Transcatheter Edge-to-Edge Treatment of Functional Tricuspid Regurgitation in an Ex Vivo Pulsatile Heart Model

BACKGROUND Although associated with left heart pathologies, functional tricuspid regurgitation (FTR) is often left untreated during left heart surgery. Hence, owing to its degenerative character, reoperation is often needed, encom-passing an impressive (25% to 35%) mortality rate. Thus transcatheter approaches to FTR are raising great interest. OBJECTIVES The authors evaluated the post-treatment effectiveness of the edge-to-edge technique using the percutaneous mitral valve repair device in an ex vivo pulsatile model of FTR. METHODS The devices were implanted in 11 porcine hearts simulating FTR. In each heart, single-clip treatments involved grasping lea ﬂ et pairs in the medial or commissural position (6 combinations). Two-clip treatments were then performed considering all possible 15 combinations of lea ﬂ et pairs and medial/commissural grasping. Cardiac output, mean pulmonary pressure, and mean diastolic valve pressure gradient were evaluated in physiological and simulated pathological conditions (FTR), and post-treatments. RESULTS Grasping the septal and anterior lea ﬂ ets allowed for the best post-procedural outcome, ensuring a complete re-establishment of physiological-like hemodynamics. Septal and posterior grasping induced a signi ﬁ cant recovery from FTR, although less marked. Conversely, grasping the anterior and posterior lea ﬂ ets did not reduce FTR, and was detrimental in some speci ﬁ c cases. CONCLUSIONS This experimental work demonstrated that the transcatheter edge-to-edge repair technique is a feasible approach for FTR. The study investigated this approach to develop a selective, speci ﬁ c structural intervention methodology for treating FTR, considering the several biomechanical factors that alter proper functionality of valvular substructures. These results can be used to guide the development of edge-to-edge repair techniques in treatment of FTR. (J Am Coll Cardiol 2016;68:1024 – 33) © 2016 by the American College of Cardiology Foundation. Published by Elsevier. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

right heart (annular dilation and ventricular enlargement) that lead to improper TV leaflet coaptation, such as functional tricuspid regurgitation (FTR).
FTR is often secondary to left heart pathologies, such as mitral valve regurgitation and stenosis (1,4).
These pathologies can induce pressure and volume overload in the right ventricle (RV), which in turn can induce ventricle enlargement and tricuspid annular dilation. In this phase, TV regurgitation is typically mild. However, annular dilation is progressive and asymmetric, mostly involving the anterior and posterior leaflets that pull away from the coaptation lines with the septal leaflet (Central Illustration, panel A).
FTR is seldom treated during left heart surgery.
Despite being well accepted that FTR is a deteriorating pathology, tricuspid treatment is usually only performed concomitantly to left heart surgery in cases of severe regurgitation. Consequently, the rate of FTR recurrence or worsening after surgical treatment of the left heart remains high, especially given the aging population (1,2,7,9). This leads to a potentially high frequency of reoperations, with in-hospital mortality as high as 25% to 35% (1,2). Thus, transcatheter approaches to FTR are considered an attractive strategy (1,2,7,10).
Among the few transcatheter devices exploitable for FTR treatment, a percutaneous mitral valve repair system (MitraClip System, Abbott Vascular, Santa Clara, California), developed for mitral valve regurgitation, is a promising option (1,2,10). It allows replicating, in a less invasive manner, the edgeto-edge surgical approach that has provided good results in addressing FTR when combined with other therapies (11).
Several published clinical applications (12)(13)(14)(15) of the percutaneous mitral valve repair system for treating TV regurgitation suggest the potential of this approach, particularly when septal and anterior leaflets are grasped (12,14). Open issues in this approach include the 3-leaflet anatomy, gaps between the leaflets, and the high density of tricuspid chordae, particularly in the commissural (Com) position. This paper presents a systematic experimental study of the transcatheter edge-to-edge repair technique applied to an ex vivo model of FTR. Our aim was to evaluate the feasibility and efficacy of this technique in the 3-leaflet TV, focusing on assessing immediate post-operative outcomes in relation to: 1) which pair of leaflets is grasped; 2) where the pair of leaflets are grasped; and 3) if a 2-clip implantation improves results.

METHODS
Derived from a mock loop extensively used to simulate human circulation, the experimental system consisted of a pulsatile pump connected to a porcine heart obtained from the abattoir. The system accurately replicated the pulse flow and heart valve function in a beating heart (16)(17)(18)(19). (More details are in the Online Appendix.) The right heart CO, mean pulmonary pressure (P pul ), and mean diastolic pressure gradient across the TV (Dp) were obtained from acquired data. Direct visualization of the valvular apparatus was recorded with a fiberscope (Olympus Europe, Hamburg, Germany) inserted in the right atrium. Echocardiographic views of the TV were acquired using an Epiq7 equipped with an X7-2t probe (Philips, Eindhoven, the Netherlands). The mock loop was set to simulate physiological rest conditions (heart rate 60 beats/ min; stroke volume 70 ml; P pul 10 to 15 mm Hg). Saline solution was used as working fluid.
EXPERIMENTAL MODEL OF FTR. We used porcine hearts from pigs weighing 170 AE 8 kg. Similar to published literature (20,21), the model exploited the tendency of the TV annulus and RV to dilate in order to achieve an experimental model of FTR. In the experimental apparatus, these extremely compliant structures started to dilate at physiological pulmonary pressure values. More specifically, the anterior and posterior portions of the TV annulus dilated, thus pulling the anterior and posterior leaflets away from the septal leaflet. Moreover, due to RV dilation, the papillary muscles anchored to the free ventricular wall were displaced, thus inducing leaflet tethering and in turn further TV incontinence. In the ex vivo model, both of these biomechanical determinants were controlled by means of 2 adjustable bands placed around the heart: 1 around the valvular plane, the other at the level of the papillary muscles. The first band was used to regulate annular diameter; the second to confine and control the RV dilation, thus adjusting papillary muscle displacement and associated leaflet tethering. To obtain physiological TV behavior, the 2 bands were adjusted until experi-  (B) The edge-to-edge technique is performed by the transcatheter clip between the A and P leaflets, in medial position. Whereas the treatment enhanced coaptation between A and P leaflets, the gap between A-P and S leaflets remain unaltered (arrows), if it is not worsened by A-P tethering induced by the treatment. Cardiac output (CO) did not change following the treatment.   Table 1 details each grasping and deployment condition. As an example, in Heart #1, after the first clip was used to grasp and release at the 6 positions, it was finally deployed in the S-A Com position.
Next, the effectiveness of a 2-clip implantation was evaluated. After the first clip was delivered and deployed in 1 of the 6 positions, the second clip was delivered to grasp the remaining 5 positions in each heart.
Endoscopic intracardiac images were acquired before and after each clip grasp procedure to qualitatively assess the pathological model and the percutaneous mitral valve repair treatment effectiveness. Echocardiographic images were used to support these evaluations. Hemodynamic raw data before and after each grasp were sampled and recorded. From the raw data, CO, P pul , and mean systolic Dp were averaged over 10 consecutive heart cycles. SINGLE-CLIP IMPLANTATION. An overall ANOVA for repeated measure of the treatments showed statistically significant differences. Table 2 summarizes our overall pooled data obtained with single-clip implantations. Comparing physiological and pretreatment pathological conditions, the mean CO and the P pul decreased by 31% (from 2.9 AE 0.4 l/min to 2.0 AE 0.4 l/min; p < 0.05) and 40% (from 11.0 AE 2 mm Hg to 6.6 AE 2.4 mm Hg; p < 0.05), respectively, whereas the Dp did not vary significantly (p ¼ 0.363).
Considering the Med treatments (MitraClip grasped at mid-leaflet location of both leaflets), TV functionality improved significantly with respect to pathological conditions. Mean CO increased to 2.6 AE 0.7 l/min, and P pul increased to 9.2 AE 3.8 mm Hg (p < 0.05 compared with pathological data). Differences between these post-treatment data and physiological condition were not statistically significant, thus indicating a full recovery of initial valve continence.
The Dp was 0.4 AE 0.5 mm Hg, with no statistical difference compared with untreated samples.
x Deployed x x *Heart 12 was discharged following initial grasp attempts due to heart structural failure related to the experimental mock loop.
A ¼ anterior leaflet; Com ¼ commissural position; Med ¼ medial position; P ¼ posterior leaflet; S ¼ septal leaflet; X ¼ grasping only.    Table 4 reports numerical data for CO and pressures grouped by leaflet and grasping position.  Abbreviations as in Tables 1 and 2.  Values are mean AE SD. *p < 0.05 (vs. pathological condition). †2 clips are grasped between the same pair of leaflets (zipping procedure). Tables 1 and 2.  This study used an ex vivo porcine model of FTR that can replicate the 2 mechanisms responsible for TV incomplete leaflet coaptation: annular dilation and papillary muscle displacement. These 2 events were independently controlled by means of mechanically constraining right heart dilation. A first constraint was aligned to the valve annulus, thus confining and controlling annular dilation. A second constraint was placed at the level of the papillary muscles, to control their displacement, thus regulating leaflet tethering.

Abbreviations as in
By tuning both such constraints, the TV leaflets achieved a coapting configuration deemed satisfactory by the heart-surgeon team ( Figure 1A). By releasing these constraints, a pathological condition, in terms of CO and pulmonary pressure decrease, were repeatedly achieved ( Figure 1B).  Table 2). In particular, 1-clip Med grasps between S-A or S-P leaflets induced noteworthy and statistically significant increases in cardiac output and mean pulmonary pressure. Simulated physiological-like conditions were restored following these treatments (Table 3).  (12,14).

AN ANATOMICAL AND BIOMECHANICAL STANDPOINT.
Results showed a relationship between procedural outcomes and the biomechanical determinants that underlie FTR. The best post-procedural results were obtained when grasping was performed between septal and anterior leaflets. The anterior leaflet functionality is known to be strongly affected by RV and TV annular dilation, in that its structural con- Transcatheter Edge-to-Edge for Tricuspid Valve