Leaflet remodeling reduces tricuspid valve function in a computational model.

Tricuspid valve leaflets have historically been considered "passive flaps". However, we have recently shown that tricuspid leaflets actively remodel in sheep with functional tricuspid regurgitation. We hypothesize that these remodeling-induced changes reduce leaflet coaptation and, therefore, contribute to valvular dysfunction. To test this, we simulated the impact of remodeling-induced changes on valve mechanics in a reverse-engineered computer model of the human tricuspid valve. To this end, we combined right-heart pressures and tricuspid annular dynamics recorded in an ex vivo beating heart, with subject-matched in vitro measurements of valve geometry and material properties, to build a subject-specific finite element model. Next, we modified the annular geometry and boundary conditions to mimic changes seen in patients with pulmonary hypertension. In this model, we then increased leaflet thickness and stiffness and reduced the stretch at which leaflets stiffen, which we call "transition-λ." Subsequently, we quantified mean leaflet stresses, leaflet systolic angles, and coaptation area as measures of valve function. We found that leaflet stresses, leaflet systolic angle, and coaptation area are sensitive to independent changes in stiffness, thickness, and transition-λ. When combining thickening, stiffening, and changes in transition-λ, we found that anterior and posterior leaflet stresses decreased by 26% and 28%, respectively. Furthermore, systolic angles increased by 43%, and coaptation area decreased by 66%; thereby impeding valve function. While only a computational study, we provide the first evidence that remodeling-induced leaflet thickening and stiffening may contribute to valvular dysfunction. Targeted suppression of such changes in diseased valves could restore normal valve mechanics and promote leaflet coaptation.

Untangling the mechanisms of pulmonary arterial hypertension-induced right ventricular stiffening in a large animal model.

Pulmonary hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) stiffening; thus, impeding diastolic filling. Multiple mechanisms may contribute to RV stiffening, including wall thickening, microstructural disorganization, and myocardial stiffening. The relative importance of each mechanism is unclear. Our objective is to use a large animal model to untangle these mechanisms. Thus, we induced pulmonary arterial hypertension (PAH) in sheep via pulmonary artery banding. After eight weeks, the hearts underwent anatomic and diffusion tensor MRI to characterize wall thickening and microstructural disorganization. Additionally, myocardial samples underwent histological and gene expression analyses to quantify compositional changes and mechanical testing to quantify myocardial stiffening. Finally, we used finite element modeling to disentangle the relative importance of each stiffening mechanism. We found that the RVs of PAH animals thickened most at the base and the free wall and that PAH induced excessive collagen synthesis, increased cardiomyocyte cross-sectional area, and led to microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with collagen synthesis. Finally, our computational models predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms. Thus, myocardial stiffening may be the most important predictor for PAH progression. Given the correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for estimating myocardial stiffness and predicting PAH outcomes. STATEMENT OF SIGNIFICANCE: Ventricular stiffening is a significant contributor to pulmonary hypertension-induced right heart failure. However, the mechanisms that lead to ventricular stiffening are not fully understood. The novelty of our work lies in answering this question through the use of a large animal model in combination with spatially- and directionally sensitive experimental techniques. We find that myocardial stiffness is the primary mechanism that leads to ventricular stiffening. Clinically, this knowledge may be used to improve diagnostic, prognostic, and therapeutic strategies for patients with pulmonary hypertension.

Papillary muscle approximation in chronic ovine functional tricuspid regurgitation.

OBJECTIVE: Isolated tricuspid ring annuloplasty remains the surgical standard for functional tricuspid regurgitation repair but offers suboptimal results when right ventricular dilation and remodeling along with papillary muscle displacement is present. Addressing subvalvular remodeling with papillary muscle approximation may improve clinical outcomes. METHODS: Functional tricuspid regurgitation and biventricular dysfunction were induced in 8 healthy sheep by rapid ventricular pacing (200-240 bpm) for 27 ± 6 days. Subsequently, animals underwent cardiopulmonary bypass for implantation of sonomicrometry crystals on the tricuspid annulus, right ventricle, and papillary muscle tips. Papillary approximation sutures were anchored between anterior-posterior and anterior-septal papillary muscles and externalized through right ventricular free wall to epicardial tourniquets. After weaning from cardiopulmonary bypass, sequential papillary muscle approximations were performed. Simultaneous hemodynamic, sonomicrometry, and echocardiographic data were collected at baseline and after each papillary muscle approximation. RESULTS: With rapid pacing, right ventricular fractional area change decreased from 59 ± 6% to 38 ± 8% (P < .001), whereas tricuspid annulus diameter increased from 2.4 ± 0.3 cm to 3.3 ± 0.6 cm (P = .003). Tricuspid regurgitation (0-4+) increased from +0 ± 0 to +3.3 ± 0.7 (P < .001). Both anterior-posterior and anterior-septal papillary muscle approximation significantly reduced functional tricuspid regurgitation from +3.3 ± 0.7 to +2 ± 0.5 and +1.9 ± 0.6, respectively (P < .001). Reduction of tricuspid insufficiency with both subvalvular interventions was associated with decreased distance of the anterior papillary muscle to the annular centroid. CONCLUSIONS: Papillary muscle approximations were effective in reducing severe ovine functional tricuspid regurgitation associated with right ventricular dilation and papillary muscle displacement. Further studies are needed to evaluate efficacy of this adjunct to ring annuloplasty in repair of severe functional tricuspid regurgitation.

Effect of papillary muscle approximation on acute ovine functional tricuspid regurgitation.

OBJECTIVES: Ring annuloplasty represents the standard surgical treatment, but offers suboptimal results in patients with severe functional tricuspid regurgitation. Addition of papillary muscles (PMs) approximation may improve clinical outcomes. METHODS: Eight healthy adult male sheep (56 ± 4 kg) underwent cardiopulmonary bypass and implantation of sonomicrometry crystals on the tricuspid annulus, PM tips and right ventricular (RV) free wall. Papillary muscles approximation sutures were anchored between anterior-posterior and anterior-septal PMs and their loose ends externalized through RV free wall to epicardial tourniquets. After weaning from cardiopulmonary bypass, acute right heart failure and tricuspid regurgitation were induced, and subsequent sequential anterior-posterior and anterior-septal PM approximations were performed. Echocardiographic, haemodynamic and sonomicrometry data were collected. RESULTS: Tricuspid regurgitation at baseline in eight sheep was none or trace in 3 and mild in 5, and after induction of acute right heart failure increased significantly to moderate in 5, moderately severe in 1 and severe in 2 (P = 0.011). RV pressure increased from 31 [28; 43] to 51 [47; 55] mmHg (P = 0.012). Anterior-posterior PM approximation decreased regurgitation grade to none or trace in 1, mild in 4 and moderate in 3 (P = 0.016) and reduced PM area from 208 [160; 241] to 108 [48; 181] mm2 (P = 0.008), and anterior-posterior PM distance from 18 [16; 20] to 10 [7; 13] mm (P = 0.037). Anterior-septal approximation also significantly reduced PM area but had no effect on regurgitation grade. CONCLUSIONS: Anterior-posterior but not anterior-septal PM approximation alleviated acute ovine tricuspid regurgitation. Selective PM approximation may offer better control of tricuspid regurgitation.

Untangling the mechanisms of pulmonary hypertension-induced right ventricular stiffening in a large animal model.

Background: Pulmonary arterial hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) remodeling and stiffening; thus, impeding diastolic filling and ventricular function. Multiple mechanisms contribute to RV stiffening, including wall thickening, microstructural disorganization, and myocardial stiffening. The relative importance of each mechanism is unclear. Our objective is to use a large animal model as well as imaging, experimental, and computational approaches to untangle these mechanisms. Methods: We induced PHT in eight sheep via pulmonary artery banding. After eight weeks, the hearts underwent anatomic and diffusion tensor MRI to characterize wall thickening and microstructural disorganization. Additionally, myocardial samples underwent histological and gene expression analyses to quantify compositional changes and mechanical testing to quantify myocardial stiffening. All findings were compared to 12 control animals. Finally, we used computational modeling to disentangle the relative importance of each stiffening mechanism. Results: First, we found that the RVs of PHT animals thickened most at the base and the free wall. Additionally, we found that PHT induced excessive collagen synthesis and microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with excess collagen synthesis. Finally, our model of normalized RV pressure-volume relationships predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms. Conclusions: In summary, we found that PHT induces wall thickening, microstructural disorganization, and myocardial stiffening. These remodeling mechanisms were both spatially and directionally dependent. Using modeling, we show that myocardial stiffness is the primary contributor to RV stiffening. Thus, myocardial stiffening may be an important predictor for PHT progression. Given the significant correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for non-invasively estimating myocardial stiffness and predicting PHT outcomes.

Septal annular dilation in chronic ovine functional tricuspid regurgitation.

INTRODUCTION: Annular reduction with prosthetic rings represents the current surgical treatment of functional tricuspid regurgitation (FTR). However, alterations of annular geometry and dynamics associated with FTR are not well characterized. METHODS: FTR was induced in 29 adult sheep with either 8 weeks of pulmonary artery banding (PAB, n = 15) or 3 weeks of tachycardia-induced cardiomyopathy (TIC, n = 14). Eight healthy sheep served as controls (CTL). At the terminal procedure, all animals underwent sternotomy, epicardial echocardiography, and implantation of sonomicrometry crystals on the tricuspid annulus (TA) and right ventricular free wall while on cardiopulmonary bypass. Simultaneous hemodynamic, sonomicrometry, and echocardiographic data were acquired after weaning from cardiopulmonary bypass and stabilization. Annular geometry and dynamics were calculated from 3-dimensional crystal coordinates. RESULTS: Mean FTR grade (0-4) was 3.2 ± 1.2 and 3.2 ± 0.5 for PAB and TIC, respectively, with both models of FTR associated with similar degree of right ventricular dysfunction (right ventricular fractional area contraction 38 ± 7% and 37 ± 9% for PAB and TIC, respectively). Left ventricular ejection fraction was significantly reduced in TIC versus baseline (33 ± 9%, vs 58 ± 4%, P = .0001). TA area was 651 ± 109 mm2, 881 ± 242 mm2, and 995 ± 232 mm2 for CTL, FTR, and TIC, respectively (P = .006) with TA area contraction of 16.6 ± 4.2%, 11.5 ± 8.0%, and 6.0 ± 4.0%, respectively (P = .003). Septal annulus increased from 33.8 ± 3.1 mm to 39.7 ± 6.4 mm and 43.1 ± 3.2 mm for CTL, PAB, and TIC, respectively (P < .0001). CONCLUSIONS: Ovine FTR was associated with annular dilation and reduced annular area contraction. Significant dilation of septal annulus was observed in both models of FTR. As tricuspid rings do not completely stabilize the septal annulus, continued remodeling may contribute to recurrent FTR after repair.

Texas TriValve 1.0 : a reverse­engineered, open model of the human tricuspid valve.

Nearly 1.6 million Americans suffer from a leaking tricuspid heart valve. To make matters worse, current valve repair options are far from optimal leading to recurrence of leakage in up to 30% of patients. We submit that a critical step toward improving outcomes is to better understand the "forgotten" valve. High-fidelity computer models may help in this endeavour. However, the existing models are limited by averaged or idealized geometries, material properties, and boundary conditions. In our current work, we overcome the limitations of existing models by (reverse) engineering the tricuspid valve from a beating human heart in an organ preservation system. The resulting finite-element model faithfully captures the kinematics and kinetics of the native tricuspid valve as validated against echocardiographic data and others' previous work. To showcase the value of our model, we also use it to simulate disease-induced and repair-induced changes to valve geometry and mechanics. Specifically, we simulate and compare the effectiveness of tricuspid valve repair via surgical annuloplasty and via transcatheter edge-to-edge repair. Importantly, our model is openly available for others to use. Thus, our model will allow us and others to perform virtual experiments on the healthy, diseased, and repaired tricuspid valve to better understand the valve itself and to optimize tricuspid valve repair for better patient outcomes.

Tricuspid leaflet kinematics after annular size reduction in ovine functional tricuspid regurgitation.

OBJECTIVE: Tricuspid annular size reduction with annuloplasty rings represents the foundation of surgical repair of functional tricuspid regurgitation. However, the precise effect of annular size reduction on leaflet motion and geometry remains unknown. METHODS: Ten sheep underwent surgical implantation of a pacemaker with an epicardial lead and were paced 200-240 beats/min to achieve biventricular dysfunction and functional tricuspid regurgitation. Subsequently, sonomicrometry crystals were implanted on the right ventricle, the tricuspid annulus, and on the belly of anterior, posterior, and septal tricuspid leaflets. Double-layer polypropylene suture was placed around the tricuspid annulus and externalized to a tourniquet. Simultaneous echocardiographic, hemodynamic, and sonomicrometry data were acquired with functional tricuspid regurgitation and during 5 consecutive annular reduction steps. Annular area, tenting height, and volume, together with each leaflet strain, radial length, and angles, were calculated from crystal coordinates. RESULTS: Rapid pacing reduced both left ventricle and right ventricle function and induced functional tricuspid regurgitation (0-3+) in all animals (from 0 ± 0 to 2.4 ± 0.7, P = .002), whereas tricuspid annulus diameter increased from 2.6 ± 0.3 cm to 3.3 ± 0.3 cm (P = .001). Tricuspid annular size reduction 1 to 5 resulted in 16% ± 7%, 37% ± 11%, 55% ± 11%, 66% ± 10%, and 76% ± 8% tricuspid annulus area reduction, respectively, and successively decreased tricuspid regurgitation. Tricuspid annular size reduction 2 to 5 induced anterior and posterior leaflet restricted motion and lower diastolic motion velocities. Tricuspid annular size reduction 5 perturbed septal leaflet range of motion but preserved its angle velocities. Tricuspid annular size reduction 3-5 generated compressive strains in all leaflets. CONCLUSIONS: Tricuspid annular area reduction of 55% perturbed anterior and posterior leaflet motion while maintaining normal septal leaflet movement. More extreme reduction triggered profound changes in anterior and posterior leaflet motion, suggesting that aggressive undersizing impairs leaflet kinematics.

The effects of a simple optical clearing protocol on the mechanics of collagenous soft tissue.

Optical clearing of biological tissues improves imaging depth for light transmission imaging modalities such as two-photon microscopy. In studies that investigate the interplay between microstructure and tissue-level mechanics, mechanical testing of cleared tissue may be useful. However, the effects of optical clearing on soft tissue mechanics have not been investigated. Thus, we set out to quantify the effects of a simple and effective optical clearing protocol on the mechanics of soft collagenous tissues using ovine mitral valve anterior leaflets as a model system. First, we demonstrate the effectiveness of an isotonic glycerol-DMSO optical clearing protocol in two-photon microscopy. Second, we evaluate the mechanical effects of optical clearing on leaflets under equibiaxial tension in a dependent study design. Lastly, we quantify the shrinkage strain while traction-free and the contractile forces while constrained during clearing. We found the optical clearing protocol to improve two-photon imaging depth from ~100 µm to ~500-800 µm, enabling full-thickness visualization of second-harmonic generation, autofluorescent, and fluorophore-tagged structures. Under equibiaxial tension, cleared tissues exhibited reduced circumferential (p < 0.001) and radial (p = 0.009) transition stretches (i.e. stretch where collagen is recruited), and reduced radial stiffness (p = 0.031). Finally, during clearing we observed ~10-15% circumferential and radial compressive strains, and when constrained, ~2mN of circumferential and radial traction forces. In summary, we suggest the use of this optical clearing agent with mechanical testing be done with care, as it appears to alter the tissue's stress-free configuration and stiffness, likely due to tissue dehydration.

Right ventricular myocardial mechanics: Multi-modal deformation, microstructure, modeling, and comparison to the left ventricle.

The right ventricular myocardium, much like the rest of the right side of the heart, has been consistently understudied. Presently, little is known about its mechanics, its microstructure, and its constitutive behavior. In this work, we set out to provide the first data on the mechanics of the mature right ventricular myocardium in both simple shear and uniaxial loading and to compare these data to the mechanics of the left ventricular myocardium. To this end, we tested ovine tissue samples of the right and left ventricle under a comprehensive mechanical testing protocol that consisted of six simple shear modes and three tension/compression modes. After mechanical testing, we conducted a histology-based microstructural analysis on each right ventricular sample that yielded high resolution fiber distribution maps across the entire samples. Equipped with this detailed mechanical and histological data, we employed an inverse finite element framework to determine the optimal form and parameters for microstructure-based constitutive models. The results of our study show that right ventricular myocardium is less stiff then the left ventricular myocardium in the fiber direction, but similarly exhibits non-linear, anisotropic, and tension/compression asymmetric behavior with direction-dependent Poynting effect. In addition, we found that right ventricular myocardial fibers change angles transmurally and are dispersed within the sheet plane and normal to it. Through our inverse finite element analysis, we found that the Holzapfel model successfully fits these data, even when selectively informed by rudimentary microstructural information. And, we found that the inclusion of higher-fidelity microstructural data improved the Holzapfel model's predictive ability. Looking forward, this investigation is a critical step towards understanding the fundamental mechanical behavior of right ventricular myocardium and lays the groundwork for future whole-organ mechanical simulations.

Effect of variable annular reduction on functional tricuspid regurgitation and right ventricular dynamics in an ovine model of tachycardia-induced cardiomyopathy.

OBJECTIVE: To investigate the effect of variable tricuspid annular reduction (TAR) on functional tricuspid regurgitation (FTR) and right ventricular (RV) dynamics in ovine tachycardia-induced cardiomyopathy. METHODS: Nine adult sheep underwent implantation of a pacemaker with an epicardial lead and were paced at 200 to 240 bpm until the development of biventricular dysfunction and functional TR was noted. During reoperation on cardiopulmonary bypass, 6 sonomicrometry crystals were placed around the tricuspid annulus (TA) and 14 were placed on the RV epicardium. Annuloplasty suture was placed around the TA and externalized to an epicardial tourniquet. After weaning from cardiopulmonary bypass, echocardiographic, hemodynamic, and sonomicrometry data were acquired at baseline and during 5 progressive TARs achieved with suture cinching. TA area and RV free wall strains and function were calculated from crystal coordinates. RESULTS: After pacing, changes in left ventricular (LV) ejection fraction and RV fractional area decreased significantly. Mean TA diameter increased from 25.1 ± 2.9 mm to 31.5 ± 3.3 mm (P = .005), and median TR (range, 0-3+) increased from 0 (0) to 3 (2) (P = .004). Progressive suture cinching reduced the TA area by 18 ± 6%, 38 ± 11%, 56 ± 10%, 67 ± 9%, and 76 ± 8%. Only aggressive annular reductions (67% and 76%) decreased TR significantly, but these were associated with deterioration of RV function and strain. A moderate annular reduction of 56% led to a substantial reduction of TR with little deleterious effect on regional RV function. CONCLUSIONS: A moderate TAR of approximately 50% may be most advantageous for correction of functional TR and simultaneous maintenance of regional RV performance. Additional subvalvular interventions may be needed to achieve complete valvular competence.

The influence of tricuspid annuloplasty prostheses on ovine annular geometry and kinematics.

BACKGROUND: Surgical repair of functional tricuspid regurgitation is centered on annular reduction with artificial rings; however, the precise effect of prosthesis implantation on annular geometry, dynamics, and strain is unknown. METHODS: Forty healthy sheep had sonomicrometry crystals implanted around the tricuspid annulus and onto right ventricle free wall. Ten animals underwent tricuspid annuloplasty with a flexible Duran AnCore ring (Medtronic, Minneapolis, Minn) (28 ± 1 mm), 10 with Contour 3D rigid ring (Medtronic) (29 ± 1 mm), 10 with hybrid Tri-Ad Adams band (Medtronic) (28 ± 1 mm), and 10 had no prosthesis (control group). Pressure sensors were inserted in the left ventricle, right ventricle, and right atrium. Data were acquired with open chest after weaning off cardiopulmonary bypass and hemodynamic stabilization. Annular area, global and regional contraction, height, and strain were calculated based on cubic spline fits to crystal locations. RESULTS: Tricuspid annular area contraction during the cardiac cycle was 11% ± 3% in the control group. The Contour 3D ring significantly impaired annular contraction (2% ± 1%) whereas the Duran AnCore ring and Tri-Ad Adams band (9% ± 3% and 8% ± 4%, respectively) permitted dynamic area change. Global perimeter reduction was 6% ± 1% in the control group and decreased in the Duran AnCore (3% ± 1%), Contour 3D (0.4% ± 0.2%), and Tri-Ad Adams (3% ± 1%) groups (all P values < .001 vs control). Annular height was 6.2 ± 2.0 mm in the control group, unchanged in the Contour 3D (4.9 ± 1.1 mm) but reduced in the Duran AnCore (3.1 ± 1.3 mm) and Tri-Ad Adams (3.1 ± 1.0 mm) groups (P < .001 Duran AnCore and Tri-Ad Adams vs control). Rings perturbed systolic global annular strain (control, 5.3% ± 1.8%; Duran AnCore, 2.3% ± 1.0%; Contour 3D, 0.6% ± 0.2%; and Tri-Ad Adams, -2.6% ± 0.7%) with Contour 3D inducing the biggest change (P < .05 vs other groups). CONCLUSIONS: In healthy ovine hearts, flexible and hybrid rings better preserved annular dynamics and strain, whereas the rigid ring maintained 3-dimensional geometry. These data may aid the design of optimal tricuspid annular prostheses and improve durability of valve repair.

Tricuspid Valve Anterior Leaflet Strains in Ovine Functional Tricuspid Regurgitation.

Functional tricuspid regurgitation (FTR) is thought to arise due to annular dilation and alteration of right ventricular (RV) geometry in the presence of normal leaflets, yet mitral leaflets have been shown to remodel significantly in functional mitral regurgitation. We set out to evaluate tricuspid valve anterior leaflet deformations in ovine FTR. Eleven animals (FTR group) underwent implantation of a pacemaker with high rate pacing to induce biventricular dysfunction and at least moderate TR. Subsequently, both FTR (n = 11) and Control (n = 12) animals underwent implantation of 6 sonomicrometry crystals around the tricuspid annulus, 4 on the anterior leaflet, and 14 on RV epicardium. Tricuspid valve geometry and anterior leaflet strains were calculated from crystal coordinates. Left ventricular ejection fraction and RV fractional area change were significantly lower in FTR animals versus Control. Tricuspid annular area, septo-lateral diameter, RV pressures were all significantly greater in the FTR group. Mean TR grade (+0-3) was 0.7 ± 0.5 in Control and 2.4 ± 0.5 in FTR (P = < 0.001). The anterior leaflet area and length increased significantly. Global radial leaflet strain was significantly lower in FTR mostly driven by decreased free edge leaflet strain. Global circumferential anterior leaflet strain was also significantly lower in FTR with more remarkable reduction in the belly region. Rapid ventricular pacing in sheep resulted in a clinically pertinent model of RV and annular dilation with FTR and leaflet enlargement. Both circumferential and radial anterior leaflet strains were significantly reduced with FTR. Functional TR may be associated with alteration of leaflet mechanical properties.

The tricuspid valve also maladapts as shown in sheep with biventricular heart failure.

Over 1.6 million Americans suffer from significant tricuspid valve leakage. In most cases this leakage is designated as secondary. Thus, valve dysfunction is assumed to be due to valve-extrinsic factors. We challenge this paradigm and hypothesize that the tricuspid valve maladapts in those patients rendering the valve at least partially culpable for its dysfunction. As a first step in testing this hypothesis, we set out to demonstrate that the tricuspid valve maladapts in disease. To this end, we induced biventricular heart failure in sheep that developed tricuspid valve leakage. In the anterior leaflets of those animals, we investigated maladaptation on multiple scales. We demonstrated alterations on the protein and cell-level, leading to tissue growth, thickening, and stiffening. These data provide a new perspective on a poorly understood, yet highly prevalent disease. Our findings may motivate novel therapy options for many currently untreated patients with leaky tricuspid valves.

Tricuspid Valve Annuloplasty Alters Leaflet Mechanics.

Tricuspid valve regurgitation is associated with significant morbidity and mortality. Its most common treatment option, tricuspid valve annuloplasty, is not optimally effective in the long-term. Toward identifying the causes for annuloplasty's ineffectiveness, we have previously investigated the technique's impact on the tricuspid annulus and the right ventricular epicardium. In our current work, we are extending our analysis to the anterior tricuspid valve leaflet. To this end, we adopted our previous strategy of performing DeVega suture annuloplasty as an experimental methodology that allows us to externally control the degree of cinching during annuloplasty. Thus, in ten sheep we successively cinched the annulus and quantified changes to leaflet motion, dynamics, and strain in the beating heart by combining sonomicrometry with our well-established mechanical framework. We found that successive cinching of the valve enforced earlier coaptation and thus reduced leaflet range of motion. Additionally, leaflet angular velocity during opening and closing decreased. Finally, we found that leaflet strains were also reduced. Specifically, radial and areal strains decreased as a function of annular cinching. Our findings are critical as they suggest that suture annuloplasty alters the mechanics of the tricuspid valve leaflets which may disrupt their resident cells' mechanobiological equilibrium. Long-term, such disruption may stimulate tissue maladaptation which could contribute to annuloplasty's sub-optimal effectiveness. Additionally, our data suggest that the extent to which annuloplasty alters leaflet mechanics can be controlled via degree of cinching. Hence, our data may provide direct surgical guidelines.

A detailed mechanical and microstructural analysis of ovine tricuspid valve leaflets.

The tricuspid valve ensures unidirectional blood flow from the right atrium to the right ventricle. The three tricuspid leaflets operate within a dynamic stress environment of shear, bending, tensile, and compressive forces, which is cyclically repeated nearly three billion times in a lifetime. Ostensibly, the microstructural and mechanical properties of the tricuspid leaflets have mechanobiologically evolved to optimally support their function under those forces. Yet, how the tricuspid leaflet microstructure determines its mechanical properties and whether this relationship differs between the three leaflets is unknown. Here we perform a microstructural and mechanical analysis in matched ovine tricuspid leaflet samples. We found that the microstructure and mechanical properties vary among the three tricuspid leaflets in sheep. Specifically, we found that tricuspid leaflet composition, collagen orientation, and valve cell nuclear morphology are spatially heterogeneous and vary across leaflet type. Furthermore, under biaxial tension, the leaflets' mechanical behaviors exhibited unequal degrees of mechanical anisotropy. Most importantly, we found that the septal leaflet was stiffer in the radial direction and not the circumferential direction as with the other two leaflets. The differences we observed in leaflet microstructure coincide with the varying biaxial mechanics among leaflets. Our results demonstrate the structure-function relationship for each leaflet in the tricuspid valve. We anticipate our results to be vital toward developing more accurate, leaflet-specific tricuspid valve computational models. Furthermore, our results may be clinically important, informing differential surgical treatments of the tricuspid valve leaflets. Finally, the identified structure-function relationships may provide insight into the homeostatic and remodeling potential of valvular cells in altered mechanical environments, such as in diseased or repaired tricuspid valves. STATEMENT OF SIGNIFICANCE: Our work is significant as we investigated the structure-function relationship of ovine tricuspid valve leaflets. This is important as tricuspid valves fail frequently and our current approach to repairing them is suboptimal. Specifically, we related the distribution of structural and cellular elements, such as collagen, glycosaminoglycans, and cell nuclei, to each leaflet's mechanical properties. We found that leaflets have different structures and that their mechanics differ. This may, in the future, inform leaflet-specific treatment strategies and help optimize surgical outcomes.

The Effect of Downsizing on the Normal Tricuspid Annulus.

Tricuspid annuloplasty is a surgical procedure that cinches the valve's annulus in order to reduce regurgitant blood flow. One of its critical parameters is the degree of downsizing. To provide insight into the effect of downsizing, we studied the annulus of healthy sheep during suture annuloplasty. To this end, we implanted fiduciary markers along the annulus of sheep and subsequently performed a DeVega suture annuloplasty. We performed five downsizing steps in each animal while recording hemodynamic and sonomicrometry data in beating hearts. Subsequently, we used splines to approximate the annulus at baseline and at each downsizing step. Based on these approximations we computed clinical metrics of annular shape and dynamics, and the continuous field metrics height, strain, and curvature. With these data, we demonstrated that annular area reduction during downsizing was primarily driven by compression of the anterior annulus. Similarly, reduction in annular dynamics was driven by reduced contractility in the anterior annulus. Finally, changes in global height and eccentricity of the annulus could be explained by focal changes in the continuous height profile and changes in annular curvature. Our findings are important as they provide insight into a regularly performed surgical procedure and may inform the design of transcatheter devices that mimic suture annuloplasty.

Vascular access site complications after transfemoral transcatheter aortic valve implantation in the POL-TAVI Registry: surgical versus percutaneous approach.

BACKGROUND: Transfemoral transcatheter aortic valve implantation (TF TAVI) has recently become an established treatment option for intermediate and high-risk surgical patients with severe aortic stenosis. Despite significant reduction in diameter of valvular delivery systems, access related vascular complications remain a major safety concern. The aim of this study was to evaluate impact of femoral access techniques: surgical versus percutaneous on in-hospital outcomes. METHODS: Polish National TAVI Registry (POL-TAVI) was used as a data source. The analysis included 1680 patients treated with TF TAVI in years 2013-2016. 677 patients were treated using percutaneous technique (Group PC) and 1003 using open surgical access (Group S). The two groups were matched and compared. All-cause mortality, length of hospital stay, procedure time and potential risk factors for vascular access site complications after TF TAVI were analyzed. RESULTS: Vascular access site complications were reported in 162 (9.64%) of 1680 patients and were found significantly more often in PC group (13.15% vs. 7.28% P>0.001). There was a significant difference between groups regarding Body Mass Index, arterial hypertension, transient ischemic attack history and NYHA classification. The data analysis showed that increased probability of all vascular complications was associated with percutaneous access. In addition, left-side access and female sex were independent risk factors for all vascular complications. CONCLUSIONS: Surgical cut-down in the groin with exposure of the artery and manual suture after the procedure seems to be a safer option for TF TAVI patients.

Nanocrystalline-Coated Silver Dressings for Patients with Type 2 Diabetes after Surgical Coronary Revascularization.

OBJECTIVE: To assess the suitability of nanocrystalline-coated silver dressings versus standard wound dressings in patients with type 2 diabetes after coronary revascularization. METHODS: The study involved 194 patients who were divided into two homogeneous groups. The control group (n = 97) received a standard sterile dressing. The intervention group (n = 97) received silver dressings. Glycosylated hemoglobin, fructosamine, and creatinine were assessed in all patients. The emergence of superficial wound infection within 30 days was the primary endpoint of the study, and deep wound infections were a secondary endpoint. MAIN RESULTS: Superficial wound infections were documented in 26 patients: 11 patients in the study group and 15 in the control group. There were no statistically significant differences between the analyzed groups regarding the occurrence of the primary endpoint. No deep wound infections were found in either the study or control group. CONCLUSIONS: The frequency of sternotomy wound infection in patients with type 2 diabetes is comparable between patients treated with traditional dressings and those receiving silver dressings; therefore, to maximize cost savings, providers should consider using standard wound dressings in this patient population.