Assessing the impact of extracellular matrix fiber orientation on breast cancer cellular metabolism.

The extracellular matrix (ECM) is a dynamic and complex microenvironment that modulates cell behavior and cell fate. Changes in ECM composition and architecture have been correlated with development, differentiation, and disease progression in various pathologies, including breast cancer [1]. Studies have shown that aligned fibers drive a pro-metastatic microenvironment, promoting the transformation of mammary epithelial cells into invasive ductal carcinoma via the epithelial-to-mesenchymal transition (EMT) [2]. The impact of ECM orientation on breast cancer metabolism, however, is largely unknown. Here, we employ two non-invasive imaging techniques, fluorescence-lifetime imaging microscopy (FLIM) and intensity-based multiphoton microscopy, to assess the metabolic states of cancer cells cultured on ECM-mimicking nanofibers in a random and aligned orientation. By tracking the changes in the intrinsic fluorescence of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, as well as expression levels of metastatic markers, we reveal how ECM fiber orientation alters cancer metabolism and EMT progression. Our study indicates that aligned cellular microenvironments play a key role in promoting metastatic phenotypes of breast cancer as evidenced by a more glycolytic metabolic signature on nanofiber scaffolds of aligned orientation compared to scaffolds of random orientation. This finding is particularly relevant for subsets of breast cancer marked by high levels of collagen remodeling (e.g. pregnancy associated breast cancer), and may serve as a platform for predicting clinical outcomes within these subsets [3-6].

Differential gene expression of leaflet tissue in chronic ovine functional tricuspid regurgitation.

OBJECTIVES: Severe functional tricuspid regurgitation (FTR) is associated with subvalvular remodelling, but leaflet tissue alterations may also contribute. We set out to investigate molecular mechanisms driving leaflet remodelling in chronic ovine FTR. METHODS: Thirteen adult sheep (55 ± 4kg) underwent left thoracotomy, epicardial echocardiography, and pulmonary artery banding (PAB) to induce right heart failure and FTR. After 16 weeks, 13 banded (FTR) and 12 control (CTL) animals underwent median sternotomy for epicardial echocardiography and were subsequently sacrificed with each tricuspid leaflet tissue harvested for RNA-seq and histology. RESULTS: After 16 weeks, 7 animals developed severe, 2 moderate, and 4 mild tricuspid regurgitation (TR). Relative to CTL, FTR animals had increased PAP, TR, tricuspid annular diameter, and right atrial volume, while tricuspid annular plane systolic excursion (TAPSE) and RV fractional area change decreased. FTR leaflets exhibited altered constituents and an increase in cellularity. RNA-seq identified 85 significantly differentially expressed genes (DEG) with 17, 53, and 127 within the anterior, posterior, and septal leaflets respectively. RRM2, PRG4, and CXCL8 (IL-8) were identified as DEGs across all leaflets and CXCL8 was differentially expressed between FTR severity grades. RRM2, PRG4, and CXCL8 significantly correlated with TAPSE, and this correlation was consistent regardless of the anatomical location of the leaflet. CONCLUSIONS: PAB in our ovine model resulted in RV failure and FTR. Leaflet RNA-seq identified several DEGs, specifically RRM2, PRG4, and CXCL8, with known roles in tissue remodelling. These data along with an overall increase in leaflet cellularity suggest tricuspid leaflets actively remodel in FTR.

Impact of tricuspid annuloplasty device shape and size on valve mechanics-a computational study.

Background: Tricuspid valve disease significantly affects 1.6 million Americans. The gold standard treatment for tricuspid disease is the implantation of annuloplasty devices. These ring-like devices come in various shapes and sizes. Choices for both shape and size are most often made by surgical intuition rather than scientific rationale. Methods: To understand the impact of shape and size on valve mechanics and to provide a rational basis for their selection, we used a subject-specific finite element model to conduct a virtual case study. That is, we implanted 4 different annuloplasty devices of 6 different sizes in our virtual patient. After each virtual surgery, we computed the coaptation area, leaflet end-systolic angles, leaflet stress, and chordal forces. Results: We found that contoured devices are better at normalizing end-systolic angles, whereas the one flat device, the Edwards Classic, maximized the coaptation area and minimized leaflet stress and chordal forces. We further found that reducing device size led to increased coaptation area but also negatively impacted end-systolic angles, stress, and chordal forces. Conclusions: Based on our analyses of the coaptation area, leaflet motion, leaflet stress, and chordal forces, we found that device shape and size have a significant impact on valve mechanics. Thereby, our study also demonstrates the value of simulation tools and device tests in "virtual patients." Expanding our study to many more valves may, in the future, allow for universal recommendations.

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.

Convection-enhanced delivery with controlled catheter movement: A parametric finite element analysis.

Convection-enhanced delivery (CED) is an investigational method for delivering therapeutics directly to the brain for the treatment of glioblastoma. However, it has not become a common clinical therapy due to an inability of CED treatments to deliver therapeutics in a large enough tissue volume to fully saturate the target region. We have recently shown that the combination of controlled catheter movement and constant pressure infusions can be used to significantly increase volume dispersed (Vd ) in an agarose gel brain tissue phantom. In the present study, we develop a computational model to predict Vd achieved by various retraction rates with both constant pressure and constant flow rate infusions. An increase in Vd is achieved with any movement rate, but increase in Vd between successive movement rates drops off at rates above 0.3-0.35 mm/min. Finally, we found that infusions with retraction result in a more even distribution in concentration level compared to the stationary catheter, suggesting a potential increased ability for moving catheters to have a therapeutic impact regardless of the required therapeutic concentration level.

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 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 Annuloplasty Rings: A Quantitative Comparison of Size, Nonplanar Shape, and Stiffness.

BACKGROUND: Functional tricuspid regurgitation due to annular and ventricular dilatation is increasingly recognized as a significant source of morbidity and mortality. To repair the annulus, surgeons implant one of many annuloplasty devices that differ in size, 3-dimensional (3D) shape, and stiffness. However, there have been no quantitative comparisons between various available devices. METHODS: Three-dimensional scanning, micro-computed tomography imaging, analytical methods, and mechanical tests were used to compare 3 Edwards Lifesciences (Irvine, CA) and 3 Medtronic (Minneapolis, MN) annuloplasty devices of all available sizes. We measured in-plane metrics of maximum diameter, perimeter, area, height, as well as elevation and curvature profiles. Furthermore, we computed bending stiffness as well as the maximum and minimum axes of the bending stiffness. RESULTS: Most annular prostheses differed little in their in-plane geometries but varied significantly in height. In-plane properties deviated significantly from measurements of healthy human tricuspid annuli. Height of the Edwards' MC3 and Medtronic's Contour 3D resembled healthy human tricuspid valve annuli, whereas the Edwards' Physio and Classic, and Medtronic's TriAd, did not. Additionally, the elevation profiles of the MC3 and Contour 3D and curvature profiles between all devices were consistent and matched those of healthy human annuli. The tested devices also differed in their bending stiffness, both in terms of absolute values and their maximum and minimum axes. CONCLUSIONS: Contoured devices, such as Edwards' MC3 and Medtronic's Contour 3D, most accurately resembled the healthy human tricuspid annulus but differed significantly in bending stiffness. To what extent prosthesis properties and shape affect tricuspid valve function remains to be determined.

Do annuloplasty rings designed to treat ischemic/functional mitral regurgitation alter left-ventricular dimensions in the acutely ischemic ovine heart?

OBJECTIVE: To quantify the effects of annuloplasty rings designed to treat ischemic/functional mitral regurgitation on left ventricular septal-lateral (S-L) and commissure-commissure (C-C) dimensions. METHODS: Radiopaque markers were placed as opposing pairs on the S-L and C-C aspects of the mitral annulus and the basal, equatorial, and apical level of the left ventricle (LV) in 30 sheep. Ten true-sized Carpentier-Edwards Physio (PHY), Edwards IMR ETlogix (ETL), and GeoForm (GEO; all from Edwards Lifesciences, Irvine, Calif) annuloplasty rings were inserted in a releasable fashion. After 90 seconds of left circumflex artery occlusion with the ring implanted (RING), 4-dimensional marker coordinates were obtained using biplane videofluoroscopy. After ring release, another data set was acquired after another 90 seconds of left circumflex artery occlusion (NO RING). S-L and C-C diameters were computed as the distances between the respective marker pairs at end-diastole. Percent change in diameters was calculated between RING versus NO RING as 100 × (diameter in centimeters [RING] - diameter in centimeters [NO RING])/diameter in centimeters [NO RING]). RESULTS: Compared with NO RING, all ring types (PHY, ETL, and GEO) reduced mitral annular S-L dimensions by -20.7 ± 5.6%, -26.8 ± 3.9%, and -34.5 ± 3.8%, respectively. GEO reduced the S-L dimensions of the LV at the basal level only by -2.3 ± 2.4%, whereas all other S-L dimensions of the LV remained unchanged with all 3 rings implanted. PHY, ETL, and GEO reduced mitral annular C-C dimensions by -17.5 ± 4.8%, -19.6 ± 2.5, and -8.3 ± 4.9%, respectively, but none of the rings altered the C-C dimensions of the LV. CONCLUSIONS: Despite radical reduction of mitral annular size, disease-specific ischemic/functional mitral regurgitation annuloplasty rings do not induce relevant changes of left ventricular dimensions in the acutely ischemic ovine heart.

Impact of tricuspid annular size reduction on right ventricular function, geometry and strain.

OBJECTIVES: Restrictive tricuspid annuloplasty is a clinically accepted approach to treat functional tricuspid regurgitation. We set out to investigate the effect of varying degrees of tricuspid annular reduction on the right ventricular (RV) function, geometry and strain. METHODS: Eight, healthy sheep (45 ± 4 kg) had 6 sonomicrometry crystals implanted around the tricuspid annulus and 20 onto the epicardium of the right ventricle defining 3 free wall regions: basal, mid and lower. A polypropylene annuloplasty suture was placed around the tricuspid annulus and externalized to an epicardial tourniquet. Simultaneous echocardiographic, haemodynamic and sonomicrometry data were acquired at baseline and during 5 consecutive annular reduction steps (TAR 1-5) with successive (5-7 mm) suture cinching. RV free wall circumferential, longitudinal and areal cardiac and interventional strains, RV radius of curvature (ROC), cross-sectional area and tricuspid annular dimensions were calculated from 3-dimensional crystal coordinates. RESULTS: TAR 1-5 resulted in 19 ± 15%, 35 ± 15%, 51 ± 15%, 60 ± 15% and 68 ± 13% tricuspid annular area reduction, respectively. TAR 1 and 2 had minimal influence on the RV function, RV-ROC and strains. TAR 4 and 5 decreased RV-ROC in basal and mid-regions, but reduced the RV cross-sectional area change (from 19 ± 4% at baseline to 14 ± 3% and 13 ± 2%, respectively, P < 0.001) and circumferential and areal strains. TAR 3 significantly decreased free wall RV-ROC from 44.0 ± 1.5 to 42.6 ± 2.4 mm P < 0.001 at the RV base but maintained the regional ventricular function and strains. CONCLUSIONS: In healthy ovine hearts, a tricuspid annular area reduction of ∼50% provides optimal conditions for reducing RV-ROC while maintaining regional RV function and strain patterns.

Parametric Study of the Design Variables of an Arborizing Catheter on Dispersal Volume Using a Biphasic Computational Model.

Convection-enhanced delivery (CED) is an investigational therapy developed to circumvent the limitations of drug delivery to the brain. Catheters are used in CED to locally infuse therapeutic agents into brain tissue. CED has demonstrated clinical utility for treatment of malignant brain tumors; however, CED has been limited by lack of CED-specific catheters. Therefore, we developed a multiport, arborizing catheter to maximize drug distribution for CED. Using a multiphasic finite element (FE) framework, we parametrically determined the influence of design variables of the catheter on the dispersal volume of the infusion. We predicted dispersal volume of a solute infused in a permeable hyperelastic solid matrix, as a function of separation distance (ranging from 0.5 to 2.0 cm) of imbedded infusion cavities that represented individual ports in a multiport catheter. To validate the model, we compared FE solutions of pressure-controlled infusions to experimental data of indigo carmine dye infused in agarose tissue phantoms. The Tc50, defined as the infusion time required for the normalized solute concentration between two sources to equal 50% of the prescribed concentration, was determined for simulations with infusion pressures ranging from 1 to 4 kPa. In our validated model, we demonstrate that multiple ports increase dispersal volume with increasing port distance but are associated with a significant increase in infusion time. Tc50 increases approximately tenfold when doubling the port distance. Increasing the infusion flow rate (from 0.7 µL/min to 8.48 µL/min) can mitigate the increased infusion time. In conclusion, a compromise of port distance and flow rate could improve infusion duration and dispersal volume.

Sonomicrometry-derived 3-dimensional geometry of the human tricuspid annulus.

OBJECTIVES: Surgical correction of functional tricuspid regurgitation is focused on prosthetic reduction and remodeling of the tricuspid annulus. We set out to investigate the precise geometry of the human tricuspid annulus to better guide surgical therapy. METHODS: Eleven human donor hearts with normal right ventricular function and without tricuspid regurgitation that were rejected for clinical transplantation were harvested. Sonomicrometry crystals were sewn around the tricuspid annulus and pressure sensors placed in the right ventricle and right atrium. The hearts were studied in the TransMedics Organ Care System (Andover, Mass) ex vivo perfusion apparatus in the right heart working model. Data were acquired at baseline and before and after bolus calcium infusion. Annular height, dimensions, strain, and curvature were calculated based on 3-dimensional crystal coordinates. RESULTS: Maximal annular area was 997 ± 258 mm2 and minimal 902 ± 257 mm2 with contraction of 10% ± 5% at baseline and 19% ± 6% after calcium (P = .007). Segmental contractility of anterior, posterior, and septal annular regions was 7% ± 5%, 6% ± 4%, and 6% ± 3%, respectively. Only anterior region had increased contractility after calcium infusion (to 15% ± 5%; P = .023). Annulus had its high points at anteroseptal commissure and the midposterior region and lowest point in the midseptal region with maximal and minimal height of 5.0 ± 1.1 mm and 4.0 ± 1.1 mm, respectively. The greatest curvature responsible for out of plane annular bending was observed at annular high points. CONCLUSIONS: The human tricuspid annulus is a complex 3-dimensional dynamic structure with its high points and maximal degree of bending at the anteroseptal commissure and midposterior annulus. These detailed geometric data may aid the design of more physiologic annular prostheses and surgical reparative techniques.

Tricuspid Annular Geometry and Strain After Suture Annuloplasty in Acute Ovine Right Heart Failure.

BACKGROUND: Tricuspid valve repair using suture annuloplasty is thought to be more physiologic, but the effect of annular reduction on annular geometry and motion is unknown. We set out to investigate the effect of DeVega suture annuloplasty (DV) on tricuspid annular geometry and dynamics during acute right heart failure (RHF). METHODS: Ten adult sheep underwent implantation of sonomicrometry crystals around the tricuspid annulus and on the right ventricle; pressure transducers were placed in right ventricle, left ventricle, and right atrium. RHF was induced by a combination of 500 mL volume infusion, posterior descending artery occlusion, and pulmonary artery constriction. Hemodynamic, echocardiographic, and sonomicrometry data were acquired at baseline, with RHF, and after two progressive (8 to 10 mm) DV suture cinches (DV-1, DV-2) during RHF. Annular size, geometry, and dynamics were determined from crystal coordinates. RESULTS: Combination of volume infusion, ischemia, and pulmonary hypertension resulted in acute RHF and significant functional tricuspid regurgitation grade (0.5 ± 0.5 versus 2.7 ± 0.8, p < 0.001). Annular area increased with RHF from 700 ± 98 mm2 to 801 ± 128 mm2 (p < 0.001). DV-1 and DV-2 reduced annular area to 342 ± 88 mm2 and 180 ± 57 mm2 while reducing regurgitation grade to 1.2 ± 0.4 and 0.4 ± 0.5, respectively (all p < 0.001 versus RHF). Tricuspid annular area contraction was 12% ± 7%, 10% ± 6%, and 12% ± 6% for RHF, DV-1, and DV-2, respectively (p = 0.25) and annular height was 4.9 ± 2.0 mm, 5.6 ± 1.4 mm, and 5.5 ± 1.7 mm (p = 0.43). Mean transvalvular gradient was 1.3 ± 0.7 mm Hg and 2.0 ± 1.0 mm Hg with DV-1 and DV-2, respectively. CONCLUSIONS: During acute ovine RHF, DeVega annuloplasty successfully treated tricuspid regurgitation and preserved normal tricuspid annular dynamics and geometry. These data may lead to more physiologic tricuspid reparative techniques.

A virtual sizing tool for mitral valve annuloplasty.

Functional mitral regurgitation, a backward leakage of the mitral valve, is a result of left ventricular growth and mitral annular dilatation. Its gold standard treatment is mitral annuloplasty, the surgical reduction in mitral annular area through the implantation of annuloplasty rings. Recurrent regurgitation rates may, however, be as high as 30% and more. While the degree of annular downsizing has been linked to improved long-term outcomes, too aggressive downsizing increases the risk of ring dehiscences and significantly impairs repair durability. Here, we prototype a virtual sizing tool to quantify changes in annular dimensions, surgically induced tissue strains, mitral annular stretches, and suture forces in response to mitral annuloplasty. We create a computational model of dilated cardiomyopathy onto which we virtually implant annuloplasty rings of different sizes. Our simulations confirm the common intuition that smaller rings are more invasive to the surrounding tissue, induce higher strains, and require larger suture forces than larger rings: The total suture force was 2.2 N for a 24-mm ring, 1.9 N for a 28-mm ring, and 0.8 N for a 32-mm ring. Our model predicts the highest risk of dehiscence in the septal and postero-lateral annulus where suture forces are maximal. These regions co-localize with regional peaks in myocardial strain and annular stretch. Our study illustrates the potential of realistic predictive simulations in cardiac surgery to identify areas at risk for dehiscence, guide the selection of ring size and shape, rationalize the design of smart annuloplasty rings and, ultimately, improve long-term outcomes after surgical mitral annuloplasty. Copyright © 2016 John Wiley & Sons, Ltd.

The emergence of extracellular matrix mechanics and cell traction forces as important regulators of cellular self-organization.

Physical cues play a fundamental role in a wide range of biological processes, such as embryogenesis, wound healing, tumour invasion and connective tissue morphogenesis. Although it is well known that during these processes, cells continuously interact with the local extracellular matrix (ECM) through cell traction forces, the role of these mechanical interactions on large scale cellular and matrix organization remains largely unknown. In this study, we use a simple theoretical model to investigate cellular and matrix organization as a result of mechanical feedback signals between cells and the surrounding ECM. The model includes bi-directional coupling through cellular traction forces to deform the ECM and through matrix deformation to trigger cellular migration. In addition, we incorporate the mechanical contribution of matrix fibres and their reorganization by the cells. We show that a group of contractile cells will self-polarize at a large scale, even in homogeneous environments. In addition, our simulations mimic the experimentally observed alignment of cells in the direction of maximum stiffness and the building up of tension as a consequence of cell and fibre reorganization. Moreover, we demonstrate that cellular organization is tightly linked to the mechanical feedback loop between cells and matrix. Cells with a preference for stiff environments have a tendency to form chains, while cells with a tendency for soft environments tend to form clusters. The model presented here illustrates the potential of simple physical cues and their impact on cellular self-organization. It can be used in applications where cell-matrix interactions play a key role, such as in the design of tissue engineering scaffolds and to gain a basic understanding of pattern formation in organogenesis or tissue regeneration.

Mechanics of the mitral annulus in chronic ischemic cardiomyopathy.

Approximately one third of all patients undergoing open-heart surgery for repair of ischemic mitral regurgitation present with residual and recurrent mitral valve leakage upon follow up. A fundamental quantitative understanding of mitral valve remodeling following myocardial infarction may hold the key to improved medical devices and better treatment outcomes. Here we quantify mitral annular strains and curvature in nine sheep 5 ± 1 weeks after controlled inferior myocardial infarction of the left ventricle. We complement our marker-based mechanical analysis of the remodeling mitral valve by common clinical measures of annular geometry before and after the infarct. After 5 ± 1 weeks, the mitral annulus dilated in septal-lateral direction by 15.2% (p = 0.003) and in commissure-commissure direction by 14.2% (p < 0.001). The septal annulus dilated by 10.4% (p = 0.013) and the lateral annulus dilated by 18.4% (p < 0.001). Remarkably, in animals with large degree of mitral regurgitation and annular remodeling, the annulus dilated asymmetrically with larger distortions toward the lateral-posterior segment. Strain analysis revealed average tensile strains of 25% over most of the annulus with exception for the lateral-posterior segment, where tensile strains were 50% and higher. Annular dilation and peak strains were closely correlated to the degree of mitral regurgitation. A complementary relative curvature analysis revealed a homogenous curvature decrease associated with significant annular circularization. All curvature profiles displayed distinct points of peak curvature disturbing the overall homogenous pattern. These hinge points may be the mechanistic origin for the asymmetric annular deformation following inferior myocardial infarction. In the future, this new insight into the mechanism of asymmetric annular dilation may support improved device designs and possibly aid surgeons in reconstructing healthy annular geometry during mitral valve repair.