Emerging Transcatheter Therapies For TR

The story of the tricuspid valve has historically been one of benign neglect. Initially, this was due to case series of intravenous drug users who underwent tricuspid valve removal without replacement, leaving severe tricuspid regurgitation (TR). Sixty-seven percent of patients survived the surgery; however, 11% went on to need eventual tricuspid valve implantation.1 Later, it was assumed that because severe TR was many times secondary to left-sided heart disease, that correction of TR at the time of either mitral or aortic valve surgery was unnecessary and the TR would improve. Recently, multiple studies have demonstrated the deleterious effects of untreated severe TR, both in isolated cases and in conjunction with other valvular heart disease.2,3 In addition, in patients with moderate TR or tricuspid annular dilatation undergoing mitral valve surgery, concomitant tricuspid valve surgery improves right-sided remodeling.4

Despite increasing rates of tricuspid valve surgery,5 there remains a substantial portion of patients with moderate or severe TR who remain untreated.6 This may be due in part to late referral of patients who have been medically managed for years and have developed end-stage TR with severe right ventricle (RV) dysfunction and hepatic and renal failure. Those patients who do undergo surgery may have an in-hospital mortality as high as 25%,7 and recurrence of TR after surgery is not uncommon.8 These factors in combination have spurred the development of percutaneous therapies to address severe TR.

To understand the mechanisms of the current percutaneous therapies for TR, it's important to understand the process by which TR occurs. The majority of cases of TR can be classified as functional, arising not from anatomic abnormalities of the leaflets but from the complex interplay of the tricuspid annulus (TA) and RV.9 In the beginning stages of functional TR, the RV and TA begin to dilate. This can be in the context of left-sided valvular heart disease, pulmonary arterial hypertension, or chronic atrial fibrillation.9,10 Progressive dilatation leads to decreasing and then malcoaptation of the leaflets themselves, causing even further dilatation and dysfunction of the RV. In later stages, the tricuspid valve leaflets become tethered, and TR can become "torrential."11 This dilatation and malcoaptation does not affect the tricuspid valve leaflets equally; rather, the anterior leaflet is more affected because it is anchored to the free wall of the RV (Figure 1).9,12

Figure 1: TA Morphology in Severe TR12

Figure 1
In functional TR, the free wall of the RV dialates, pulling the anterior and the posterior valve leaflets away from the septal leaflet. This leads to malcoaptation of the valve leaflets and worsening TR.12

Several of the current percutaneous devices designed to treat TR attempt to correct this dilatation. The first of these is the Mitralign device (Mitralign, Inc.; Tewksbury, MA.) The concept of the device is rooted in the surgical Kay bicuspidalization of the tricuspid valve (Figure 2A). Utilizing a transjugular approach, two 8-French sheaths are placed. This allows the advancement of a wire delivery catheter in the RV retrograde across the tricuspid valve. Once in place and under two-dimensional and three-dimensional transesophageal (TEE) guidance, a radiofrequency wire is advanced from the base of the leaflet at the annulus toward the right atrium. With the wire in place, a pledget delivery catheter is advanced over the wire, across the annulus to the RV. After removal of the delivery catheter, the other half of the pledget is delivered on the atrial surface of the annulus. The process is repeated on the other side of the posterior leaflet. Once both pledgets are in place, a locking mechanism is deployed that puts tension on the pledgets, plicating the annulus and creating a bicuspid valve.13 Recently, 30-day results from the early feasibility trial of the device in patients with chronic functional TR SCOUT-1 (Early Feasibility of the Mitralign Percutaneous Tricuspid Valve Annuloplasty System [PTVAS] Also Known as TriAlign™) trial were presented.14 There was a 100% acute implant success rate, as well as improvements in both tricuspid valve annulus area (from 12.3 ± 3.1 cm2 to 11.3 ± 2.7 cm2, p = 0.019), 6-minute walk test (from 236.5 m ± 107.4 to 305.1 m ± 106.5, p = 0.003), and Minnesota Living with Heart Failure Score (from 49.6 ± 15.7 to 18.8 ± 12.0, p < 0.001). The trial is currently ongoing.

Annular reduction is also the concept behind the TriCinch System (4Tech Cardio Ltd.; Galway, Ireland.) The system is composed of two parts, the first of which is a corkscrew that is implanted into the anteroposterior TV annulus (Figure 2B). During the implant, right coronary artery angiography is performed to exclude vessel compromise given the proximity of the corkscrew to this vessel. The corkscrew is connected via a Dacron band to a self-expanding nitinol stent, which is anchored in the inferior vena cava (IVC). Under real-time TEE guidance, tension is applied to the Dacron band to decrease the septolateral dimension of the annulus and promote increased coapatation of the valve leaflets.15 Once a satisfactory decrease in TR is observed, the nitinol stent is deployed. Because the IVC may be dilated in chronic TR, the stent comes in varying diameters (27 to 43 mm) and is 60 mm in length.16 The advantages of the device are that it is reversible until two thirds of stent deployment and that, because the procedure is performed on the beating heart, tension of the device can be individualized for each patient.17 In the first-in-human report, there was a successful decrease in septolateral diameter of the tricuspid valve annulus (41 to 38 mm) with a decrease in TR grade (4+ to 3+.) At 6 months, the patient was reported to have an improved quality of life.16 In a second case, a 77-year-old woman with 4+ TR underwent implantation. TR grade improved to 3+, and the patient improved her 6-minute walk (150 to 250 m) at 6 months.17 The safety and feasibility trial of the device (PREVENT [Percutaneous Treatment of Tricuspid Valve Regurgitation With the TriCinch System™]) is currently ongoing.

Figure 2: Devices That Reduce Annular Dimension

Figure 2
(A) With the Mitralign device, pledgeted sutures are placed on either side of the posterior leaflet and tension then applied to exclude the posterior leaflet of the tricuspid valve.13 (B) the Tricinch device applies variable tension to the tricuspid valve annulus, restoring native leaflet coaptation.16

The FORMA device (Edwards Lifesciences; Irvine, CA) is a valve spacer that occupies the regurgitant orifice of the tricuspid valve, producing a platform for leaflet coaptation to reduce TR. The device is implanted via a 24-French sheath placed in the left axillary vein to accommodate the largest spacer available (15 mm) (Figure 3A). A steerable delivery catheter is advanced into the RV to deliver an anchor and rail to the RV wall perpendicular to the annulus.18 Under TEE guidance, the valve spacer is advanced to the regurgitant orifice and positioned for maximal reduction in TR. The excess rail length is coiled proximally and placed into a subcutaneous pocket and then locked. In a high-risk group of 7 patients, Campelo-Prada et al. showed improvements in New York Heart Association (NYHA) functional class in 6 patients at 30 days without any complications related to the device or access. TR severity was moderate by echocardiogram in all patients. In the United States, the Early Feasibility Study of the Edwards FORMA Tricuspid Transcatheter Repair System is currently recruiting patients.

Figure 3: Devices That Affect Tricuspid Valve Leaflets

Figure 3
(A) With the Forma spacing system, the spacer is anchored in the RV to provide a coaptation surface for the tricuspid valve leaflets.18 (B) Echocardiographic images demonstrate mitral clip in the tricuspid valve position. Degree of TR reduced from severe to mild.19

The success of the the MitraClip device (Abbott Laboratories; Abbott Park, IL) in patients with mitral regurgitation has led physicians to try this device in the tricuspid position. In a model of TR in porcine hearts, Vismara and colleagues demonstrated increases in cardiac output with single clipping of the medial posterioseptal and anteroseptal leafts.12 In the initial human case series of three patients, clipping was attempted via a transjugular approach; the procedure has also been described using the transfemoral approach.19 The procedure was successfully completed in all patients, and there were no severe procedural complications. There was reduction of TR in all patients as defined by a decrease in the effective regurgitation orifice area, tricuspid valve annular diameters, and IVC width. The second of the patients of the series had very severe TR, and the use of the three clips reduced the effective regurgitation orifice area; however, the clinical improvement was less dramatic.20 This case demonstrates the challenges of treating patients with severe TR, many of whom have had symptoms for many years and may have poor RV function combined with a severely dilated TA. Clinical trials further evaluating MitraClip for severe TR are ongoing (for example, MitraClip for Severe TR [TVrepair]).

Caval valve implant is another treatment that attempts to address the downstream stream effects of TR, right-heart congestion, and volume overload (Figure 4). With implantation of a one-way valve in the IVC or both IVC and superior vena cava, the renal and hepatic veins are then protected from the transmission of the volume from the RV.21 Much of the current experience with the technique is with the Edwards SAPIEN transcatheter aortic valve (Edwards Lifesciences; Irvine, CA). Pre-procedural computed tomography imaging is performed to exclude those patients with massive IVC dilatation in whom valve implant would not be feasible, as well as to evaluate the relationship of the hepatic veins to the IVC/RA junction.22 As the IVC is not calcified, preparation of the "landing zone" for the valve is then performed using a stent.23 Once the stent is deployed, the SAPIEN valve is advanced into position and deployed. Post-implant angiography may then be performed to assess for residual reflux into the IVC, and TEE may assess for residual hepatic vein flow reversal.

Figure 4: Caval Valve Implant

Figure 4
(A) Deployment of Edwards SAPIEN valve within the previously placed stent.21 (B) Computed tomography showing stent and valve post-deployment.22

In the first-in-human case for caval valve implant, performed in a patient with multiple previous open-heart surgeries and severe TR, placement of a self-designed, self-expanding stent and valve in the IVC successfully obliterated the venous v-wave transmitted to the IVC and showed continuous antegrade flow in the IVC and no flow reversal in the hepatic veins. The patient's functional class improved from NYHA IV to III.24 In a series of three patients who underwent caval valve implant with an Edwards SAPIEN XT valve, all patients experienced improvements in NYHA class at 30 days. In addition, indices of RV function improved, and hepatic vein diameter decreased. The longer term effects of redirection of flow from the IVC to the right atrium are unknown, although right atrial pressure does appear to decrease in IVC caval valve implant as patients undergo diuresis in the intermediate term.25 As seen recently in an experience with pulmonic valve replacement, this reduction in volume may itself lead to improvements in TR,26 although further studies are needed to confirm this finding. Dedicated devices for caval valve implant are currently in development (Tric Valve Vertriebs GmbH; Vienna, Austria), and initial human studies are promising.27 In addition, two trials are underway investigating caval valve implant with the Edwards SAPIEN valve: the HOVER (Heterotopic Implantation of the Edwards-Sapien XT Transcatheter Valve in the Inferior Vena Cava for the Treatment of Severe Tricuspid Regurgitation) trial in the United States and TRICAVAL (Treatment of Severe Secondary Tricuspid Regurgitation in Patients With Advance Heart Failure With Caval Vein Implantation of the Edwards Sapien XT Valve) in Europe.

Several challenges remain in the development of percutaneous devices for the treatment of severe TR. The first of these is timing of intervention. Many patients tolerate severe TR for some time, during which progressive volume overload leads to RV dysfunction. Only when patients become refractory to diuretics are they referred for surgery, by which time their operative mortality may preclude meaningful recovery. Hence, trials are needed to determine optimal timing for surgery, which will in turn guide timing for trials for percutaneous therapies. Currently, multiple different endpoints are used to determine success in percutaneous device development. Standardized performance endpoints, similar to those designed for percutaneous mitral valve therapies,28 are needed to help evaluate the effectiveness of multiple different devices that act differently in the valve annulus or on the downstream effects of TR. Echocardiographic techniques, including three-dimensional imaging, will require continued refinement to assist in both quantitative assessment of TR and visualization of the tricuspid valve annulus for device insertion. The field of percutaneous development for treatment of TR continues to evolve rapidly. It is because of this that we will no longer "forget" the tricuspid valve.

References

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Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Pulmonary Hypertension, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Echocardiography/Ultrasound, Nuclear Imaging, Mitral Regurgitation

Keywords: Angiography, Aortic Valve, Atrial Fibrillation, Atrial Pressure, Axillary Vein, Cardiac Output, Coronary Vessels, Echocardiography, Heart Atria, Heart Failure, Heart Ventricles, Hepatic Veins, Hypertension, Pulmonary, Mitral Valve, Mitral Valve Insufficiency, Polyethylene Terephthalates, Renal Insufficiency, Stents, Tomography, Tricuspid Valve, Tricuspid Valve Insufficiency, Vena Cava, Superior, Vena Cava, Inferior


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