Browsing by Author "Stephens, Elizabeth H."

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    Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction
    (Springer, 2015) Stephens, Elizabeth H.; Fahrenholtz, Monica M.; Connell, Patrick S.; Timek, Tomasz A.; Daughters, George T.; Kuo, Joyce J.; Patton, Aaron M.; Ingels, Neil B. Jr.; Miller, D. Craig; Grande-Allen, K. Jane; Bioengineering
    Regional heterogeneity in mitral annular contraction, which is generally ascribed to the fibrous vs. muscular annular composition, ensures proper leaflet motion and timing of coaptation. It is unknown whether the fibroblast-like cells in the annulus modulate this heterogeneity, even though valvular interstitial cells (VICs) can be mechanically “activated.” Fourteen sheep underwent implantation of radiopaque markers around the mitral annulus defining four segments: septal (SEPT), lateral (LAT), and anterior (ANT-C) and posterior (POST-C) commissures. Segmental annular contraction was calculated using biplane videofluoroscopy. Immunohistochemistry of annular cross sections assessed regional matrix content, matrix turnover, and cell phenotype. Micropipette aspiration measured the effective modulus of the leaflets adjacent to the myocardial border. Whereas SEPT contained more collagen I and III, LAT demonstrated more collagen and elastin turnover as shown by greater decorin, lysyl oxidase, and matrix metalloprotease (MMP)-13 and smooth muscle alpha-actin (SMaA). This greater matrix turnover paralleled greater annular contraction in LAT vs. SEPT (22.5 vs. 4.1%). Similarly, POST-C had more SMaA and MMP13 than ANT-C, consistent with greater annular contraction in POST-C (18.8 vs. 11.1%). Interestingly, POST-C had the greatest effective modulus, significantly higher than LAT. These data suggest that matrix turnover by activated VICs relates to annular motion heterogeneity, maintains steady-state mechanical properties in the annulus, and could be a therapeutic target when annular motion is impaired. Conversely, alterations in this heterogeneous annular contraction, whether through disease or secondary to ring annuloplasty, could disrupt this normal pattern of cell-mediated matrix remodeling and further adversely impact mitral valve function.
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    Heterogeneity of Mitral Leaflet Matrix Composition and Turnover Correlates with Regional Leaflet Strain
    (Springer, 2015) Stephens, Elizabeth H.; Connell, Patrick S.; Fahrenholtz, Monica M.; Timek, Tomasz A.; Daughters, George T.; Kuo, Joyce J.; Patton, Aaron M.; Ingels, Neil B.; Miller, D. Craig; Grande-Allen, K. Jane; Bioengineering
    To determine how extracellular matrix and contractile valvular cells contribute to the heterogeneous motion and strain across the mitral valve (MV) during the cardiac cycle, regional MV material properties, matrix composition, matrix turnover, and cell phenotype were related to regional leaflet strain. Radiopaque markers were implanted into 14 sheep to delineate the septal (SEPT), lateral (LAT), and anterior and posterior commissural leaflets (ANT-C, POST-C). Videofluoroscopy imaging was used to calculate radial and circumferential strains. Mechanical properties were assessed using uniaxial tensile testing and micropipette aspiration. Matrix composition and cell phenotypes were immunohistochemically evaluated within each leaflet region [basal leaflet (BL), mid-leaflet (ML), and free edge]. SEPT-BL segments were stiffer and stronger than other valve tissues, while LAT segments demonstrated more extensibility and strain. Collagens I and III in SEPT were greater than in LAT, although LAT showed greater collagen turnover [matrix metalloprotease (MMP)-13, lysyl oxidase] and cell activation [smooth muscle alpha-actin (SMaA), and non-muscle myosin (NMM)]. MMP13, NMM, and SMaA were strongly correlated with each other, as well as with radial and circumferential strains in both SEPT and LAT. SMaA and MMP13 in POST-C ML was greater than ANT-C, corresponding to greater radial strains in POST-C. This work directly relates leaflet strain, material properties, and matrix turnover, and suggests a role for myofibroblasts in the heterogeneity of leaflet composition and strain. New approaches to MV repair techniques and ring design should preserve this normal coupling between leaflet composition and motion.
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    Hyaluronan turnover and hypoxic brown adipocytic differentiation are co-localized with ossification in calcified human aortic valves
    (Elsevier, 2012) Stephens, Elizabeth H.; Saltarrelli, Jerome G. Jr.; Balaoing, Liezl R.; Baggett, L. Scott; Nandi, Indrajit; Anderson, Kristin M.; Morrisett, Joel D.; Reardon, Michael J.; Simpson, Melanie A.; Weigel, Paul H.; Olmsted-Davis, Elizabeth A.; Davis, Alan R.; Grande-Allen, K. Jane; Bioengineering; Statistics
    The calcification process in aortic stenosis has garnered considerable interest but only limited investigation into selected signaling pathways. This study investigated mechanisms related to hypoxia, hyaluronan homeostasis, brown adipocytic differentiation, and ossification within calcified valves. Surgically explanted calcified aortic valves (nﾠ=ﾠ14) were immunostained for markers relevant to these mechanisms and evaluated in the center (NodCtr) and edge (NodEdge) of the calcified nodule (NodCtr), tissue directly surrounding nodule (NodSurr); center and tissue surrounding small ﾓprenodulesﾔ (PreNod, PreNodSurr); and normal fibrosa layer (CollFibr). Pearson correlations were determined between staining intensities of markers within regions. Ossification markers primarily localized to NodCtr and NodEdge, along with markers related to hyaluronan turnover and hypoxia. Markers of brown adipocytic differentiation were frequently co-localized with markers of hypoxia. In NodCtr and NodSurr, brown fat and ossification markers correlated with hyaluronidase-1, whereas these markers, as well as hypoxia, correlated with hyaluronan synthases in NodEdge. The protein product of tumor necrosis factor-? stimulated gene-6 strongly correlated with ossification markers and hyaluronidase in the regions surrounding the nodules (NodSurr, PreNodSurr). In conclusion, this study suggests roles for hyaluronan homeostasis and the promotion of hypoxia by cells demonstrating brown fat markers in calcific aortic valve disease.