title: 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 150N/m. The simulated MVIC moduli for the four layers were found to be all within a narrow range of 4.71-5.35kPa, 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.
authors: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences (ICES), Department of Biomedical Engineering, The University of Texas at Austin, 201 East 24th Street, POB 5.236, 1 University Station C0200, Austin, TX 78712, USA.
authors: Chung-Hao
authors: CH
authors: Lee
authors: Cardiac Rhythm Disease Management (CRDM) Clinical Specialist, Medtronic, Minneapolis, MN 55432, USA.
authors: Christopher A
authors: CA
authors: Carruthers
authors: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences (ICES), Department of Biomedical Engineering, The University of Texas at Austin, 201 East 24th Street, POB 5.236, 1 University Station C0200, Austin, TX 78712, USA.
authors: Salma
authors: S
authors: Ayoub
authors: Gorman Cardiovascular Research Group, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.
authors: Robert C
authors: RC
authors: Gorman
authors: Gorman Cardiovascular Research Group, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.
authors: Joseph H
authors: JH
authors: Gorman
authors: Center for Cardiovascular Simulation, Institute for Computational Engineering and Sciences (ICES), Department of Biomedical Engineering, The University of Texas at Austin, 201 East 24th Street, POB 5.236, 1 University Station C0200, Austin, TX 78712, USA. Electronic address: msacks@ices.utexas.edu.
authors: Michael S
authors: MS
authors: Sacks
mesh_terms: D000818:Animals; D048430:Cell Shape / Q000502:physiology; D004548:Elasticity; D005109:Extracellular Matrix / Q000502:physiology; D020342:Finite Element Analysis; D008943:Mitral Valve / Q000166:cytology* / Q000502:physiology; D008955:Models, Cardiovascular; D012756:Sheep; D013314:Stress, Mechanical; D016474:Weight-Bearing
keywords: Finite element simulations; MPM imaging analysis; MVIC microenvironment; Multi-level macro–micro modeling; Simplified structural constitutive model