Person: Schoen, Frederick
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Schoen
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Frederick
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Schoen, Frederick
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Publication Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction(American Society for Clinical Investigation, 2000) Ducharme, Anique; Frantz, Stefan; Aikawa, Masanori; Rabkin, Elena; Lindsey, Merry; Rohde, Luis E.; Schoen, Frederick; Kelly, Ralph A.; Werb, Zena; Libby, Peter; Lee, RichardMatrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI.Publication The pathology and pathobiology of bicuspid aortic valve: State of the art and novel research perspectives†(John Wiley and Sons Inc., 2015) Mathieu, Patrick; Bossé, Yohan; Huggins, Gordon S; Corte, Alessandro Della; Pibarot, Philippe; Michelena, Hector I.; Limongelli, Giuseppe; Boulanger, Marie‐Chloé; Evangelista, Arturo; Bédard, Elisabeth; Citro, Rodolfo; Body, Simon C; Nemer, Mona; Schoen, FrederickAbstract Bicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of long‐term morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. Herein, we review the pathobiology of bicuspid aortic valve with a special emphasis on translational aspects of these basic findings. Important but unresolved problems in the pathology of bicuspid aortic valve and thoracic aortic aneurysm and dissection are discussed, along with the molecular processes involved.Publication Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling(John Wiley and Sons Inc., 2016) Ben‐Zvi, Danny; Savion, Naphtali; Kolodgie, Frank; Simon, Amos; Fisch, Sudeshna; Schäfer, Katrin; Bachner‐Hinenzon, Noa; Cao, Xin; Gertler, Arieh; Solomon, Gili; Kachel, Erez; Raanani, Ehud; Lavee, Jacob; Kotev Emeth, Shlomo; Virmani, Renu; Schoen, Frederick; Schneiderman, JacobBackground: Ascending thoracic aortic aneurysm (ATAA) is driven by angiotensin II (AngII) and contributes to the development of left ventricular (LV) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments AngII‐induced abdominal aortic aneurysms in apolipoprotein E–deficient mice. We hypothesized that locally synthesized leptin mediates AngII‐induced ATAA. Methods and Results: Following demonstration of leptin synthesis in samples of human ATAA associated with different etiologies, we modeled in situ leptin expression in apolipoprotein E–deficient mice by applying exogenous leptin on the surface of the ascending aorta. This treatment resulted in local aortic stiffening and dilation, LV hypertrophy, and thickening of aortic/mitral valve leaflets. Similar results were obtained in an AngII‐infusion ATAA mouse model. To test the dependence of AngII‐induced aortic and LV remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in AngII‐infused mice. Locally applied single low‐dose leptin antagonist moderated AngII‐induced ascending aortic dilation and protected mice from ATAA rupture. Furthermore, LV hypertrophy was attenuated and thickening of aortic valve leaflets was moderated. Last, analysis of human aortic valve stenosis leaflets revealed de novo leptin synthesis, whereas exogenous leptin stimulated proliferation and promoted mineralization of human valve interstitial cells in culture. Conclusions: AngII‐induced ATAA is mediated by locally synthesized leptin. Aortoventricular hemodynamic coupling drives LV hypertrophy and promotes early aortic valve lesions, possibly mediated by valvular in situ leptin synthesis. Clinical implementation of local leptin antagonist therapy may attenuate AngII‐induced ATAA and moderate related LV hypertrophy and pre–aortic valve stenosis lesions. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00449306.Publication A Computational Model of Aging and Calcification in the Aortic Heart Valve(Public Library of Science, 2009) Weinberg, Eli J.; Schoen, Frederick; Mofrad, Mohammad R. K.The aortic heart valve undergoes geometric and mechanical changes over time. The cusps of a normal, healthy valve thicken and become less extensible over time. In the disease calcific aortic stenosis (CAS), calcified nodules progressively stiffen the cusps. The local mechanical changes in the cusps, due to either normal aging or pathological processes, affect overall function of the valve. In this paper, we propose a computational model for the aging aortic valve that connects local changes to overall valve function. We extend a previous model for the healthy valve to describe aging. To model normal/uncomplicated aging, leaflet thickness and extensibility are varied versus age according to experimental data. To model calcification, initial sites are defined and a simple growth law is assumed. The nodules then grow over time, so that the area of calcification increases from one model to the next model representing greater age. Overall valve function is recorded for each individual model to yield a single simulation of valve function over time. This simulation is the first theoretical tool to describe the temporal behavior of aortic valve calcification. The ability to better understand and predict disease progression will aid in design and timing of patient treatments for CAS.Publication Heart Valve Tissue Engineering: Concepts, Approaches, Progress, and Challenges(Kluwer Academic Publishers-Plenum Publishers, 2006) Mendelson, Karen; Schoen, FrederickPotential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function. This review focuses on the engineering of heart valve tissue, a goal which involves a unique combination of biological, engineering, and technological hurdles. We emphasize basic concepts, approaches and methods, progress made, and remaining challenges. To provide a framework for understanding the enabling scientific principles, we first examine the elements and features of normal heart valve functional structure, biomechanics, development, maturation, remodeling, and response to injury. Following a discussion of the fundamental principles of tissue engineering applicable to heart valves, we examine three approaches to achieving the goal of an engineered tissue heart valve: (1) cell seeding of biodegradable synthetic scaffolds, (2) cell seeding of processed tissue scaffolds, and (3) in-vivo repopulation by circulating endogenous cells of implanted substrates without prior in-vitro cell seeding. Lastly, we analyze challenges to the field and suggest future directions for both preclinical and translational (clinical) studies that will be needed to address key regulatory issues for safety and efficacy of the application of tissue engineering and regenerative approaches to heart valves. Although modest progress has been made toward the goal of a clinically useful tissue engineered heart valve, further success and ultimate human benefit will be dependent upon advances in biodegradable polymers and other scaffolds, cellular manipulation, strategies for rebuilding the extracellular matrix, and techniques to characterize and potentially non-invasively assess the speed and quality of tissue healing and remodeling.Publication Hemodynamic Environments from Opposing Sides of Human Aortic Valve Leaflets Evoke Distinct Endothelial Phenotypes In Vitro(Springer US, 2010) Weinberg, Eli J.; Mack, Peter J.; Schoen, Frederick; García-Cardeña, Guillermo; Kaazempur Mofrad, Mohammad R.The regulation of valvular endothelial phenotypes by the hemodynamic environments of the human aortic valve is poorly understood. The nodular lesions of calcific aortic stenosis (CAS) develop predominantly beneath the aortic surface of the valve leaflets in the valvular fibrosa layer. However, the mechanisms of this regional localization remain poorly characterized. In this study, we combine numerical simulation with in vitro experimentation to investigate the hypothesis that the previously documented differences between valve endothelial phenotypes are linked to distinct hemodynamic environments characteristic of these individual anatomical locations. A finite-element model of the aortic valve was created, describing the dynamic motion of the valve cusps and blood in the valve throughout the cardiac cycle. A fluid mesh with high resolution on the fluid boundary was used to allow accurate computation of the wall shear stresses. This model was used to compute two distinct shear stress waveforms, one for the ventricular surface and one for the aortic surface. These waveforms were then applied experimentally to cultured human endothelial cells and the expression of several pathophysiological relevant genes was assessed. Compared to endothelial cells subjected to shear stress waveforms representative of the aortic face, the endothelial cells subjected to the ventricular waveform showed significantly increased expression of the “atheroprotective” transcription factor Kruppel-like factor 2 (KLF2) and the matricellular protein Nephroblastoma overexpressed (NOV), and suppressed expression of chemokine Monocyte-chemotactic protein-1 (MCP-1). Our observations suggest that the difference in shear stress waveforms between the two sides of the aortic valve leaflet may contribute to the documented differential side-specific gene expression, and may be relevant for the development and progression of CAS and the potential role of endothelial mechanotransduction in this disease.