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2017 Cardiovascular Research Day Abstract Book

59 Multilevel Mechanical

59 Multilevel Mechanical Testing of Cardiac Valves Arielle Waller 1 • Daniel Perry 1 • Luke Knudson 1 • RS Baker 2 • David Morales, MD 3 • Farhan Zafar, MD 2 • Daria Narmoneva, PhD 1 1Biomedical Engineering, University of Cincinnati • 2 Division of Pediatric Cardiothoracic Surgery, The Heart Institute, Cincinnati Children's Hospital • 3 Division of Pediatric Cardiothoracic Surgery, The Heart Institute, Cincinnati Children's Hospital Graduate Student The lack of adequate heart valve replacement options represents a major problem in pediatric care, where multiple operations are required to accommodate patient growth. Bioengineered valves may provide a viable alternative to existing strategies. Knowledge of the relationship between macroand micro-biomechanical properties and functional behavior of native or engineered valve tissue is critical for success of bioengineered valves, yet it is still poorly understood. Here, a tubular tricuspid valve bioprosthesis made of small intestinal submucosa-derived extracellular matrix (SIS- ECM) was used as a valve replacement in the in vivo sheep model. Current study developed distinct multilevel testing approaches to determine valve tissue biomechanical properties and quantify the structure-function and behaviors. The following analyses were performed: (i) tissue/organ level uniaxial testing of valve samples; (ii) microanalyses (cellular/subcellular level) of adjacent fullthickness valve sections using atomic force microscopy (AFM) to determine valve mechanical properties. The AFM approach was used in combination with MATLAB-based quantitative 2D histological mapping of valve matrix content (collagen & proteoglycans), for functional analyses of biomechanical behavior. Results demonstrated that valve tensile elastic modulus was higher for the valve annulus vs. the cusp, consistent with proteoglycan rich regions on the distal end of the cusp, and a collagen rich region on the proximal end of the cusp and fibrosa. Compression stiffness from AFM testing demonstrated an increased Young’s modulus for the fibrosa vs. spongiosa, with intermediate values for atrialis (mitral and tricuspid) and ventricularis (aortic and pulmonary), consistent with a collagen-rich fibrosa, proteoglycan-rich spongiosa, and elastin-rich atrialis/ventricularis. In summary, this demonstrates feasibility of this multilevel testing approach in functional assessment of bioengineered valve and its ability to provide necessary mechanical function immediately upon implantation, and to attain structural and biomechanical properties of the native tissue during growth and remodeling. 75

60 CHROME: a Long Non-coding RNA that Regulates Cholesterol Homeostasis Kathryn Moore, PhD 1 1Medicine, New York University Faculty Thousands of long non-coding RNAs (lncRNAs) have been identified in the human genome, many of which are not conserved in lower mammals. The majority of these lncRNAs remain functionally uncharacterized and may have important implications in human physiology and disease. We identified a primate-specific lncRNA, CHROME, which is increased in the plasma and atherosclerotic plaques of individuals with coronary artery disease compared to healthy controls. Using gain- and loss-of-function approaches, we show that CHROME functions as a competing endogenous RNA of microRNAs (miRNAs) that repress cellular cholesterol efflux and plasma high density lipoproteins (HDL) levels, and regulates the concentration and biological functions of these miRNAs. CHROME knockdown in primary hepatocytes increases levels of its miRNA binding partners, thereby reducing expression of their target gene networks, hepatic cholesterol and phospholipid efflux, and the formation of nascent HDL particles. Consistent with these findings, hepatic levels of CHROME are positively correlated with plasma levels of HDL cholesterol in healthy individuals. Collectively, our findings identify CHROME as a central component of the non-coding RNA circuitry controlling cholesterol homeostasis in humans. 76

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