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RESEARCH PAPERS

# In-Situ Deformation of the Aortic Valve Interstitial Cell Nucleus Under Diastolic Loading

[+] Author and Article Information

Engineered Tissue Mechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of Pittsburgh, Pittsburgh, PA 15219

Jun Liao

Engineered Tissue Mechanics Laboratory, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219

Michael S. Sacks1

Engineered Tissue Mechanics Laboratory, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219msacks@pitt.edu

1

Corresponding author.

J Biomech Eng 129(6), 880-889 (Apr 19, 2007) (10 pages) doi:10.1115/1.2801670 History: Received September 03, 2006; Revised April 19, 2007

## Abstract

Within the aortic valve (AV) leaflet resides a population of interstitial cells (AVICs), which serve to maintain tissue structural integrity via protein synthesis and enzymatic degradation. AVICs are typically characterized as myofibroblasts, exhibit phenotypic plasticity, and may play an important role in valve pathophysiology. While it is known that AVICs can respond to mechanical stimuli in vitro, the level of in vivo AVIC deformation and its relation to local collagen fiber reorientation during the cardiac cycle remain unknown. In the present study, the deformation of AVICs was investigated using porcine AV glutaraldehyde fixed under $0–90mmHg$ transvalvular pressures. The resulting change in nuclear aspect ratio (NAR) was used as an index of overall cellular strain, and dependencies on spatial location and pressure loading levels quantified. Local collagen fiber alignment in the same valves was also quantified using small angle light scattering. A tissue-level finite element (FE) model of an AVIC embedded in the AV extracellular matrix was also used explore the relation between AV tissue- and cellular-level deformations. Results indicated large, consistent increases in AVIC NAR with transvalvular pressure (e.g., from mean of 1.8 at $0mmHg$ to a mean of 4.8 at $90mmHg$), as well as pronounced layer specific dependencies. Associated changes in collagen fiber alignment indicated that little AVIC deformation occurs with the large amount of fiber straightening for pressures below $∼1mmHg$, followed by substantial increases in AVIC NAR from $4mmHgto90mmHg$. While the tissue-level FE model was able to capture the qualitative response, it also underpredicted the extent of AVIC deformation. This result suggested that additional micromechanical and fiber-compaction effects occur at high pressure levels. The results of this study form the basis of understanding transvalvular pressure-mediated mechanotransduction within the native AV and first time quantitative data correlating AVIC nuclei deformation with AV tissue microstructure and deformation.

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## Figures

Figure 1

(a) An aortic valve leaflet showing gross structural features such as large surface undulations, along with the anatomical circumferential (C) and radial (R) axes. (b) A cross section of the AV leaflet 3D reconstructed to reveal the fibrosa (F), spongiosa (S), and ventricularis (V) layers, along with the 3D tissue coordinate system (T transmural)

Figure 2

(a) A panoramic image was created from four to five overlapped images of histological sections in order to span all three AV leaflet layers. (b) A representative image of AVIC nuclei (highlighted red) within Masson’s stained AV tissue section. The major- and minor-axis lengths used in calculated NAR are identified (yellow lines). The C‐T coordinates of the nuclei centroids were computed and converted to a normalized thickness position, with the origin arbitrarily defined at the ventricular surface.

Figure 3

(a) Schematic illustrating an AV leaflet subjected to a uniform tension T at the edge and a uniform pressure p. The model boundary stresses for the RVE were based on the applied external tensions T, and were located at the center of the leaflet. (b) The FE mesh consisting of an AVIC nucleus within leaflet ECM (cell membrane and cytoplasm were considered negligible).

Figure 4

(a) AVIC NAR versus normalized thickness at zero-, low- and high-TVP levels. At 0mmHg TVP, AVIC NAR values were highly uniform across the entire leaflet thickness. For normalized thickness positions between 0 and 0.3 (i.e., within the ventricularis layer), AVIC exhibited similar NAR values of ∼2.2 (0mmHg and 4mmHg) and ∼3(90mmHg). In sharp contrast, for normalized thickness positions between 0.4 and 1 (i.e., within the fibrosa layer) the AVIC NAR exhibited a trend of increased value with increased thickness position, approaching an average value of ∼4.8 at 90mmHg. These data indicate that AVICs in the different leaflet layers are subjected to dramatically different external stresses. “N.S.” indicates no statistically significant differences. (b) Comparison of the mean transmural AVIC NAR with the NOI (a measure of the degree of collagen fiber orientation). A complex relationship consisting of three distinct regions was observed (see text for details).

Figure 5

AVIC NAR versus NOI in the ventricularis and fibrosa layers for all TVP levels. Although both responses were qualitatively similar, the ventricularis underwent overall larger changes in NOI but lower changes in NAR. The fibrosa layer demonstrated a greater NAR change over a smaller range of NOI compared to the ventricularis layer, and the maximum NAR was significantly higher in the fibrosa compared with the ventricularis (∼5 versus ∼4), suggesting that the AVICs in this layer are more highly compressed.

Figure 6

Schematic representations of AVIC nucleus geometry at (a) 0mmHg and (b) 90mmHg. Deformations of the AVIC nucleus at 90mmHg in the circumferential and radial directions were taken from our experimental data, with the transmural dimensions calculated based on an incompressibility assumption. Although similar to valvular tissue-level deformations, AVIC nuclei experienced greater dimensional changes due to a disparity in mechanical properties compared to the leaflet ECM.

Figure 7

(a) A comparison of experimentally measured AVIC NAR values with values predicted by the RVE model plotted against the experimentally applied levels of TVP. While the RVE model captured the overall trend, discrepancies with the experimental data increased at greater TVPs. (b) Model predicted data as a function of material stiffness, indicating insensitivity to the material model.

Figure 8

TEM images of intact AVIC within the leaflet ECM. (a, b) Overall morphology of cell-ECM integration. Cell nucleus is indicated by a black arrow. (c, d) connections between collagen fibrils and cell membrane highlighted by white arrows. Scale bars=2μm in (b) and 500nm (a, c and d).

Figure 9

A summary schematic depicting fiber straightening and compaction effects with corresponding AVIC nuclei deformation. The percent error between the experimental data and model predictions is indicated.

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