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

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 0-90 mm Hg 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 0 mm Hg to a mean of 4.8 at 90 mm Hg), 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 approximately 1 mm Hg, followed by substantial increases in AVIC NAR from 4 mm Hg to 90 mm Hg. 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.

Tri-layered elastomeric scaffolds for engineering heart valve leaflets

“…However, the collagen concentration extracted from engineered tissues was far lower than those measured in native sheep porcine AV and PV. The reported values are consistent with recently measured collagen concentration of porcine AV and PV using the same collagen assay protocol [62]. Considering the previous study results and current results (4 weeks cultivation of engineered scaffolds particularly in static condition), collagen formation is considerable but yet incomparable with native leaflet collagen concentration.…”

Valve interstitial cell contractile strength and metabolic state are dependent on its shape

“…Shorter and wider VICs generated less contractile stress and were at a less biosynthetic and proliferative state, while elongated narrower VICs had greater contractile stress generation, more biosynthesis, increased proliferation and α-SMA activation, correlating with greater organization of the actin cytoskeleton. Our results suggest that VICs in a higher pressure environment in vivo , which are more elongated with typical ARs of 1:7, 4–5 have a greater potential for increased cellular activity, proliferation and myofibroblast differentiation.…”

Heart Valve Biomechanics and Underlying Mechanobiology

“…To link valve leaflet tissue deformation to cell deformation (Figs. 1 and 2), our group performed a study on the effects of TVP on AVIC deformation (114). As described previously (217), porcine AV leaflets were fixed under varying pressures and Movat stained histological sections were imaged and analyzed.…”