Quantification and simulation of layer-specific mitral valve interstitial cells deformation under physiological loading

Abstract

Within each of the four layers of mitral valve (MV) leaflet tissues there resides a heterogeneous population of interstitial cells that maintain the structural integrity of the MV tissue via protein biosynthesis and enzymatic degradation. There is increasing evidence that tissue stress-induced MV interstitial cell (MVIC) deformations can have deleterious effects on their biosynthetic states that are potentially related to the reduction of tissue-level maintenance and to subsequent organ-level failure. To better understand the interrelationships between tissue-level loading and cellular responses, we developed the following integrated experimental-computational approach. Since in-vivo cellular deformations are not directly measurable, we quantified the in-situ layer-specific MVIC deformations for each of the four layers under a controlled biaxial tension loading device coupled to multi-photon microscopy. Next, we explored the interrelationship between the MVIC stiffness and deformation to layer-specific tissue mechanical and structural properties using a macro-micro finite element computational model. Experimental results indicated that the MVICs in the fibrosa and ventricularis layers deformed significantly more than those in the atrialis and spongiosa layers, reaching a nucleus aspect ratio of 3.3 under an estimated maximum physiological tension of 150 N/m. The simulated MVIC moduli for the four layers were found to be all within a narrow range of 4.71–5.35 kPa, suggesting that MVIC deformation is primarily controlled by each tissue layer’s respective structure and mechanical behavior rather than the intrinsic MVIC stiffness. This novel result further suggests that while the MVICs may be phenotypically and biomechanically similar throughout the leaflet, they experience layer-specific mechanical stimulatory inputs due to distinct extracellular matrix architecture and mechanical behaviors of the four MV leaflet tissue layers. This also suggests that MVICs may behave in a layer-specific manner in response to mechanical stimuli in both normal and surgically modified MVs.

Mitral valve leaflet remodelling during pregnancy: insights into cell-mediated recovery of tissue homeostasis

“…In order to estimate changes in MVIC deformation throughout pregnancy, we performed FE simulations using ABAQUS (Dassault Systèmes Simulia Corp.) for a representative volume element (RVE) of valve leaflet tissue under biaxial tension, following established procedures [17]. Briefly, 10 MVICs were embedded in a 100 Â 100 mm 2 ECM region as Saint VenantKirchhoff ellipsoidal inclusions of approximately 5 kPa stiffness, with an initial NAR equal to the average found for NP specimens.…”

“…As the insertion of new fibrils causes the fibres to become longer and more undulated, recruitment stretch would steadily increase and normal MVIC geometry would be restored. In direct correlation with local collagen fibre density, it has been shown that MVIC deformation varies across the different tissue layers of the MV leaflet [17]. It is therefore not surprising that MV growth and remodelling is also layer-specific, as demonstrated by the non-uniform changes in layer thicknesses seen in pregnancy [13].…”

“…Moreover, we linked tissue-level and cellular changes by quantifying how MVIC geometry changes throughout pregnancy (figure 1). This additional focus on MVIC geometry was based in part on the role of MVICs (particularly their induced deformations over the cardiac cycle) in MV tissue maintenance [17]. Because both the LV and MV are otherwise healthy throughout pregnancy, our results provided insights into how valvular tissues adapt without the confounding pathological factors that must be considered in other diseased systems.…”

On the Presence of Affine Fibril and Fiber Kinematics in the Mitral Valve Anterior Leaflet

“…Moreover, tissue stressinduced MVIC deformation can have deleterious effects on the biosynthetic states of MVICs that are related to the reduction of tissue maintenance as well as the organ-level failure. Therefore, to better understand the interrelationships between tissue-level loading and cellular responses, we developed an integrated experimental-computational approach in a parallel study (60) to quantify the in situ layer-specific MVIC deformations under controlled biaxial tension loading, and to explore the interrelationship between the MVIC stiffness and deformation to layer-specific tissue mechanical and structural properties. We found that MVIC deformation is primarily controlled by each tissue layer's respective structure and mechanical behavior rather than the intrinsic MVIC stiffness.…”

Stabilized Collagen and Elastin-Based Scaffolds for Mitral Valve Tissue Engineering

“…[6][7][8][9][10] The MV surface is covered with endothelial cells, which interact with VICs to maintain the integrity of valves and also regulate the leaflets' mechanical properties. 11 MV insufficiency leading to regurgitation affects >2% of the population and, most frequently, is caused by mitral valve prolapse (MVP). 12,13 MVP is mainly due to myxomatous degeneration, leading to altered mechanical stress and turbulent flow in the proximity to the MV leaflets.…”