Introduction: Previous studies suggest that crimping causes permanent structural damage to the leaflet tissues of transcatheter heart valves (THV). However, this damage is not yet known to facilitate calcification process. Hypothesis: Our hypothesis is to test whether crimp-induced damage promotes valvular calcification. Methods: Self-expandable THVs with Glutaraldehye-fixed bovine pericardial leaflets was used. The valves were divided into two groups; crimped and uncrimped, and each group was split into two to be exposed either to a calcifying solution or to a control -normal phosphate buffered saline- solution. For the crimped group, the valves were carefully crimped with a standard crimper at 14Fr and held crimped for 20 minutes. The calcifying solution contains ionic concentrations corresponding to normal human plasma. All groups were maintained at pH 7.5, 37°C, on an orbital shaker at 400 rpm for 7 weeks. At the end, each tissue sample was individually embedded, sectioned and stained for calcium stain (Von Kossa), Verhoff’s Van Geison (VVG) stain for elastin and collagen stain (trichrome III). Results: Fig 1A show the normal bovine pericardium with arranged collagen layers in blue whereas intermittent striations are seen across the collagen fibers in the crimped group (Fig 1B). VVG stains show similar results with continuous elastin fibers (black) in the uncrimped group (Fig 1C) versus fragmented elastin fibers in the crimped group (Fig 1D). Of most significance are the results from the von kossa stains where crimped samples in saline show minimal hydroxyapatite deposition (Fig 1E) while crimped samples in calcifying buffer show brown deposits of hydroxyapatite along the crimped regions (Fig 1F). No hydroxyapatite deposition was observed in uncrimped group exposed to calcifying solution. Conclusions: Our results indicate that severe structural changes due to crimping are associated with greater levels of calcium deposition along the crimped sites.

The extracellular matrix of the atrioventricular (AV) valves' leaflets has a key role in the ability of these valves to properly remodel in response to constantly varying physiological loads. While the loading on mitral and tricuspid valves is significantly different, no information is available on how collagen fibers change their orientation in response to these loads. This study delineates the effect of physiological loading on AV valves' leaflets microstructures using Second Harmonic Generation (SHG) microscopy. Fresh natural porcine tricuspid and mitral valves' leaflets (n = 12/valve type) were cut and prepared for the experiments. Histology and immunohistochemistry were performed to compare the microstructural differences between the valves. The specimens were imaged live during the relaxed, loading, and unloading phases using SHG microscopy. The images were analyzed with Fourier decomposition to mathematically seek changes in collagen fiber orientation. Despite the similarities in both AV valves as seen in the histology and immunohistochemistry data, the microstructural arrangement, especially the collagen fiber distribution and orientation in the stress-free condition, were found to be different. Uniaxial loading was dependent on the arrangement of the fibers in their relaxed mode, which led the fibers to reorient in-line with the load throughout the depth of the mitral leaflet but only to reorient in-line with the load in deeper layers of the tricuspid leaflet. Biaxial loading arranged the fibers in between the two principal axes of the stresses independently from their relaxed states. Unlike previous findings, this study concludes that the AV valves' three-dimensional extracellular fiber arrangement is significantly different in their stress-free and uniaxially loaded states; however, fiber rearrangement in response to the biaxial loading remains similar.

There are an estimated 14,000 randomized trials published in chronic kidney disease. The most frequently reported outcomes are biochemical endpoints, rather than clinical and patient-reported outcomes including cardiovascular disease, mortality, and quality of life. While many trials have focused on optimizing kidney health, the heterogeneity and uncertain relevance of outcomes reported across trials may limit their policy and practice impact. The international Standardized Outcomes in Nephrology (SONG) Initiative was formed to identify core outcomes that are critically important to patients and health professionals, to be reported consistently across trials. We convened a SONG Implementation Workshop to discuss the implementation of core outcomes. Eighty-two patients/caregivers and health professionals participated in plenary and breakout discussions. In this report, we summarize the findings of the workshop in two main themes: socializing the concept of core outcomes, and demonstrating feasibility and usability. We outline implementation strategies and pathways to be established through partnership with stakeholders, which may bolster acceptance and reporting of core outcomes in trials, and encourage their use by end-users such as guideline producers and policymakers to help improve patient-important outcomes.