultant aortic insufficiency. The inability to easily retrieve these devices poses a great challenge. The limited repositionability of the CoreValve and the complete lack of repositionability of the Edwards device are important factors in their use. The contrast with procedures such as atrial septal defect closure, where the devices are completely retrievable in most cases, highlights the importance of this design feature.

Next-generation Devices

A second generation of devices is in the early stages of human use and several devices are in the early design phase in a preclinical arena. The next-generation devices comprise a spectrum of technologies. Some are completely novel in concept and construction. Others are variations on the theme of stent-mounted devices. They share in common the use of tissue leaflets, but employ novel delivery and anchoring mechanisms. Since the human experience with all of these devices is limited, it is not realistic to report on patient implant outcomes in this review. Where some human experience has been obtained, I will try to broadly summarize the status of that experience. The development of these devices has all occurred with many iterations. The device descriptions contained here are all works in progress, and are likely to be significantly different by the time of publication. However, the broad concepts will remain constant.

Direct Flow Medical Percutaneous Aortic Valve. This novel device system (Direct Flow Medical, Inc., Santa Rosa, California) is comprised of three components: a bovine pericardial tissue valve; a sheathed delivery/recovery system; and a solidifying inflation liquid that forms the support structure.^21–23 The tissue valve is trileaflet. The leaflet tissue is attached to a Dacron fabric cuff, which conforms to the native annulus (Figures 1 and 2). The fabric cuff is inflatable and creates a seal against the native valve annulus. This minimizes the potential for paravalvular aortic insufficiency. The ventricular and aortic cuff rings are independently inflatable. These two rings encircle the native valve annulus to anchor the device and at the same time provide a large effective orifice area. The implant is initially inflated with a saline and contrast mixture. This allows fluoroscopic visualization and testing of the position and seal of the device. The saline-contrast mixture can be exchanged for an inflation medium that solidifies and hardens to form a permanent support structure. Considering that this is a fabric device, the rigidity of the hardened structure is remarkable. An inflation medium is injected into the fabric cuffs and displaces the contrast and saline. This medium begins solidifying in minutes and achieves most of its final hardness within several hours. The inflation and medium is biocompatible and is made from two component liquids containing a water-soluble epoxy and a radiopaque medium. About 8 atmospheres of pressure are maintained in the Dacron cuff throughout the curing process. This results in a durable polymeric matrix support structure, which permanently fixes the implant in the native annulus. The delivery system is a 15 French (Fr) multi-lumen catheter with an outer sheath at the distal portion without WHICH houses the valve (Figures 3, 4 and 5). The distal caliber is 22 Fr. The catheter is comprised of three lumens which are attached to the implant. Two of these are used to inflate the cuff and all three are used to position and align the implant within the native annulus, which allows for repositioning. A handle contains a locking mechanism and a recovery device is also part of the system. The device can be retrieved through a 22 Fr introducer sheath (Figure 6). The system is delivered over a 0.035 inch guidewire. There has been human implant experience with the 22 Fr system in over 30 patients, with good outcomes at 1 year in several patients. An 18.5 Fr system is under development. The device has demonstrated proof of concept including retrievability in this early experience.

Sadra Medical Lotus™ Valve. The Lotus Valve System (Sadra Medical, Inc., Los Gatos, California) is designed to be a fully repositionable technology for percutaneous aortic valve replacement. In addition to its repositioning and self-centering features it allows early leaflet function during valve deployment. This gives the ability to pause, assess, lock, unlock, incrementally reverse, resheath and, if needed, retrieve the valve prior to final release. The system consists of the valve, a bovine tissue trileaflet bioprosthetic aortic valve, the delivery catheter, a delivery system for guidance and placement of the Lotus Valve, and the 18 Fr introducer (Figures 7, 8 and 9). The valve implant is made of bovine pericardium. A nitinol self-expanding structure holds the valve in position, while adapting to the variations in annular geometry among patients. The implant is positioned below the coronary ostia. An adaptive seal technology on the outer diameter of the structure is designed to minimize or eliminate perivalvular leakage. The valve is deployed in a beating heart with no dependence on rapid pacing and begins to function early in the release process, providing stabilized hemodynamic functionality immediately. The delivery system enables gradual, phased deployment of the implant using small increments to optimize placement in patients. Prior to releasing the valve it may be locked, unlocked and partially or fully recaptured into the sheath of the delivery system for repositioning either distally or proximally. The delivery system has been streamlined to include only two controls that ensure that the correct deployment sequence is followed. The system also features a simple three-point attachment to the Lotus Valve System. First clinical use of the Lotus Valve System took place in July of 2007. Four patients have reached the 12-month follow-up mark, with the longest exceeding 24 months. The Lotus Valve continues to perform well in these patients with valve areas exceeding 1.5 cm2 and pressure gradients of Heart Leaflet Technologies. The Heart Leaflet Technologies (HLT) valve (Heart Leaflet Technologies, Inc., Maple Grove, Minnesota) is composed of four primary elements (Figures 10 and 11): (i) a glutaraldehyde cross-linked trileaflet porcine pericardial tissue valve; (ii) a superelastic nitinol wire form that supports the valve structure; (iii) a superelastic nitinol mesh, which supports the prosthetic valve and keeps the valve fixed within the native valve annulus; and (iv) a braided polyester liner integrated within the support structure to prevent regurgitant flow around the valve. There are seven components of the HLT valve delivery system including: (i) a custom guidewire/actuator (0.021 inch proximal, 0.035 inch distal); (ii) a 17 Fr delivery catheter that delivers the valve from the femoral artery through the aortic annulus; (iii) the dilator, which is designed to provide a smooth transition from the delivery catheter tip to the guidewire; (iv) the funnel catheter, designed to protect the tissue portion of the aortic valve prosthesis during loading and delivery; (v) the valve retention cables, which provide three attachment points to the HLT valve that are released once the proper anatomical position is achieved; (vi) the loader catheter, in conjunction with the funnel catheter and the valve retention cables, provides a means for loading and advancing the valve into the delivery catheter; and (vii) the Backstop, a tool positioned against the ventricular aspect of the aortic annulus to ensure proper valve placement. The Backstop is also used as a dilation tool to help expand and seat the valve prosthesis following delivery. It uses a unique “flow-through” configuration that does not restrict blood flow and therefore eliminates the need for rapid ventricular pacing when expanded. The HLT valve implantation procedure includes many elements common to other percutaneous valve technologies. The device is delivered via the femoral artery and access can be obtained using a conventional percutaneous puncture. Valve sizing is performed with transesophageal echocardiography (TEE) measurements at the time of implantation, with critical measurements being obtained from the mid-esophageal long-axis view during systole. Catheter guidance, valve positioning and delivery are achieved utilizing standard fluoroscopic imaging techniques and planes. There are several specific procedural steps related to the HLT valve. After standard aortic valvuloplasty, the HLT delivery catheter and dilator are advanced across the native aortic valve into the left ventricle utilizing a custom guidewire. The dilator is then removed and the loader catheter, containing the loaded HLT valve and Backstop, is advanced over the guidewire and mounted to the proximal hub of the delivery catheter. The HLT valve is advanced through the delivery catheter and across the native aortic valve. The Backstop is deployed against the ventricular aspect of the aortic annulus. The HLT valve cuff is then expressed from the catheter against the Backstop. When a sufficient amount of the cuff has been deployed, the cuff inverts upon itself, further increasing radial force. Following inversion, the remainder of the valve is then deployed from the catheter and into the expanded cuff. Correct valve position and function are verified by TEE and fluoroscopic imaging. The valve is then dilated utilizing the Backstop to ensure that the support structure is round and well seated in the aortic annulus. The valve can be retrieved and the procedure re-started if the desired results are not achieved. If the results are satisfactory, the valve retention cables are released, the delivery system and guidewire are removed and the procedure completed.

JenaValve™. JenaValve Technology (Munich, Germany) is developing transcatheter systems designed for both transapical and transfemoral delivery. Both transapical and transfemoral prosthesis platforms utilize a self-expanding nitinol stent (Figures 12 and 13). The valves are constructed with biological materials that were chosen based on a history of use in heart valves. While the transapical system utilizes a porcine valve (Figure 14), bovine pericardium was selected for the transfemoral system, allowing for a smaller catheter diameter. The JenaClip design uses integrated feelers as a clipping mechanism. The clipping mechanism captures the leaflets, which along with proper positioning, avoids potential coronary flow obstruction. The overall valve height is 30 mm for the largest-sized valve. A full range of sizes from 19 mm to 27 mm is intended to match the native annulus and optimize the anchoring forces. Two catheter-based delivery systems are being developed so the prosthesis can be placed at the aortic annulus retrogradely via a transfemoral approach, or antegradely via a transapical approach (Figure 15). Both systems can deploy the prosthesis with the heart beating, without the use of cardiopulmonary bypass or rapid pacing. In the first deployment step, the feelers of the JenaClip stent are unsheathed from the catheter to allow the physician to assure proper positioning. The feelers can be fully retracted back into the catheter sheath for repositioning and redeployment, if necessary. Once the feelers are determined to be in the proper position, the rest of the prosthesis can be deployed in two distinct steps to securely anchor the valve base in the native annulus and to be released from the delivery system. The delivery systems are over-the-wire designs with 1:1 torque and are steerable. The JenaClip feelers can be deployed and retracted for repositioning and redeployment, if necessary. JenaValve technology is the process of implementing a first-in-man trial for its transapical device.

Medtronic Engager (formerly Ventor). The majority of the devices described previously are intended either for transfemoral or both transfemoral and transapical delivery. Among the new entrants into the percutaneous valve arena, the Engager (Medtronic, Inc., Minneapolis, Minnesota) is the only device specifically dedicated to apical delivery (Figures 16 and 17). The leaflets are made of bovine pericardium attached to a self-expanding nitinol frame. There is a nitinol main frame, and an additional support frame featuring three commissural posts, with a configuration similar to traditional surgical aortic valve prostheses. In addition, there are fixation hooks for the delivery system and barbs at the left ventricular outflow tract side of the device. A polyester skirt is contiguous with the bovine pericardial leaflets. Human trials are pending.

Summary

The first generation of percutaneous aortic valve replacement devices has been very successful, but these devices have several limitations. They are not repositionable or retrievable, and they have a large profile. The next wave of devices promises to address these limitations. Completeley removable valve prostheses and lower-profile valves are in development. The pace of development remains to be seen, and the challenges of creating these new devices are significant, but it is clear that the field of catheter-based aortic valve replacement will continue to develop with innovative new approaches. *Figure 17 complete legend: The Medtronic Engager valve in situ, demonstrating positioning and some of the features of the anchoring system. The arms are at the floor of the sinuses, with prosthetic commissural posts riding astride the native commissures. The native leaflets are prevented from being pushed against coronary ostia and are held against the mainframe and thus recruited to seal off potential perivalvular regurgitation. The native leaflets are kept below the prosthetic leaflets, allowing the prosthetic leaflets to interact with the natural vortex flow in the sinuses for optimal closing.

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