Heart Valve Biomechanics and Underlying Mechanobiology.

Heart valves control unidirectional blood flow within the heart during the cardiac cycle. They have a remarkable ability to withstand the demanding mechanical environment of the heart, achieving lifetime durability by processes involving the ongoing remodeling of the extracellular matrix. The focus of this review is on heart valve functional physiology, with insights into the link between disease-induced alterations in valve geometry, tissue stress, and the subsequent cell mechanobiological responses and tissue remodeling. We begin with an overview of the fundamentals of heart valve physiology and the characteristics and functions of valve interstitial cells (VICs). We then provide an overview of current experimental and computational approaches that connect VIC mechanobiological response to organ- and tissue-level deformations and improve our understanding of the underlying functional physiology of heart valves. We conclude with a summary of future trends and offer an outlook for the future of heart valve mechanobiology, specifically, multiscale modeling approaches, and the potential directions and possible challenges of research development. © 2016 American Physiological Society. Compr Physiol 6:1743-1780, 2016.

[1]  A. Gown,et al.  Characterization of the Early Lesion of ‘Degenerative’ Valvular Aortic Stenosis: Histological and Immunohistochemical Studies , 1994, Circulation.

[2]  Fotis Sotiropoulos,et al.  Toward patient-specific simulations of cardiac valves: state-of-the-art and future directions. , 2013, Journal of biomechanics.

[3]  R A Levine,et al.  Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. , 1997, Circulation.

[4]  Wei Sun,et al.  Computational modeling of cardiac valve function and intervention. , 2014, Annual review of biomedical engineering.

[5]  Kevin Kit Parker,et al.  Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve , 2011, Proceedings of the National Academy of Sciences.

[6]  R. Tubbs,et al.  The anatomy of the aortic root , 2014, Clinical anatomy.

[7]  T. Imamura,et al.  [Bone formation and inflammation]. , 2005, Nihon rinsho. Japanese journal of clinical medicine.

[8]  Frank P T Baaijens,et al.  Improved prediction of the collagen fiber architecture in the aortic heart valve. , 2005, Journal of biomechanical engineering.

[9]  Frederick J Schoen,et al.  Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. , 2004, The Journal of heart valve disease.

[10]  R. P. Cochran,et al.  Fluid–structure interaction models of the mitral valve: function in normal and pathological states , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[11]  J. Zamorano,et al.  Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. , 2007, Journal of the American College of Cardiology.

[12]  Paul Dagum,et al.  Mitral Leaflet Remodeling in Dilated Cardiomyopathy , 2006, Circulation.

[13]  I Vesely,et al.  The role of elastin in aortic valve mechanics. , 1997, Journal of biomechanics.

[14]  M R de Leval,et al.  Innervation of human atrioventricular and arterial valves. , 1996, Circulation.

[15]  J. Bavaria,et al.  Osteopontin–CD44v6 Interaction Mediates Calcium Deposition via Phospho-Akt in Valve Interstitial Cells From Patients With Noncalcified Aortic Valve Sclerosis , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[16]  C. Ruwhof,et al.  Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. , 2000, Cardiovascular research.

[17]  J. González-Rosa,et al.  Building the vertebrate heart - an evolutionary approach to cardiac development. , 2009, The International journal of developmental biology.

[18]  C. Tei,et al.  Size and Motion of the Mitral Valve Annulus in Man: I. A Two‐dimensional Echocardiographic Method and Findings in Normal Subjects , 1981, Circulation.

[19]  B. Helmke,et al.  Hemodynamics and the focal origin of atherosclerosis: a spatial approach to endothelial structure, gene expression, and function. , 2001, Annals of the New York Academy of Sciences.

[20]  S. Haskill,et al.  Signal transduction from the extracellular matrix , 1993, The Journal of cell biology.

[21]  A H Chester,et al.  Mitogenic and secretory responses of human valve interstitial cells to vasoactive agents. , 2000, The Journal of heart valve disease.

[22]  R M Nerem,et al.  Oscillatory shear stress stimulates adhesion molecule expression in cultured human endothelium. , 1998, Circulation research.

[23]  Tomoki Nakamura,et al.  Neural Crest Cells Retain Multipotential Characteristics in the Developing Valves and Label the Cardiac Conduction System , 2006, Circulation research.

[24]  David Liang,et al.  Annular remodeling in chronic ischemic mitral regurgitation: ring selection implications. , 2003, The Annals of thoracic surgery.

[25]  Robert C Gorman,et al.  Preoperative Three-Dimensional Valve Analysis Predicts Recurrent Ischemic Mitral Regurgitation After Mitral Annuloplasty. , 2016, The Annals of thoracic surgery.

[26]  J. Bavaria,et al.  Human myxomatous mitral valve prolapse: Role of bone morphogenetic protein 4 in valvular interstitial cell activation , 2012, Journal of cellular physiology.

[27]  Kristine Wyss,et al.  The elastic properties of valve interstitial cells undergoing pathological differentiation. , 2012, Journal of biomechanics.

[28]  R C Gorman,et al.  Dynamic three-dimensional imaging of the mitral valve and left ventricle by rapid sonomicrometry array localization. , 1996, The Journal of thoracic and cardiovascular surgery.

[29]  N. Sinha,et al.  Effect of Inoue balloon mitral valvotomy on severe pulmonary arterial hypertension in 315 patients with rheumatic mitral stenosis: immediate and long-term results. , 2000, The Journal of heart valve disease.

[30]  Katherine E Yutzey,et al.  Development of heart valve leaflets and supporting apparatus in chicken and mouse embryos , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[31]  B H Smaill,et al.  An assessment of the mechanical properties of leaflets from four second-generation porcine bioprostheses with biaxial testing techniques. , 1989, The Journal of thoracic and cardiovascular surgery.

[32]  T. Guy,et al.  Mitral valve prolapse. , 2012, Annual review of medicine.

[33]  R M Nerem,et al.  Effects of pulsatile flow on cultured vascular endothelial cell morphology. , 1991, Journal of biomechanical engineering.

[34]  Y. Lanir Mechanisms of residual stress in soft tissues. , 2009, Journal of biomechanical engineering.

[35]  A. Yoganathan,et al.  Planar Biaxial Creep and Stress Relaxation of the Mitral Valve Anterior Leaflet , 2006, Annals of Biomedical Engineering.

[36]  G. Booz,et al.  Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. , 1995, Cardiovascular research.

[37]  M. Thubrikar,et al.  The design of the normal aortic valve. , 1981, The American journal of physiology.

[38]  Y. Fung,et al.  Residual Stress in Arteries , 1986 .

[39]  T. Arts,et al.  Stresses in the closed mitral valve: a model study. , 1983, Journal of biomechanics.

[40]  J D Humphrey,et al.  Stress-modulated growth, residual stress, and vascular heterogeneity. , 2001, Journal of biomechanical engineering.

[41]  A P Yoganathan,et al.  Fluid mechanics of aortic stenosis. , 1988, European heart journal.

[42]  Francois Dagenais,et al.  Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation. , 2016, The New England journal of medicine.

[43]  V. Mow,et al.  The mechanical environment of the chondrocyte: a biphasic finite element model of cell-matrix interactions in articular cartilage. , 2000, Journal of biomechanics.

[44]  E. Blackstone,et al.  Durability of combined aortic and mitral valve repair. , 2001, The Annals of thoracic surgery.

[45]  Michael S Sacks,et al.  An inverse modeling approach for stress estimation in mitral valve anterior leaflet valvuloplasty for in-vivo valvular biomaterial assessment. , 2014, Journal of biomechanics.

[46]  Michael S Sacks,et al.  On the biaxial mechanical properties of the layers of the aortic valve leaflet. , 2005, Journal of biomechanical engineering.

[47]  I Vesely,et al.  Micromechanics of the fibrosa and the ventricularis in aortic valve leaflets. , 1992, Journal of biomechanics.

[48]  R. Hinton,et al.  Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves. , 2011, Journal of molecular and cellular cardiology.

[49]  P. Davies,et al.  Mechanisms involved in endothelial responses to hemodynamic forces. , 1997, Atherosclerosis.

[50]  C. Otto,et al.  Is it time for a new paradigm in calcific aortic valve disease? , 2009, JACC. Cardiovascular imaging.

[51]  K. J. Grande-Allen,et al.  The Effects of Mitral Regurgitation Alone Are Sufficient for Leaflet Remodeling , 2008, Circulation.

[52]  D. Wilcken,et al.  Collagen composition of normal and myxomatous human mitral heart valves. , 1984, The Biochemical journal.

[53]  Frederick J Schoen,et al.  Evolution of cell phenotype and extracellular matrix in tissue-engineered heart valves during in-vitro maturation and in-vivo remodeling. , 2002, The Journal of heart valve disease.

[54]  L. Sakai,et al.  Elastic extracellular matrix of the embryonic chick heart: An immunohistological study using laser confocal microscopy , 1994, Developmental dynamics : an official publication of the American Association of Anatomists.

[55]  B L Bass,et al.  Dual structural and functional phenotypes of the porcine aortic valve interstitial population: characteristics of the leaflet myofibroblast. , 1994, The Journal of surgical research.

[56]  M. S. Sacks,et al.  Surface Strains in the Anterior Leaflet of the Functioning Mitral Valve , 2002, Annals of Biomedical Engineering.

[57]  K. J. Grande-Allen,et al.  Calcific Aortic Valve Disease : Not Simply a Degenerative Process A Review and Agenda for Research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group , 2012 .

[58]  S. Young,et al.  Calcific Aortic Valve Stenosis in Old Hypercholesterolemic Mice , 2006, Circulation.

[59]  B. Nebe,et al.  Mechanical Stressing of Integrin Receptors Induces Enhanced Tyrosine Phosphorylation of Cytoskeletally Anchored Proteins* , 1998, The Journal of Biological Chemistry.

[60]  Jun Liao,et al.  Functional collagen fiber architecture of the pulmonary heart valve cusp. , 2009, The Annals of thoracic surgery.

[61]  Alberto Redaelli,et al.  Mitral valve finite-element modelling from ultrasound data: a pilot study for a new approach to understand mitral function and clinical scenarios , 2008, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[62]  A. G. Gittenberger-de Groot,et al.  Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions. , 1998, Circulation research.

[63]  E. Dodou,et al.  The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. , 2005, Developmental biology.

[64]  Deck Jd,et al.  Endothelial cell orientation on aortic valve leaflets , 1986 .

[65]  Frederick J Schoen,et al.  Cardiac valves and valvular pathology: update on function, disease, repair, and replacement. , 2005, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[66]  B. Bellhouse,et al.  Fluid Mechanics of the Mitral Valve , 1969, Nature.

[67]  A Piwnica,et al.  Reconstructive surgery of mitral valve incompetence: ten-year appraisal. , 1980, The Journal of thoracic and cardiovascular surgery.

[68]  M. Daemen,et al.  Structural alterations in heart valves during left ventricular pressure overload in the rat. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[69]  C M Otto,et al.  Clinical practice. Evaluation and management of chronic mitral regurgitation. , 2001, The New England journal of medicine.

[70]  K. Masters,et al.  Regulation of valvular interstitial cell phenotype and function by hyaluronic acid in 2-D and 3-D culture environments. , 2011, Matrix biology : journal of the International Society for Matrix Biology.

[71]  Frederick J. Schoen,et al.  Evolving Concepts of Cardiac Valve Dynamics: The Continuum of Development, Functional Structure, Pathobiology, and Tissue Engineering , 2008, Circulation.

[72]  Jonathan T Butcher,et al.  Aortic valve disease and treatment: the need for naturally engineered solutions. , 2011, Advanced drug delivery reviews.

[73]  Lin Yang,et al.  The relation between collagen fibril kinematics and mechanical properties in the mitral valve anterior leaflet. , 2007, Journal of biomechanical engineering.

[74]  J. Sadoshima,et al.  The cellular and molecular response of cardiac myocytes to mechanical stress. , 1997, Annual review of physiology.

[75]  M. Thubrikar,et al.  Normal aortic valve function in dogs. , 1977, The American journal of cardiology.

[76]  Eli J Weinberg,et al.  Transient, Three-dimensional, Multiscale Simulations of the Human Aortic Valve , 2007, Cardiovascular engineering.

[77]  H. Beppu,et al.  BMP type II receptor regulates positioning of outflow tract and remodeling of atrioventricular cushion during cardiogenesis. , 2009, Developmental biology.

[78]  Guang-Zhong Yang,et al.  Helical and Retrograde Secondary Flow Patterns in the Aortic Arch Studied by Three‐Directional Magnetic Resonance Velocity Mapping , 1993, Circulation.

[79]  A. Yoganathan,et al.  Biaixal Stress–Stretch Behavior of the Mitral Valve Anterior Leaflet at Physiologic Strain Rates , 2006, Annals of Biomedical Engineering.

[80]  Robert M Nerem,et al.  Valvular endothelial cells and the mechanoregulation of valvular pathology , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[81]  Michael S Sacks,et al.  On the presence of affine fibril and fiber kinematics in the mitral valve anterior leaflet. , 2015, Biophysical journal.

[82]  J. Thomas,et al.  Cosgrove-Edwards Annuloplasty System: midterm results. , 2000, The Annals of thoracic surgery.

[83]  J. Seward,et al.  The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. , 1997, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[84]  J. Bavaria,et al.  Analysis of osteopontin levels for the identification of asymptomatic patients with calcific aortic valve disease. , 2012, The Annals of thoracic surgery.

[85]  Craig A. Simmons,et al.  Spatial Heterogeneity of Endothelial Phenotypes Correlates With Side-Specific Vulnerability to Calcification in Normal Porcine Aortic Valves , 2005, Circulation research.

[86]  A. Henney,et al.  Collagen biosynthesis in normal and abnormal human heart valves. , 1982, Cardiovascular research.

[87]  I Vesely,et al.  Biaxial strain analysis of the porcine aortic valve. , 1995, The Annals of thoracic surgery.

[88]  Zhaoming He,et al.  Normal Physiological Conditions Maintain the Biological Characteristics of Porcine Aortic Heart Valves: An Ex Vivo Organ Culture Study , 2005, Annals of Biomedical Engineering.

[89]  Ellen Kuhl,et al.  Evidence of adaptive mitral leaflet growth. , 2012, Journal of the mechanical behavior of biomedical materials.

[90]  L V McIntire,et al.  Rapid Flow‐Induced Responses in Endothelial Cells , 2001, Biotechnology progress.

[91]  G. Christie,et al.  Mechanical properties of porcine pulmonary valve leaflets: how do they differ from aortic leaflets? , 1995, The Annals of thoracic surgery.

[92]  Blevins Tl,et al.  Phenotypic characterization of isolated valvular interstitial cell subpopulations. , 2006 .

[93]  A. Weyman Principles and Practice of Echocardiography , 1994 .

[94]  Tak W. Mak,et al.  Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum , 1998, Nature.

[95]  P. G. Reinhall,et al.  Haemodynamic determinants of the mitral valve closure sound: A finite element study , 2004, Medical and Biological Engineering and Computing.

[96]  R Haaverstad,et al.  Finite element analysis of the mitral apparatus: annulus shape effect and chordal force distribution , 2009, Biomechanics and modeling in mechanobiology.

[97]  G. Andelfinger,et al.  Loss of Gata5 in mice leads to bicuspid aortic valve. , 2011, The Journal of clinical investigation.

[98]  K. Jane Grande-Allen,et al.  Reversible Secretion of Glycosaminoglycans and Proteoglycans by Cyclically Stretched Valvular Cells in 3D Culture , 2008, Annals of Biomedical Engineering.

[99]  Ajit P Yoganathan,et al.  In vitro dynamic strain behavior of the mitral valve posterior leaflet. , 2005, Journal of biomechanical engineering.

[100]  Neelesh Jain,et al.  Endothelium and valvular diseases of the heart , 2003, Microscopy research and technique.

[101]  R. Hinton,et al.  Heart valve structure and function in development and disease. , 2011, Annual review of physiology.

[102]  M. Thubrikar,et al.  The mechanism of opening of the aortic valve. , 1979, The Journal of thoracic and cardiovascular surgery.

[103]  V. Ferrans,et al.  Porcine aortic valve bioprostheses: a morphologic comparison of the effects of fixation pressure. , 1990, Journal of biomedical materials research.

[104]  Santanu Chakraborty,et al.  Wnt signaling in heart valve development and osteogenic gene induction. , 2010, Developmental biology.

[105]  S. Debiasi,et al.  Presence of a smooth muscle system in aortic valve leaflets , 2004, Anatomy and Embryology.

[106]  A. Tedgui,et al.  Cellular mechanics and gene expression in blood vessels. , 2003, Journal of biomechanics.

[107]  Suzanne Sullivan,et al.  Active Adaptation of the Tethered Mitral Valve: Insights Into a Compensatory Mechanism for Functional Mitral Regurgitation , 2009, Circulation.

[108]  M. Thubrikar,et al.  The Elastic Modulus of Canine Aortic Valve Leaflets in Vivo and in Vitro , 1980, Circulation research.

[109]  E. Dejana,et al.  -Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse , 2004 .

[110]  K. J. Grande-Allen,et al.  Differential proteoglycan and hyaluronan distribution in calcified aortic valves. , 2011, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[111]  Michael J. Grusby,et al.  The transcription factor NF-ATc is essential for cardiac valve formation , 1998, Nature.

[112]  Magdi H. Yacoub,et al.  Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. , 2006, Cardiovascular research.

[113]  R. Kist,et al.  Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development. , 2007, Developmental biology.

[114]  Secondary flow velocity patterns in a pulmonary artery model with varying degrees of valvular pulmonic stenosis: pulsatile in vitro studies. , 1990, Journal of biomechanical engineering.

[115]  Brian P. Helmke,et al.  Hemodynamics and the Focal Origin of Atherosclerosis , 2001, Annals of the New York Academy of Sciences.

[116]  C. Otto,et al.  Look more closely at the valve: imaging calcific aortic valve disease. , 2012, Circulation.

[117]  David A. Vorp,et al.  Surface Geometric Analysis of Anatomic Structures Using Biquintic Finite Element Interpolation , 2004, Annals of Biomedical Engineering.

[118]  Lei Ming,et al.  Study of the closing mechanism of natural heart valves , 1986 .

[119]  J. Bavaria,et al.  Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis. , 2013, Cardiovascular research.

[120]  K S Kunzelman,et al.  Altered collagen concentration in mitral valve leaflets: biochemical and finite element analysis. , 1998, The Annals of thoracic surgery.

[121]  M. Thubrikar,et al.  Stress sharing between the sinus and leaflets of canine aortic valve. , 1986, The Annals of thoracic surgery.

[122]  Ray W. Ogden,et al.  Nonlinear Elasticity, Anisotropy, Material Stability and Residual Stresses in Soft Tissue , 2003 .

[123]  Frank McCormick,et al.  Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. , 2004, Genes & development.

[124]  M. Thubrikar,et al.  Stresses of natural versus prosthetic aortic valve leaflets in vivo. , 1980, The Annals of thoracic surgery.

[125]  N Fujita,et al.  Velocity-encoded cine MRI in the evaluation of left ventricular diastolic function: measurement of mitral valve and pulmonary vein flow velocities and flow volume across the mitral valve. , 1993, American heart journal.

[126]  Michael S Sacks,et al.  Design and analysis of tissue engineering scaffolds that mimic soft tissue mechanical anisotropy. , 2006, Biomaterials.

[127]  Q. Wang,et al.  Finite Element Modeling of Mitral Valve Dynamic Deformation Using Patient-Specific Multi-Slices Computed Tomography Scans , 2012, Annals of Biomedical Engineering.

[128]  A P Yoganathan,et al.  Left ventricular blood flow patterns in normal subjects: a quantitative analysis by three-dimensional magnetic resonance velocity mapping. , 1995, Journal of the American College of Cardiology.

[129]  K. J. Grande-Allen,et al.  Functional Coupling of Valvular Interstitial Cells and Collagen Via α2β1 Integrins in the Mitral Leaflet , 2010, Cellular and molecular bioengineering.

[130]  G. Holzapfel,et al.  Transversely isotropic membrane shells with application to mitral valve mechanics. Constitutive modelling and finite element implementation , 2007 .

[131]  Michael S Sacks,et al.  In-situ deformation of the aortic valve interstitial cell nucleus under diastolic loading. , 2007, Journal of biomechanical engineering.

[132]  K S Kunzelman,et al.  Anatomic basis for mitral valve modelling. , 1994, The Journal of heart valve disease.

[133]  Eli J Weinberg,et al.  On the multiscale modeling of heart valve biomechanics in health and disease , 2010, Biomechanics and modeling in mechanobiology.

[134]  David E. Schmidt,et al.  On the biomechanics of heart valve function. , 2009, Journal of biomechanics.

[135]  M. Sacks,et al.  Biaxial mechanical properties of the native and glutaraldehyde-treated aortic valve cusp: Part II--A structural constitutive model. , 2000, Journal of biomechanical engineering.

[136]  Catherine M. Otto,et al.  Evaluation and Management of Chronic Mitral Regurgitation , 2001 .

[137]  Y. Suematsu,et al.  Age-associated aortic stenosis in apolipoprotein E-deficient mice. , 2005, Journal of the American College of Cardiology.

[138]  A. Cucina,et al.  Shear stress induces changes in the morphology and cytoskeleton organisation of arterial endothelial cells. , 1995, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[139]  T. Mihaljevic,et al.  Transcriptional profiling and growth kinetics of endothelium reveals differences between cells derived from porcine aorta versus aortic valve. , 2003, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[140]  Robert M Nerem,et al.  Porcine aortic valve interstitial cells in three-dimensional culture: comparison of phenotype with aortic smooth muscle cells. , 2004, The Journal of heart valve disease.

[141]  K. Grande-Allen,et al.  Phenotypic characterization of isolated valvular interstitial cell subpopulations. , 2006, The Journal of heart valve disease.

[142]  M. Yacoub,et al.  Specific regional and directional contractile responses of aortic cusp tissue. , 2004, The Journal of heart valve disease.

[143]  R. Sainger,et al.  Insights into the use of biomarkers in calcific aortic valve disease. , 2010, The Journal of heart valve disease.

[144]  F. Luscinskas,et al.  Integrins as dynamic regulators of vascular function , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[145]  P. Libby,et al.  Activated Interstitial Myofibroblasts Express Catabolic Enzymes and Mediate Matrix Remodeling in Myxomatous Heart Valves , 2001, Circulation.

[146]  R A Levine,et al.  Dynamics of Mitral Regurgitant Flow and Orifice Area: Physiologic Application of the Proximal Flow Convergence Method: Clinical Data and Experimental Testing , 1994, Circulation.

[147]  钱勤建,et al.  Study of the closing mechanism of natural heart valves , 1986 .

[148]  B. Iung,et al.  Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. , 2005, European heart journal.

[149]  R. Nerem,et al.  Shear stress modulates endothelial cell morphology and F‐actin organization through the regulation of focal adhesion‐associated proteins , 1995, Journal of cellular physiology.

[150]  K. Yutzey,et al.  VEGF and RANKL Regulation of NFATc1 in Heart Valve Development , 2009, Circulation research.

[151]  F. Yin,et al.  Biaxial mechanical behavior of excised porcine mitral valve leaflets. , 1995, The American journal of physiology.

[152]  G. Christie,et al.  Age-dependent changes in the radial stretch of human aortic valve leaflets determined by biaxial testing. , 1995, The Annals of thoracic surgery.

[153]  A. Yoganathan,et al.  Heart valve function: a biomechanical perspective , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[154]  M. Sacks,et al.  A meso-scale layer-specific structural constitutive model of the mitral heart valve leaflets. , 2016, Acta biomaterialia.

[155]  K. Grande-Allen,et al.  Synthesis of glycosaminoglycans in differently loaded regions of collagen gels seeded with valvular interstitial cells. , 2007, Tissue engineering.

[156]  Catherine M. Otto,et al.  Clinical Factors Associated With Calcific Aortic Valve Disease , 1997 .

[157]  R. T. Eppink,et al.  Stress analysis of porcine bioprosthetic heart valves in vivo. , 1982, Journal of biomedical materials research.

[158]  R. Hinton,et al.  Extracellular Matrix Remodeling and Organization in Developing and Diseased Aortic Valves , 2006, Circulation research.

[159]  Francesca N. Delling,et al.  Mitral valve disease—morphology and mechanisms , 2015, Nature Reviews Cardiology.

[160]  Javier Bermejo,et al.  Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[161]  C F Dewey,et al.  Turbulent fluid shear stress induces vascular endothelial cell turnover in vitro. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[162]  Alberto Redaelli,et al.  An annular prosthesis for the treatment of functional mitral regurgitation: finite element model analysis of a dog bone-shaped ring prosthesis. , 2005, The Annals of thoracic surgery.

[163]  Bruce J Aronow,et al.  Shared gene expression profiles in developing heart valves and osteoblast progenitor cells. , 2008, Physiological genomics.

[164]  Willem Flameng,et al.  Recurrence of Mitral Valve Regurgitation After Mitral Valve Repair in Degenerative Valve Disease , 2003, Circulation.

[165]  Ivan Vesely,et al.  Characteristics of compressive strains in porcine aortic valves cusps. , 2002, The Journal of heart valve disease.

[166]  Magdi H. Yacoub,et al.  The cardiac valve interstitial cell. , 2003, The international journal of biochemistry & cell biology.

[167]  Kristi S Anseth,et al.  Statins Block Calcific Nodule Formation of Valvular Interstitial Cells by Inhibiting α-Smooth Muscle Actin Expression , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[168]  Elaine L. Shelton,et al.  Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development. , 2008, Developmental biology.

[169]  S. Wells,et al.  Physiological remodeling of the mitral valve during pregnancy. , 2012, American journal of physiology. Heart and circulatory physiology.

[170]  Robert C Gorman,et al.  The effect of regional ischemia on mitral valve annular saddle shape. , 2004, The Annals of thoracic surgery.

[171]  M. Thubrikar,et al.  The cyclic changes and structure of the base of the aortic valve. , 1980, American heart journal.

[172]  R M Nerem,et al.  Flow-related responses of intracellular inositol phosphate levels in cultured aortic endothelial cells. , 1993, Circulation research.

[173]  Qingbo Xu,et al.  Mechanical stress-initiated signal transductions in vascular smooth muscle cells. , 2000, Cellular signalling.

[174]  Alberto Redaelli,et al.  The Geoform disease-specific annuloplasty system: a finite element study. , 2007, The Annals of thoracic surgery.

[175]  Michael S Sacks,et al.  The effects of cellular contraction on aortic valve leaflet flexural stiffness. , 2006, Journal of biomechanics.

[176]  Rachel M. Buchanan,et al.  On intrinsic stress fiber contractile forces in semilunar heart valve interstitial cells using a continuum mixture model. , 2016, Journal of the mechanical behavior of biomedical materials.

[177]  J. Deck,et al.  Endothelial cell orientation on aortic valve leaflets. , 1986, Cardiovascular research.

[178]  J. Gardin,et al.  Burden of valvular heart diseases: a population-based study , 2006, The Lancet.

[179]  B J Bellhouse,et al.  Fluid mechanics of the aortic valve. , 1969, British heart journal.

[180]  S. Pringle,et al.  Reference values and reproducibility of Doppler echocardiography in the assessment of the tricuspid valve and right ventricular diastolic function in normal subjects. , 1991, The American journal of cardiology.

[181]  S. Oyre,et al.  Three-dimensional visualization of velocity profiles in the human main pulmonary artery with magnetic resonance phase-velocity mapping. , 1994, American heart journal.

[182]  A. McMahon,et al.  Fate of the mammalian cardiac neural crest. , 2000, Development.

[183]  Fotis Sotiropoulos,et al.  Direction and magnitude of blood flow shear stresses on the leaflets of aortic valves: is there a link with valve calcification? , 2010, Journal of biomechanical engineering.

[184]  R. Levine,et al.  Mitral valve prolapse in the general population: the benign nature of echocardiographic features in the Framingham Heart Study. , 2002, Journal of the American College of Cardiology.

[185]  M. Thubrikar,et al.  Comparison of the in vivo and in vitro mechanical properties of aortic valve leaflets. , 1986, The Journal of thoracic and cardiovascular surgery.

[186]  Robert M. Nerem,et al.  Transcriptional Profiles of Valvular and Vascular Endothelial Cells Reveal Phenotypic Differences: Influence of Shear Stress , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[187]  E. Cuppen,et al.  The Wnt/β-catenin pathway regulates cardiac valve formation , 2003, Nature.

[188]  Vladimir Kasyanov,et al.  Comparison of biomechanical and structural properties between human aortic and pulmonary valve. , 2004, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[189]  K. J. Grande-Allen,et al.  Effects of static and cyclic loading in regulating extracellular matrix synthesis by cardiovascular cells. , 2006, Cardiovascular research.

[190]  Ellen Kuhl,et al.  A critical review, an in vivo parameter identification, and the effect of prestrain , 2013 .

[191]  J. Lincoln,et al.  Heart valve development, maintenance, and disease: the role of endothelial cells. , 2012, Current topics in developmental biology.

[192]  E L Yellin,et al.  Mechanisms of mitral valve motion during diastole. , 1981, The American journal of physiology.

[193]  Robert H. Anderson,et al.  Lineage and Morphogenetic Analysis of the Cardiac Valves , 2004, Circulation research.

[194]  Magdi H Yacoub,et al.  Profile and localization of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in human heart valves. , 2002, The Journal of heart valve disease.

[195]  B J Bellhouse,et al.  Instantaneous velocity measurement in major blood vessels: its value in the study of normal and abnormal circulation. , 1969, British heart journal.

[196]  M. Smith,et al.  Echocardiographic follow-up study of the Ross procedure in older versus younger patients. , 2001, American heart journal.

[197]  Hai Lin,et al.  Differences in tissue-remodeling potential of aortic and pulmonary heart valve interstitial cells. , 2007, Tissue engineering.

[198]  R. Hinton,et al.  BMP and FGF regulatory pathways in semilunar valve precursor cells , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[199]  C. Otto,et al.  Aortic Stenosis: Clinical Aspects of Diagnosis and Management, With 10 Illustrative Case Reports From a 25-Year Experience , 2010, Medicine.

[200]  F. Guilak,et al.  Correlation between heart valve interstitial cell stiffness and transvalvular pressure: implications for collagen biosynthesis. , 2006, American journal of physiology. Heart and circulatory physiology.

[201]  N G Smedira,et al.  Durability of mitral valve repair for degenerative disease. , 1998, The Journal of thoracic and cardiovascular surgery.

[202]  M. Sacks,et al.  Pregnancy-Induced Remodeling of Collagen Architecture and Content in the Mitral Valve , 2014, Annals of Biomedical Engineering.

[203]  Magdi H Yacoub,et al.  Novel approaches to cardiac valve repair: from structure to function: Part II. , 2004, Circulation.

[204]  A. Wessels,et al.  Origin and fate of cardiac mesenchyme , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[205]  Joyce Bischoff,et al.  Heart valve development: endothelial cell signaling and differentiation. , 2004, Circulation research.

[206]  T. Binder,et al.  Mitral valve repair with the Colvin-Galloway Future Band. , 2004, The Annals of thoracic surgery.

[207]  Karyn S Kunzelman,et al.  The relationship of normal and abnormal microstructural proliferation to the mitral valve closure sound. , 2005, Journal of biomechanical engineering.

[208]  M Thubrikar,et al.  Mechanism of opening of the natural aortic valve in relation to the design of trileaflet prostheses. , 1977, Surgical forum.

[209]  C. Otto,et al.  Calcific aortic valve disease: outflow obstruction is the end stage of a systemic disease process. , 2009, European heart journal.

[210]  C. Simmons,et al.  Aortic valve: turning over a new leaf(let) in endothelial phenotypic heterogeneity. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[211]  Ajit P Yoganathan,et al.  Effects of papillary muscle position on in-vitro dynamic strain on the porcine mitral valve. , 2003, The Journal of heart valve disease.

[212]  Dorin Comaniciu,et al.  An integrated framework for finite-element modeling of mitral valve biomechanics from medical images: Application to MitralClip intervention planning , 2012, Medical Image Anal..

[213]  D. Mozaffarian,et al.  Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. , 2010, Circulation.

[214]  Frederick J. SchoenT Review Article Cardiac valves and valvular pathology B Update on function, disease, repair, and replacement , 2005 .

[215]  G. Christie,et al.  Biaxial mechanical properties of explanted aortic allograft leaflets. , 1995, The Annals of thoracic surgery.

[216]  R. Hinton,et al.  Scleraxis Is Required for Cell Lineage Differentiation and Extracellular Matrix Remodeling During Murine Heart Valve Formation In Vivo , 2008, Circulation research.

[217]  Bjørn Skallerud,et al.  Nonlinear solid finite element analysis of mitral valves with heterogeneous leaflet layers , 2009 .

[218]  Richard P. Cochran,et al.  Collagen Synthesis Is Upregulated in Mitral Valves Subjected to Altered Stress , 1996, ASAIO journal.

[219]  A H Chester,et al.  Receptor-mediated contraction of aortic valve leaflets. , 2000, The Journal of heart valve disease.

[220]  R. Prescott,et al.  A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. , 2005, The New England journal of medicine.

[221]  Jennifer L West,et al.  Mitral valvular interstitial cell responses to substrate stiffness depend on age and anatomic region. , 2011, Acta biomaterialia.

[222]  W. Roberts,et al.  Frequency by Decades of Unicuspid, Bicuspid, and Tricuspid Aortic Valves in Adults Having Isolated Aortic Valve Replacement for Aortic Stenosis, With or Without Associated Aortic Regurgitation , 2005, Circulation.

[223]  Mechanics of cryopreserved aortic and pulmonary homografts. , 2000, The Journal of heart valve disease.

[224]  K. Yutzey,et al.  Hearts and bones: shared regulatory mechanisms in heart valve, cartilage, tendon, and bone development. , 2006, Developmental biology.

[225]  Y C Fung,et al.  On residual stresses in arteries. , 1986, Journal of biomechanical engineering.

[226]  Ajit P. Yoganathan,et al.  An Ex Vivo Study of the Biological Properties of Porcine Aortic Valves in Response to Circumferential Cyclic Stretch , 2006, Annals of Biomedical Engineering.

[227]  Robert A. Weinberg,et al.  Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. , 2008, Developmental cell.

[228]  C. Otto Calcific aortic valve disease: new concepts. , 2010, Seminars in thoracic and cardiovascular surgery.

[229]  Y. C. Fung,et al.  What are the residual stresses doing in our blood vessels? , 2006, Annals of Biomedical Engineering.

[230]  K. Yutzey,et al.  Heart Valve Development: Regulatory Networks in Development and Disease , 2009, Circulation research.

[231]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2014 update: a report from the American Heart Association. , 2014, Circulation.

[232]  R. Freeman,et al.  Management of asymptomatic valvular aortic stenosis. , 2002, Indian heart journal.

[233]  Christopher A. Durst,et al.  Age-related changes in material behavior of porcine mitral and aortic valves and correlation to matrix composition. , 2010, Tissue engineering. Part A.

[234]  I Vesely,et al.  Comparison of the compressive buckling of porcine aortic valve cusps and bovine pericardium. , 1998, The Journal of heart valve disease.

[235]  A E Becker,et al.  Anatomy of the human atrioventricular junctions revisited , 2000, The Anatomical record.

[236]  S. Achenbach,et al.  Aortic valve stenosis: CT contributions to diagnosis and therapy. , 2010, Journal of cardiovascular computed tomography.

[237]  J. Chambers,et al.  Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. , 2008, The New England journal of medicine.

[238]  A. Yoganathan,et al.  In-vivo dynamic deformation of the mitral valve anterior leaflet. , 2006, The Annals of thoracic surgery.

[239]  C. Simmons,et al.  Cofilin is a marker of myofibroblast differentiation in cells from porcine aortic cardiac valves. , 2008, American journal of physiology. Heart and circulatory physiology.

[240]  A. Tajik,et al.  Human Aortic Valve Calcification Is Associated With an Osteoblast Phenotype , 2003, Circulation.

[241]  Robert M Nerem,et al.  Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. , 2006, Tissue engineering.

[242]  Rosario V. Freeman,et al.  Spectrum of Calcific Aortic Valve Disease: Pathogenesis, Disease Progression, and Treatment Strategies , 2005, Circulation.

[243]  Gabriel Acevedo-Bolton,et al.  First finite element model of the left ventricle with mitral valve: insights into ischemic mitral regurgitation. , 2010, The Annals of thoracic surgery.

[244]  Michael S. Sacks,et al.  A novel bioreactor for the dynamic flexural stimulation of tissue engineered heart valve biomaterials. , 2003 .

[245]  N P Smith,et al.  At the heart of computational modelling , 2012, The Journal of physiology.

[246]  F. Yin,et al.  A constitutive law for mitral valve tissue. , 1998, Journal of biomechanical engineering.

[247]  R. Akdemir,et al.  Color M‐Mode Regurgitant Flow Propagation Velocity: A New Echocardiographic Method for Grading of Mitral Regurgitation , 2004, Echocardiography.

[248]  David B. Smith,et al.  The aortic valve microstructure: effects of transvalvular pressure. , 1998, Journal of biomedical materials research.

[249]  M. Thubrikar,et al.  Design and dynamic variations of aortic valve leaflets in vivo. , 1979, Surgical forum.

[250]  W. S. Ring,et al.  Finite element analysis of the mitral valve. , 1993, The Journal of heart valve disease.

[251]  M. Sacks,et al.  Effects of mechanical fatigue on the bending properties of the porcine bioprosthetic heart valve. , 1999, ASAIO journal.

[252]  M. Sacks,et al.  Biaxial mechanical properties of the natural and glutaraldehyde treated aortic valve cusp--Part I: Experimental results. , 2000, Journal of biomechanical engineering.

[253]  K. J. Grande-Allen,et al.  Age-related changes in collagen synthesis and turnover in porcine heart valves. , 2007, The Journal of heart valve disease.

[254]  F J Schoen,et al.  Aortic valve structure-function correlations: role of elastic fibers no longer a stretch of the imagination. , 1997, The Journal of heart valve disease.

[255]  A. Yoganathan,et al.  Axial flow velocity patterns in a normal human pulmonary artery model: pulsatile in vitro studies. , 1990, Journal of biomechanics.

[256]  Robert M Nerem,et al.  Unique Morphology and Focal Adhesion Development of Valvular Endothelial Cells in Static and Fluid Flow Environments , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[257]  D. Towler Molecular and cellular aspects of calcific aortic valve disease. , 2013, Circulation research.

[258]  B. Griffin,et al.  Glycosaminoglycan profiles of myxomatous mitral leaflets and chordae parallel the severity of mechanical alterations. , 2003, Journal of the American College of Cardiology.

[259]  C. Schmidtke,et al.  Echocardiographic and hemodynamic characteristics of reconstructed bicuspid aortic valves at rest and exercise , 2005, Zeitschrift für Kardiologie.

[260]  Alberto Redaelli,et al.  Mitral Valve Patient-Specific Finite Element Modeling from Cardiac MRI: Application to an Annuloplasty Procedure , 2011 .

[261]  Y C Fung,et al.  Relationship between hypertension, hypertrophy, and opening angle of zero-stress state of arteries following aortic constriction. , 1989, Journal of biomechanical engineering.

[262]  P. Davies,et al.  Mechanical stress mechanisms and the cell. An endothelial paradigm. , 1993, Circulation research.

[263]  Johnson Cm,et al.  Porcine cardiac valvular endothelial cells in culture. A relative deficiency of fibronectin synthesis in vitro. , 1983 .

[264]  Frederick J Schoen,et al.  Clinical pulmonary autograft valves: pathologic evidence of adaptive remodeling in the aortic site. , 2004, The Journal of thoracic and cardiovascular surgery.

[265]  G. Gerosa,et al.  The Pulmonary Valve: Is It Mechanically Suitable for Use as an Aortic Valve Replacement? , 1994, ASAIO journal.

[266]  F. Schoen,et al.  Human Semilunar Cardiac Valve Remodeling by Activated Cells From Fetus to Adult: Implications for Postnatal Adaptation, Pathology, and Tissue Engineering , 2006, Circulation.

[267]  B Skallerud,et al.  Modeling active muscle contraction in mitral valve leaflets during systole: a first approach , 2011, Biomechanics and modeling in mechanobiology.

[268]  D. C. Miller,et al.  Significant Changes in Mitral Valve Leaflet Matrix Composition and Turnover With Tachycardia-Induced Cardiomyopathy , 2009, Circulation.

[269]  K. Grande-Allen,et al.  Valve proteoglycan content and glycosaminoglycan fine structure are unique to microstructure, mechanical load and age: Relevance to an age-specific tissue-engineered heart valve. , 2008, Acta biomaterialia.

[270]  J. Hoffman,et al.  The incidence of congenital heart disease. , 2002, Journal of the American College of Cardiology.

[271]  K. Yutzey,et al.  BMP and FGF regulatory pathways control cell lineage diversification of heart valve precursor cells. , 2006, Developmental biology.

[272]  E. Blackstone,et al.  Recurrent mitral regurgitation after annuloplasty for functional ischemic mitral regurgitation , 2005 .

[273]  Jacques M Huyghe,et al.  Computational analyses of mechanically induced collagen fiber remodeling in the aortic heart valve. , 2003, Journal of biomechanical engineering.

[274]  M. Thubrikar,et al.  Patterns of calcific deposits in operatively excised stenotic or purely regurgitant aortic valves and their relation to mechanical stress. , 1986, The American journal of cardiology.

[275]  Paul Dagum,et al.  Tachycardia-induced cardiomyopathy in the ovine heart: mitral annular dynamic three-dimensional geometry. , 2003, The Journal of thoracic and cardiovascular surgery.

[276]  M. Thubrikar,et al.  Analysis of the design and dynamics of aortic bioprostheses in vivo. , 1982, The Journal of thoracic and cardiovascular surgery.

[277]  Christopher A. Carruthers,et al.  Quantification and simulation of layer-specific mitral valve interstitial cells deformation under physiological loading. , 2015, Journal of theoretical biology.

[278]  Karyn S Kunzelman,et al.  A coupled fluid-structure finite element model of the aortic valve and root. , 2003, The Journal of heart valve disease.

[279]  D. Stewart,et al.  Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase. , 2000, Circulation.

[280]  S Michael Gharacholou,et al.  Aortic valve sclerosis and clinical outcomes: moving toward a definition. , 2011, The American journal of medicine.

[281]  A. Gotlieb,et al.  Cell biology of valvular interstitial cells. , 1996, The Canadian journal of cardiology.

[282]  A. Carpentier,et al.  Cardiac valve surgery--the "French correction". , 1983, The Journal of thoracic and cardiovascular surgery.

[283]  M. Simionescu,et al.  Interstitial Cells of the Heart Valves Possess Characteristics Similar to Smooth Muscle Cells , 1986, Circulation research.

[284]  Bonnie K. Lind,et al.  Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. , 1997, Journal of the American College of Cardiology.

[285]  C. Yeh,et al.  Cardiac transgenic matrix metalloproteinase-2 expression induces myxomatous valve degeneration: a potential model of mitral valve prolapse disease. , 2009, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[286]  Raymond B. Runyan,et al.  Cell biology of cardiac cushion development. , 2005, International review of cytology.

[287]  R. Levine,et al.  Developmental basis of adult cardiovascular diseases , 2010, Annals of the New York Academy of Sciences.

[288]  F. Veglia,et al.  Do statins improve outcomes and delay the progression of non-rheumatic calcific aortic stenosis? , 2011, Heart.

[289]  P. Thompson,et al.  Midterm outcomes using the physio ring in mitral valve reconstruction: experience in 492 patients. , 2005, The Annals of thoracic surgery.

[290]  R. Schwartz,et al.  Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning , 2005, Development.

[291]  V. Ferrans,et al.  Optical methods for the nondestructive evaluation of collagen morphology in bioprosthetic heart valves. , 1986, Journal of biomedical materials research.

[292]  Emile R. Mohler,et al.  Bone Formation and Inflammation in Cardiac Valves , 2001, Circulation.

[293]  Y C Fung,et al.  Changes of zero-stress state of rat pulmonary arteries in hypoxic hypertension. , 1991, Journal of applied physiology.

[294]  Michael S Sacks,et al.  Interlayer micromechanics of the aortic heart valve leaflet , 2013, Biomechanics and Modeling in Mechanobiology.

[295]  Magdi H Yacoub,et al.  Novel approaches to cardiac valve repair: from structure to function: Part I. , 2004, Circulation.

[296]  Interpretation of aortic root angiography in dogs and in humans. , 1982, Cardiovascular research.

[297]  A. Yoganathan,et al.  Axial flow velocity patterns in a pulmonary artery model with varying degrees of valvular pulmonic stenosis: pulsatile in vitro studies. , 1990, Journal of biomechanics.

[298]  Michael S Sacks,et al.  Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast. , 2007, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[299]  Ajit P Yoganathan,et al.  Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. , 2009, American journal of physiology. Heart and circulatory physiology.

[300]  Robert A Levine,et al.  Mitral Leaflet Adaptation to Ventricular Remodeling: Occurrence and Adequacy in Patients With Functional Mitral Regurgitation , 2008, Circulation.

[301]  W. Pu,et al.  Genetic fate mapping demonstrates contribution of epicardium-derived cells to the annulus fibrosis of the mammalian heart. , 2010, Developmental biology.

[302]  Suzanne Sullivan,et al.  Mitral Leaflet Adaptation to Ventricular Remodeling: Prospective Changes in a Model of Ischemic Mitral Regurgitation , 2009, Circulation.

[303]  Craig A Simmons,et al.  Cell–Matrix Interactions in the Pathobiology of Calcific Aortic Valve Disease: Critical Roles for Matricellular, Matricrine, and Matrix Mechanics Cues , 2011, Circulation research.