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[Figure: see text].

Objective: The activation of valve interstitial cells (VICs) toward an osteogenic phenotype characterizes aortic valve sclerosis, the early asymptomatic phase of calcific aortic valve disease. Osteopontin is a phosphorylated acidic glycoprotein that accumulates within the aortic leaflets and labels VIC activation even in noncalcified asymptomatic patients. Despite this, osteopontin protects VICs against in vitro calcification. Here, we hypothesize that the specific interaction of osteopontin with CD44v6, and the related intracellular pathway, prevents calcium deposition in human-derived VICs from patients with aortic valve sclerosis., Approach and Results: On informed consent, 23 patients and 4 controls were enrolled through the cardiac surgery and heart transplant programs. Human aortic valves and VICs were tested for osteogenic transdifferentiation, ex vivo and in vitro. Osteopontin-CD44 interaction was analyzed using proximity ligation assay and the signaling pathways investigated. A murine model based on angiotensin II infusion was used to mimic early pathological remodeling of the aortic valves. We report osteopontin-CD44 functional interaction as a hallmark of early stages of calcific aortic valve disease. We demonstrated that osteopontin-CD44 interaction mediates calcium deposition via phospho-Akt in VICs from patients with noncalcified aortic valve sclerosis. Finally, microdissection analysis of murine valves shows increased cusp thickness in angiotensin II-treated mice versus saline infused along with colocalization of osteopontin and CD44 as seen in human lesions., Conclusions: Here, we unveil a specific protein-protein association and intracellular signaling mechanisms of osteopontin. Understanding the molecular mechanisms of early VIC activation and calcium deposition in asymptomatic stage of calcific aortic valve disease could open new prospective for diagnosis and therapeutic intervention., (© 2014 American Heart Association, Inc.)

Epidural steroid injections are commonly used in the treatment of low back pain and radiculopathy based on their antiinflammatory and analgesic benefits. However, steroids are known to affect collagen synthesis, material strength, and tissue healing. The purpose of this study was to assess the effects of serial epidural steroid injections on the material properties of the lumbar dura mater. Serial epidural steroid injections of saline or methylprednisolone at 2-week intervals were performed in three paired groups of canines; a separate noninjected group was used as controls. Postmortem, dural sample testing to failure and histologic analysis was performed. Mechanical failure testing revealed no clinically significant change in the transverse dorsal dura tensile strength between all saline-injected, steroid-injected, or noninjected controls. Histologic analysis demonstrated no overt disruption of collagen matrix organization; however, electron microscopy demonstrated a significant decrease in the number of intracytoplasmic mitochondria of dural fibroblasts in steroid-injected animals, suggesting a metabolic inhibitory effect within steroid-injected dura mater. In the clinical time frame of this study, serial epidural steroid injections appeared to produce no significant material or matrix changes in the lumbar dura.

The mechanisms underlying the failure of porcine bioprosthetic aortic heart valves are not well understood. One possible explanation is that delaminations of the layered leaflet structure occur through flexion, leading to calcification and further delaminations, and finally resulting in valve failure. We investigated the changes in flexural rigidity of the belly of aortic valve cusps subjected to accelerated durability testing. We used three-point bending wherein a load was applied to the center of each specimen by a thin stainless steel bar calibrated to a known load-displacement relationship. Ten circumferential and 15 radial specimens from valves fatigued to 0, 50, 100, and 200 million cycles were flexed both with and against the curvature of the cusp. Linear beam theory was applied as a means to compare the relative bending stiffness between groups. Although specimens aligned to the circumferential direction were stiffer when bent against the cuspal curvature, the radial oriented specimens exhibited no bending directional dependence. Both the radial and circumferential specimens experienced a significant decrease in the bending stiffness with an increased number of accelerated test cycles. Overall, our results suggest that it is the fibrosa that experiences the greatest loss of stiffness with mechanically induced fatigue damage.

Small-angle light scattering (SALS) was used to quantify the collagen fiber architecture of 12 bovine pericardium (BP) specimens overlying the right and left anterior surfaces of the heart. The collagen fiber architecture was described in terms of preferred collagen fiber directions, volume fractions (Vf), and degree of orientation. To explore the relationship between BP collagen architecture and mechanical anisotropy, biaxial mechanical tests were performed on two specimens chosen for their extremes of collagen fiber architecture. About 38% of the SALS test locations showed the occurrence of two distinct collagen fiber populations, with the primary population Vf typically 90%. Structurally, the left anterior specimens appeared to be the most homogeneous, with an overall preferred direction close to the circumferential direction of the heart. The right side specimens were inconsistent, with a broad range of fiber orientations. The direction of greatest stiffness was consistent with the underlying collagen fiber architecture. Overall, these results suggest that 1) the mechanical behavior of BP is quantitatively consistent with its collagen fiber architecture; 2) the variability of BP mechanical anisotropy is caused by variations in collagen fiber preferred directions; and 3) the left anterior side of the bovine pericardial sac might be a good material selection site for bioprosthesis fabrication.