Alteration of the native mitral valve (MV) shape has been hypothesized to have a profound effect on the local tissue stress distribution, and is potentially linked to limitations in repair durability. The present study was undertaken to elucidate the relation between MV annular shape and central mitral valve anterior leaflet (MVAL) strain history, using flat annuloplasty in an ovine model. In addition, we report for the first time the presence of residual in-vivo leaflet strains. In-vivo leaflet deformations were measured using sonocrystal transducers sutured to the MVAL (n=10), with the 3D positions acquired over the full cardiac cycle. In six animals a flat ring was sutured to the annulus and the transducer positions recorded, while in the remaining four the MV was excised from the exsanguinated heart and the stress-free transducer positions obtained. In the central region of the MVAL the peak stretch values, referenced to the minimum left ventricular pressure (LVP), were 1.10 ± 0.01 and 1.31 ± 0.03 (mean ± standard error) in the circumferential and radial directions, respectively. Following flat ring annuloplasty, the central MVAL contracted 28% circumferentially and elongated 16% radially at minimum LVP, and the circumferential direction was under a negative strain state during the entire cardiac cycle. After valve excision from the exsanguinated heart, the MVAL contracted significantly (18% and 30% in the circumferential and radial directions, respectively), indicating the presence of substantial in-vivo residual strains. While the physiological function of the residual strains (and their associated stresses) are at present unknown, accounting for their presence is clearly necessary for accurate computational simulations of MV function. Moreover, we demonstrated that changes in annular geometry dramatically alter valvular functional strains in-vivo. As levels of homeostatic strains are related to tissue remodeling and homeostasis, our results suggest that surgically-introduced alterations in MV shape could lead to the long term MV mechanobiological and microstructural alterations that could ultimately affect MV repair durability.

Background Studies of the biomechanical response of the left ventricle (LV) to myocardial infarction (MI) have identified infarct expansion as an important phenomenon that both initiates and sustains adverse LV remodeling. We tested the hypothesis that infarct modification via material-induced infarct stiffening and thickening limits infarct expansion and LV remodeling. Methods Twenty-one sheep had anteroapical infarction and were randomized to either injection of 2.6ml of saline or 2.6ml of a tissue filler material into the infarct within 3 hours of coronary occlusion. Animals were followed for 8 weeks with echocardiography to assess infarct expansion and global LV remodeling. Post-mortem morphometric measurements were performed on the excised heart to quantify infarct thickness; regional blood flow was assessed with colored microspheres. Infarct material properties were directly measured using biaxial tensile testing. Results Treatment animals had less infarct expansion and reduced LV dilatation 8 weeks after MI (LV systolic volumes 60.8±4.3ml vs. 80.3±6.9ml, p<0.05). Ejection fraction was greater in the treatment animals (31.0±2.6% vs. 27.6±1.3%, p<0.05). The treatment group had thicker infarcts (5.5±0.2mm vs. 2.2±0.3mm, p<0.05) and greater infarct blood flow than control groups (0.22±0.04ml/min/g vs. 0.11±0.03ml/min/g, p<0.05). The longitudinal peak strain in the treatment group was less (0.05014±0.0141) than the control group (0.1024±0.0101), indicating increased stiffness of the treated infarcts. Conclusion Durable infarct thickening and stiffening can be achieved by infarct biomaterial injection resulting in the amelioration of both infarct expansion and global LV remodeling. Further material optimization will allow for clinical translation of this novel treatment paradigm.

While the role of collagen and elastin fibrous components in heart valve valvular biomechanics has been extensively investigated [see Sacks et al. 2009 J. Biomech. 42, 1804-24], the biomechanical role of the glycosaminoglycan (GAG) gelatinous-like material phase remains unclear. In the present study, we investigated the biomechanical role of GAGs in porcine aortic valve (AV) leaflets under tension utilizing enzymatic removal. Tissue specimens were removed from the belly region of porcine AVs and subsequently treated with either an enzyme solution for GAG removal, or a control (buffer with no enzyme) solution. A dual stress level test methodology was used to determine the effects at low and high (physiological) stress levels). In addition, planar biaxial tests were conducted both on-axis (i.e. aligned to the circumferential and radial axes) and at 45° off-axis to induce maximum shear, to explore the effects of augmented fiber rotations on the fiber-fiber interactions. Changes in hysteresis were used as the primary metric of GAG functional assessment. A simulation of the low force experimental setup was also conducted to clarify the internal stress system and provide viscoelastic model parameters fo this loading range. Results indicated that under planar tension the removal of GAGs had no measureable affect extensional mechanical properties (either on- or 45° off-axis) including peak stretch, hysteresis, or creep. Interestingly, in the low force range, hysteresis was markedly reduced from 35.96 ± 2.65% in control group to 25.00 ± 1.64% (p < 0.001) as a result of GAG removal. Collectively, these results suggest that GAGs do not play a direct role in modulating the time-dependent tensile properties of valvular tissues. Rather, they appear to be strongly connected with fiber-fiber and fiber-matrix interactions at low forces levels. Thus, we speculate that GAGs may be important in providing a damping mechanism to reduce leaflet flutter when the leaflet is not under high tensile stress.

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The Analysis of Interagency Registry for Mechanically Assisted Circulatory Support data showed greater durability for continuous flow than for pulsatile left ventricular assist devices. Even longer durations of support can be expected if pump durability continues to improve.

Though mitral valve (MV) repair surgical procedures have increased in the United States [Gammie, J. S., et al. Ann. Thorac. Surg. 87(5):1431-1437, 2009 Nowicki, E. R., et al. Am. Heart J. 145(6):1058-1062], studies suggest that altering MV stress states may have an effect on tissue homeostasis, which could impact the long-term outcome [Accola, K. D., et al. Ann. Thorac. Surg. 79(4):1276-1283 Fasol, R., et al. Ann. Thorac. Surg. 77(6):1985-1988, 2004; Flameng, W., P. Herijgers, and K. Bogaerts. Circulation 107(12): 1609-1613 Gillinov, A. M., et al. Ann. Thorac. Surg. 69(3):717-721, 2000]. Improved computational modeling that incorporates structural and geometrical data as well as cellular components has the potential to predict such changes; however, the absence of important boundary condition information limits current efforts. In this study, novel high definition in vivo annular kinematic data collected from surgically implanted sonocrystals in sheep was fit to a contiguous 3D spline based on quinticorder hermite shape functions with C 2 continuity. From the interpolated displacements, the annular axial strain and strain rate, bending, and twist along the entire annulus were calculated over the cardiac cycle. Axial strain was shown to be regionally and temporally variant with minimum and maximum values of −10 and 4%, respectively, observed. Similarly, regionally and temporally variant strain rate values, up to 100%/s contraction and 120%/s elongation, were observed. Both annular bend and twist data showed little deviation from unity with limited regional variations, indicating that most of the energy for deformation was associated with annular axial strain. The regionally and temporally variant strain/strain rate behavior of the annulus are related to the varied fibrous-muscle structure and contractile behavior of the annulus and surrounding ventricular structures, although specific details are still unavailable. With the high resolution shape and displacement information described in this work, high fidelity boundary conditions can be prescribed in future MV finite element models, leading to new insights into MV function and strategies for repair.

There is a significant gap in our knowledge of engineered heart valve tissue (EHVT) development regarding detailed three-dimensional (3D) tissue formation and remodeling from the point of in vitro culturing to full in vivo function. As a step toward understanding the complexities of EHVT formation and remodeling, a novel serial confocal microscopy technique was employed to obtain 3D micro-structural information of pre-implant (PRI) and post-implant for 12 weeks (POI) EHVT fabricated from PGA: PLLA scaffolds and seeded with ovine bone-marrow-derived mesenchymal stem cells. Custom scaffold fiber tracking software was developed to quantify scaffold fiber architectural features such as length, tortuosity, and minimum scaffold fiber-fiber separation distance and scaffold fiber orientation was quantified utilizing a 3D fabric tensor. In addition, collagen and cellular density of ovine pulmonary valve leaflet tissue were also analyzed for baseline comparisons. Results indicated that in the unseeded state, scaffold fibers formed a continuous, oriented network. In the PRI state, the scaffold showed some fragmentation with a scaffold volume fraction of 7.79%. In the POI specimen, the scaffold became highly fragmented, forming a randomly distributed short fibrous network (volume fraction of 2.03%) within a contiguous, dense collagenous matrix. Both PGA and PLLA scaffold fibers were observed in the PRI and POI specimens. Collagen density remained similar in both PRI and POI specimens (74.2 and 71.5%, respectively), though the distributions in the transmural direction appeared slightly more homogenous in the POI specimen. Finally, to guide future 2D histological studies for largescale studies (since acquisition of high-resolution volumetric data is not practical for all specimens), we investigated changes in relevant collagen and scaffold metrics (collagen density and scaffold fiber orientation) with varying section spacing. It was found that a sectioning spacing up to 25 μm (for scaffold morphology) and 50 μm (for collagen density) in both PRI and POI tissues did not result in loss of information fidelity, and that sectioning in the circumferential or radial direction provides the greatest preservation of information. This is the first known work to investigate EHVT microstructure over a large volume with high resolution and to investigate time evolving in vivo EHVT morphology. The important scaffold fiber structural changes observed provide morphological information crucial for guiding future structurally based constitutive modeling efforts focused on better understanding EHVT tissue formation and remodeling.

This work provides a foundation for future studies aimed at increasing the understanding of air leaks to better inform means of mitigating the risk of air leaks under clinically relevant conditions.