An Animal Model of Functional Tricuspid Regurgitation by Leaflet Tethering Using Image-Guided Chordal Encircling Snares.

Several interventional therapies are in development to treat functional tricuspid regurgitation. Most have failed to achieve adequate efficacy, as animal models of this lesion are lacking. We developed a new image-guided technique in swine, by tethering the tricuspid valve chordae using echo-guided chordal encircling snares. Five swine underwent baseline echocardiographic assessment of tricuspid valve function, followed by echo-guided placement of snares that encircle the chordae inserting into the anterior and posterior tricuspid valve leaflets. Tethering these snares and stabilizing them on the right ventricle caused the regurgitant fraction to increase from 8.48±5.38% to 48.76±12.5%, and the valve tenting area to increase from 60.26±52.19 to 160.9±86.92 mm2. Image-guided chordal encircling snares could reproducibly induce clinically significant levels of functional tricuspid regurgitation and create a valve geometry like that seen in patients, providing a new animal model for use to study novel interventional devices.

In vivo efficacy of a polymer layered decellularized matrix composite as a cell honing cardiovascular tissue substitute.

Cardiovascular surgery involves reconstruction of tissues that are under cyclical mechanical loading, and in constant contact with pulsatile blood flow. Durable biomaterials for such tissue reconstruction are scarce, as they need to be mechanically strong, hemocompatible, and resist structural deterioration from calcification. While homografts are ideal, they are scarce; xenografts are immunogenic and rendered inactive from glutaraldehyde fixation, causing them to calficy and structurally deteriorate over time; decellularized xenografts are devoid of cells, mechanically weak; and synthetic polymeric scaffolds are thrombogenic or too dense to enable host cell infiltration. In this work, we report the in vivo feasibility of a new polymer-decellularized matrix composite material (decellularized bovine pericardium-polycaprolactone: chitosan) fabricated by electrospinning, which is designed to be mechanically strong and achieve programmed host cell honing to integrate into the host. In a rodent and sheep model, this new material was found to be hemocompatible, and enabled host cell infiltration into the polymer and the decellularized matrix core underlying the polymer. Presence of M2 macrophages and several vascular cell types, with matrix remodeling in the vicinity of the cells was observed in the explanted tissues. In summary, the proposed composite material is a novel approach to create in-situ host integrating tissue substitutes, with better non-thrombogenicity, reduced infections and endocarditis, and potentially the ability to grow with the patient and remodeling into a native tissue structure.

Patient-Specific Three-Dimensional Ultrasound Derived Computational Modeling of the Mitral Valve.

Several new techniques to repair the mitral valve affected by functional mitral regurgitation are in development. However, due to the heterogeneity of valve lesions between patients, predicting the outcomes of novel treatment approaches is challenging. We present a patient-specific, 3D ultrasound-derived computational model of the mitral valve for procedure planning, that faithfully mimics the pathological valve dynamics. 3D ultrasound images were obtained in three pigs induced with heart failure and which developed functional mitral regurgitation. For each case, images were segmented, and finite element model of mitral valve was constructed. Annular and papillary muscle dynamics were extracted and imposed as kinematic boundary conditions, and the chordae were pre-strained to induce valve tethering. Valve closure was simulated by applying physiologic transvalvular pressure on the leaflets. Agreement between simulation results and truth datasets was confirmed, with accurate location of regurgitation jets and coaptation defects. Inclusion of kinematic patient-specific boundary conditions was necessary to achieve these results, whereas use of idealized boundary conditions deviated from the truth dataset. Due to the impact of boundary conditions on the model, the effect of repair strategies on valve closure varied as well, indicating that our approach of using patient-specific boundary conditions for mitral valve modeling is valid.

Hemodynamic outcomes after undersizing ring annuloplasty and focal suture annuloplasty for surgical repair of functional tricuspid regurgitation.

OBJECTIVE: Surgical annuloplasty for functional tricuspid regurgitation (FTR) is on the rise and can be performed in several ways with varied outcomes. In this study, we sought to compare the hemodynamic outcomes of tricuspid annuloplasty performed with a commercially available annuloplasty ring (tricuspid valve annuloplasty [TVA]) compared with focal suture annuloplasty (Hetzer) in an experimental FTR model. METHODS: An ex vivo FTR model was developed by inducing right ventricular dilatation by acute afterload elevation, causing severe tricuspid valve tethering and annular dilatation, leading to regurgitation. Ten porcine hearts in which FTR was induced underwent TVA with a 26-mm Edwards MC3 ring and Hetzer annuloplasty with a pledgeted suture cinching the anteroposterior and septal annulus. FTR was measured before after each repair, and tenting geometry, valve kinematics, and subvalvular geometry were measured with echocardiography. RESULTS: At baseline, none of the hearts had FTR, but upon afterload elevation an FTR volume of 17.7 ± 9.2 mL (26.38 ± 17.47% regurgitant fraction) was measured (P < .0001). TVA reduced regurgitation by 50% and Hetzer annuloplasty by 56% , respectively, but both left persistent FTR. Anteroseptal tenting area was 279.0 ± 158.9 mm2 before repair and decreased significantly to 147.2 ± 134.8 mm2 (P = .0195) with Hetzer but not with TVA. Posteroseptal tenting area was 425.1 ± 169.2 mm2 before repair and was significantly reduced by both techniques (TVA: 200.3 ± 102.9 mm2 [P = .0012]; Hetzer: 237.6 ± 127.6 mm2 [P = .0270]). CONCLUSIONS: Tricuspid annuloplasty with a ring or a focal suture can reduce FTR but not eliminate it. Annular approaches did not relieve tricuspid valve tethering and reduced leaflet mobility persisted. Either subannular repairs or judicious use of valve replacement may be necessary.

Image-Guided Targeted Mitral Valve Tethering with Chordal Encircling Snares as a Preclinical Model of Secondary Mitral Regurgitation.

Development of transcatheter mitral valve interventions has ushered a significant need for large animal models of secondary mitral regurgitation. Though currently used heart failure models that chronically develop secondary mitral regurgitation are viable, the severity is lower than patients, the incubation time is long, and mortality is high. We sought to develop a swine model of acute secondary mitral regurgitation that uses image-guided placement of snares around the mitral chordae. Twenty-seven adult swine (n = 27) were assigned to secondary mitral regurgitation induced by valve tethering with image-guided chordal encircling snares (group 1, n = 7, tether MR (tMR)); secondary mitral regurgitation by percutaneous posterolateral myocardial infarction causing ventricular dysfunction and regurgitation (group 2, n = 6, functional MR (fMR)); and control animals (group 3, n = 14). Regurgitant fraction in tMR was 42.1 ± 14.2%, in fMR was 22 ± 9.6%, and in controls was 5.3 ± 3.8%. Mitral tenting height was 9.6 ± 1.3 mm in tMR, 10.1 ± 1.5 mm in fMR, and 5.8 ± 1.2 mm in controls. Chordal encircling tethers reproducibly induce clinically relevant levels of secondary mitral regurgitation, providing a new animal model for use in translational research.

Papillary Muscle Approximation Reduces Systolic Tethering Forces and Improves Mitral Valve Closure in the Repair of Functional Mitral Regurgitation.

Background: Undersizing mitral annuloplasty (UMA) to repair functional mitral regurgitation lacks durability, as it forces leaflet coaptation without relieving the sub-leaflet tethering forces. In this biomechanical study, we demonstrate that papillary muscle approximation (PMA) prior to UMA can drastically relieve tethering forces and improve valve function, without the need for significant annular downsizing. Methods: An ex vivo model of functional mitral regurgitation (FMR) was used, in which pig mitral valves were geometrically perturbed to induce FMR, and the repairs were performed. Nine pig mitral valves were studied as follows: normal(baseline), functional mitral regurgitation (FMR), true-sized annuloplasty to 30mm (TSR), and undersized annuloplasty to 26mm (DSR); and concomitant papillary muscle approximation (PMA) at both ring sizes. Mitral regurgitation, valve kinematics, and chordal forces were measured and compared between groups. Results: FMR geometry induced a 16.31±7.33% regurgitant fraction, compared to none at baseline. 30mm/TSR reduced regurgitation to 6.05±5.63% and a 26mm/DSR to 5.06±6.76%. Addition of papillary muscle approximation prior to either rings, reduced regurgitation to 3.87±6.79% with the true sized ring (TSR+PMA), and 3.71±6.25% with the downsized ring (DSR+PMA). Peak anterior and posterior marginal chordal forces were elevated to 0.09±0.1N and 0.12±0.1N respectively with FMR, which were not reduced by annuloplasty of either sizes. Addition of PMA, reduced the forces significantly to 0.23±0.02N and 0.51±0.04N. Conclusion: This biomechanical study, demonstrates that papillary muscle approximation relieves tethering forces and when added to annuloplasty, and mobilizes the leaflets to achieve a good valve closure. Such a result could be achieved without the need for extensive annular downsizing.

Left Ventricular Thinning and Distension in Pig Hearts as a Reproducible Ex Vivo Model of Functional Mitral Regurgitation.

Functional mitral regurgitation in the setting of an enlarged heart is challenging to repair surgically with an annular approach, and the need to develop subannular and ventricular approaches is recognized yet unrealized because of the lack of models for investigations. In this study, we report a novel model of functional mitral regurgitation induced by left ventricular thinning and distension in pig hearts. Seven pig hearts were explanted at a local slaughterhouse, and left ventricular distension induced by thinning the ventricular myocardium by 60-65% of its original thickness. Distension of the thinned hearts with a 120 mmHg column confirmed significant left ventricular dilatation and mitral valve tethering. These hearts were then mounted into a pulsatile flow model and animated at 120 mmHg left ventricular pressure, 5 L/min cardiac output at 70 beats/min. Echocardiography was used to assess valvular kinematics and hemodynamics. Left ventricular wall thickness reduced by 60.5% ± 10.1% at the basal plane, 64.8% ± 11.3% at the equatorial plane, and 64.0% ± 11.4% at the apical plane after thinning. Upon distension, ventricular volumes increased by 852.4% ± 639.8% after left ventricular thinning, with an 89.5% ± 33.9% increase in sphericity index. Mitral valve systolic tenting height increased from 7.92 ± 2.06 to 15.02 ± 3.89 mm, systolic tethering area increased from 130.7 ± 38.2 to 409.9 ± 124.6 mm and an average mitral regurgitation fraction of 24.4% ± 16.6% was measured. In a case study, use of multimodality imaging to test the efficacy of transcatheter mitral devices was confirmed. Ventricular wall thinning leading to passive left ventricular distension and dilatation is a reproducible ex vivo model of mitral valve tethering and functional mitral regurgitation, which in combination with multimodality imaging provides a good simulation model.