Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease.

Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.

[1]  L. Marshall,et al.  Calcific aortic stenosis , 2016, Nature Reviews Disease Primers.

[2]  Magdi H Yacoub,et al.  Expression of smooth muscle cell markers and co-activators in calcified aortic valves. , 2015, European heart journal.

[3]  Thoralf M Sundt,et al.  2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. , 2014, Circulation.

[4]  A. Vaidya,et al.  Interactions between adrenal-regulatory and calcium-regulatory hormones in human health , 2014, Current opinion in endocrinology, diabetes, and obesity.

[5]  Annette Lee,et al.  Bone morphogenetic protein-focused strategies to induce cytotoxicity in lung cancer cells. , 2014, Anticancer research.

[6]  K. Yutzey,et al.  Conserved transcriptional regulatory mechanisms in aortic valve development and disease. , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[7]  Y. Bossé,et al.  Elevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease: implications for valve mineralization. , 2014, Journal of the American College of Cardiology.

[8]  M. Sandhu,et al.  Lipoprotein(a) levels, genotype and incident aortic stenosis: a prospective Mendelian randomization study and replication in a case-control cohort , 2013 .

[9]  B. Nordestgaard,et al.  Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. , 2013, Journal of the American College of Cardiology.

[10]  J. Stone,et al.  Cellular and Molecular Pathobiology of Cardiovascular Disease , 2014 .

[11]  F. Schoen,et al.  Calcific and Degenerative Heart Valve Disease , 2014 .

[12]  C. Giachelli,et al.  An Inducible, Ligand-Independent Receptor Activator of NF-κB Gene to Control Osteoclast Differentiation from Monocytic Precursors , 2013, PloS one.

[13]  M. Puato,et al.  Aortic valve calcification in chronic kidney disease. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[14]  S. Colucci,et al.  The Role of TNF-α and TNF Superfamily Members in the Pathogenesis of Calcific Aortic Valvular Disease , 2013, TheScientificWorldJournal.

[15]  R. Bonow,et al.  Transcatheter aortic valve replacement: current status and future directions. , 2013, Seminars in thoracic and cardiovascular surgery.

[16]  P. Libby,et al.  Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. , 2013, American heart journal.

[17]  B. Carabello.  Introduction to aortic stenosis. , 2013, Circulation research.

[18]  Craig A Simmons,et al.  Hemodynamic and cellular response feedback in calcific aortic valve disease. , 2013, Circulation research.

[19]  R. Bonow,et al.  Current management of calcific aortic stenosis. , 2013, Circulation research.

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

[21]  R. Weiss,et al.  Fibrocalcific aortic valve disease: opportunity to understand disease mechanisms using mouse models. , 2013, Circulation research.

[22]  K. Yutzey,et al.  Developmental Pathways in CAVD , 2013 .

[23]  Jeffrey A. Jones,et al.  Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease. , 2013, The Journal of thoracic and cardiovascular surgery.

[24]  Elena Aikawa,et al.  Macrophage-Derived Matrix Vesicles: An Alternative Novel Mechanism for Microcalcification in Atherosclerotic Plaques , 2013, Circulation research.

[25]  Joshua D. Hutcheson,et al.  MicroRNA in Cardiovascular Calcification: Focus on Targets and Extracellular Vesicle Delivery Mechanisms , 2013, Circulation research.

[26]  C. Giachelli,et al.  Vascular Calcification: An Update on Mechanisms and Challenges in Treatment , 2013, Calcified Tissue International.

[27]  Kathleen F. Kerr,et al.  Genetic associations with valvular calcification and aortic stenosis. , 2013, The New England journal of medicine.

[28]  Y. Bossé,et al.  High Expression of the Pi-Transporter SLC20A1/Pit1 in Calcific Aortic Valve Disease Promotes Mineralization through Regulation of Akt-1 , 2013, PloS one.

[29]  S. Verma,et al.  miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis. , 2012, The Journal of thoracic and cardiovascular surgery.

[30]  K. Yutzey,et al.  Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease. , 2012, Journal of molecular and cellular cardiology.

[31]  C. Rapezzi,et al.  The elusive link between aortic wall histology and echocardiographic anatomy in bicuspid aortic valve: implications for prophylactic surgery. , 2012, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[32]  E. V. van Beek,et al.  Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients With Aortic Stenosis , 2012, Circulation.

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

[34]  R. Sacco,et al.  Aortic valve calcification in mild primary hyperparathyroidism. , 2011, The Journal of clinical endocrinology and metabolism.

[35]  S. Aakhus,et al.  Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis , 2011, Journal of Internal Medicine.

[36]  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 .

[37]  S. Leal,et al.  Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1 , 2011, Nature Genetics.

[38]  M. Henein,et al.  Challenges in the management of severe asymptomatic aortic stenosis. , 2011, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[39]  C. Shanahan,et al.  Arterial Calcification in Chronic Kidney Disease: Key Roles for Calcium and Phosphate , 2011, Circulation research.

[40]  D. Towler,et al.  The regulation of valvular and vascular sclerosis by osteogenic morphogens. , 2011, Circulation research.

[41]  Craig A. Simmons,et al.  Animal Models of Calcific Aortic Valve Disease , 2011, International journal of inflammation.

[42]  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.

[43]  R. Nerem,et al.  Discovery of Side- and Shear-Dependent miRNAs and mRNAs in Human Aortic Valvular Endothelial Cells , 2011 .

[44]  T. Brady,et al.  Imaging of the aortic valve using fluorodeoxyglucose positron emission tomography increased valvular fluorodeoxyglucose uptake in aortic stenosis. , 2011, Journal of the American College of Cardiology.

[45]  R. Nerem,et al.  Preferential Activation of SMAD1/5/8 on the Fibrosa Endothelium in Calcified Human Aortic Valves - Association with Low BMP Antagonists and SMAD6 , 2011, PloS one.

[46]  R. Weiss,et al.  Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms , 2011, Circulation research.

[47]  E. Aikawa,et al.  Molecular Imaging Insights Into Early Inflammatory Stages of Arterial and Aortic Valve Calcification , 2011, Circulation research.

[48]  R. Levine,et al.  Mitral Valve Endothelial Cells With Osteogenic Differentiation Potential , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[49]  J. Horowitz,et al.  Pathogenesis of aortic stenosis: not just a matter of wear and tear. , 2011, American journal of cardiovascular disease.

[50]  R. Brooks,et al.  Evidence for Active Regulation of Pro-Osteogenic Signaling in Advanced Aortic Valve Disease , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[51]  A. Redaelli,et al.  Biomechanical implications of the congenital bicuspid aortic valve: a finite element study of aortic root function from in vivo data. , 2010, The Journal of thoracic and cardiovascular surgery.

[52]  Luis Luna-Zurita,et al.  Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation. , 2010, The Journal of clinical investigation.

[53]  C. Salaün,et al.  Identification of a Novel Transport-independent Function of PiT1/SLC20A1 in the Regulation of TNF-induced Apoptosis* , 2010, The Journal of Biological Chemistry.

[54]  J. Mayer,et al.  Intravital molecular imaging of small-diameter tissue-engineered vascular grafts in mice: a feasibility study. , 2010, Tissue engineering. Part C, Methods.

[55]  Oscar L. Sierra,et al.  Activation of Vascular Smooth Muscle Parathyroid Hormone Receptor Inhibits Wnt/&bgr;-Catenin Signaling and Aortic Fibrosis in Diabetic Arteriosclerosis , 2010, Circulation research.

[56]  R. Weissleder,et al.  Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation , 2010, European heart journal.

[57]  Ajit P Yoganathan,et al.  Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. , 2010, The American journal of pathology.

[58]  D. Srivastava,et al.  Altered microRNAs in bicuspid aortic valve: a comparison between stenotic and insufficient valves. , 2010, The Journal of heart valve disease.

[59]  R. Kronmal,et al.  Incidence and progression of aortic valve calcium in the Multi-ethnic Study of Atherosclerosis (MESA). , 2010, The American journal of cardiology.

[60]  K. Teo,et al.  Effect of Lipid Lowering With Rosuvastatin on Progression of Aortic Stenosis: Results of the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) Trial , 2010, Circulation.

[61]  M. Kirby,et al.  The role of secondary heart field in cardiac development. , 2009, Developmental biology.

[62]  D. Srivastava,et al.  Notch1 represses osteogenic pathways in aortic valve cells. , 2009, Journal of molecular and cellular cardiology.

[63]  A. Levin,et al.  Elevated osteoprotegerin is associated with all-cause mortality in CKD stage 4 and 5 patients in addition to vascular calcification. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[64]  Eli J. Weinberg,et al.  A Computational Model of Aging and Calcification in the Aortic Heart Valve , 2009, PloS one.

[65]  Craig A Simmons,et al.  Calcification by Valve Interstitial Cells Is Regulated by the Stiffness of the Extracellular Matrix , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[66]  S. Young,et al.  Lowering Plasma Cholesterol Levels Halts Progression of Aortic Valve Disease in Mice , 2009, Circulation.

[67]  Ajit P Yoganathan,et al.  Endothelium-dependent regulation of the mechanical properties of aortic valve cusps. , 2009, Journal of the American College of Cardiology.

[68]  P. Libby,et al.  Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease , 2009, Circulation.

[69]  Ajit P Yoganathan,et al.  Altered Shear Stress Stimulates Upregulation of Endothelial VCAM-1 and ICAM-1 in a BMP-4– and TGF-&bgr;1–Dependent Pathway , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[70]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2009, Circulation.

[71]  M. Budoff,et al.  Relationship of Metabolic Syndrome With Incident Aortic Valve Calcium and Aortic Valve Calcium Progression , 2009, Diabetes.

[72]  Siew Yen Ho,et al.  Structure and anatomy of the aortic root. , 2009, European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology.

[73]  T. Hisada,et al.  The sinus of Valsalva relieves abnormal stress on aortic valve leaflets by facilitating smooth closure. , 2008, The Journal of thoracic and cardiovascular surgery.

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

[75]  C. Otto,et al.  Calcific aortic stenosis--time to look more closely at the valve. , 2008, The New England journal of medicine.

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

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

[78]  R. Weissleder,et al.  Notch Signaling in Cardiovascular Disease and Calcification , 2008, Current cardiology reviews.

[79]  M. Budoff,et al.  Soluble intercellular adhesion molecule-1 (sICAM-1) and aortic valve calcification in the multi-ethnic study of atherosclerosis (MESA). , 2008, Journal of Heart Valve Disease.

[80]  M. Yacoub,et al.  Localisation and function of nerves in the aortic root. , 2008, Journal of molecular and cellular cardiology.

[81]  J. Kappes,et al.  Oxidative Stress Induces Vascular Calcification through Modulation of the Osteogenic Transcription Factor Runx2 by AKT Signaling* , 2008, Journal of Biological Chemistry.

[82]  M. Budoff,et al.  Ethnic differences between extra-coronary measures on cardiac computed tomography: multi-ethnic study of atherosclerosis (MESA). , 2008, Atherosclerosis.

[83]  P. Libby,et al.  Activatable Magnetic Resonance Imaging Agent Reports Myeloperoxidase Activity in Healing Infarcts and Noninvasively Detects the Antiinflammatory Effects of Atorvastatin on Ischemia-Reperfusion Injury , 2008, Circulation.

[84]  G. Nickenig,et al.  Differential profile of the OPG/RANKL/RANK-system in degenerative aortic native and bioprosthetic valves. , 2008, The Journal of heart valve disease.

[85]  M. Yacoub,et al.  The need for a global perspective on heart valve disease epidemiology. The SHVD working group on epidemiology of heart valve disease founding statement. , 2008, The Journal of heart valve disease.

[86]  C. Simmons,et al.  Mechanobiology of the aortic heart valve. , 2008, The Journal of heart valve disease.

[87]  A. Yoganathan,et al.  Heart valve function: a biomechanical perspective , 2008, Philosophical Transactions of the Royal Society B: Biological Sciences.

[88]  Timur Shtatland,et al.  Osteogenesis Associates With Inflammation in Early-Stage Atherosclerosis Evaluated by Molecular Imaging In Vivo , 2007, Circulation.

[89]  V. Joag,et al.  The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. , 2007, The American journal of pathology.

[90]  M. Budoff,et al.  Kidney function and aortic valve and mitral annular calcification in the Multi-Ethnic Study of Atherosclerosis (MESA). , 2007, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[91]  R. Bonow,et al.  Calcific aortic stenosis: an update , 2007, Nature Clinical Practice Cardiovascular Medicine.

[92]  Ralph Weissleder,et al.  Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor , 2007, Circulation.

[93]  S. Takai,et al.  Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits. , 2007, Journal of the American College of Cardiology.

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

[95]  Ralph Weissleder,et al.  Multimodality Molecular Imaging Identifies Proteolytic and Osteogenic Activities in Early Aortic Valve Disease , 2007, Circulation.

[96]  C. Otto,et al.  Indications for Aortic Valve Replacement in Aortic Stenosis , 2007, Journal of intensive care medicine.

[97]  C. Eisenberg,et al.  Toward cell therapy for vascular calcification: osteoclast-mediated demineralization of calcified elastin. , 2007, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[98]  K. Griendling,et al.  Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. , 2007, American journal of physiology. Cell physiology.

[99]  Mark L. Johnson,et al.  Diseases of Wnt signaling , 2007, Reviews in Endocrine and Metabolic Disorders.

[100]  Hans Clevers,et al.  Wnt/β-Catenin Signaling in Development and Disease , 2006, Cell.

[101]  Vasilis Ntziachristos,et al.  Inflammation in Atherosclerosis: Visualizing Matrix Metalloproteinase Action in Macrophages In Vivo , 2006, Circulation.

[102]  J. Després,et al.  Metabolic syndrome negatively influences disease progression and prognosis in aortic stenosis. , 2006, Journal of the American College of Cardiology.

[103]  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.

[104]  R. Bonow,et al.  Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. , 2006, Journal of the American College of Cardiology.

[105]  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.

[106]  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.

[107]  A. Yoganathan,et al.  Differential immediate-early gene responses to elevated pressure in porcine aortic valve interstitial cells. , 2006, The Journal of heart valve disease.

[108]  D. Levy,et al.  Cross-sectional association of kidney function with valvular and annular calcification: the Framingham heart study. , 2006, Journal of the American Society of Nephrology : JASN.

[109]  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.

[110]  B. Lüderitz,et al.  Cells of primarily extra-valvular origin in degenerative aortic valves and bioprostheses. , 2005, European heart journal.

[111]  S. Hagl,et al.  Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. , 2005, International journal of molecular medicine.

[112]  R. Derner,et al.  The bone morphogenic protein. , 2005, Clinics in podiatric medicine and surgery.

[113]  D. Srivastava,et al.  Mutations in NOTCH1 cause aortic valve disease , 2005, Nature.

[114]  Kristi S Anseth,et al.  Activation of valvular interstitial cells is mediated by transforming growth factor-beta1 interactions with matrix molecules. , 2005, Matrix biology : journal of the International Society for Matrix Biology.

[115]  S. Stock,et al.  Atorvastatin Inhibits Hypercholesterolemia-Induced Calcification in the Aortic Valves via the Lrp5 Receptor Pathway , 2005, Circulation.

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

[117]  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.

[118]  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.

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

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

[121]  Su‐Li Cheng,et al.  Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. , 2005, The Journal of clinical investigation.

[122]  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.

[123]  S. Hagl,et al.  Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. , 2005, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[124]  Christopher K Breuer,et al.  Application of tissue-engineering principles toward the development of a semilunar heart valve substitute. , 2004, Tissue engineering.

[125]  E. Mohler.  Mechanisms of aortic valve calcification. , 2004, The American journal of cardiology.

[126]  M. Mäyränpää,et al.  Induction of local angiotensin II-producing systems in stenotic aortic valves. , 2004, Journal of the American College of Cardiology.

[127]  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.

[128]  M. Schemper,et al.  Statins but Not Angiotensin-Converting Enzyme Inhibitors Delay Progression of Aortic Stenosis , 2004, Circulation.

[129]  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.

[130]  H. Reichenspurner,et al.  Angiogenic activation of valvular endothelial cells in aortic valve stenosis. , 2004, Experimental cell research.

[131]  L. Leinwand,et al.  Valvular Myofibroblast Activation by Transforming Growth Factor-&bgr;: Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease , 2004, Circulation research.

[132]  W. Hörl.  The clinical consequences of secondary hyperparathyroidism: focus on clinical outcomes. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[133]  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.

[134]  L. Hofbauer,et al.  Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. , 2004, JAMA.

[135]  S. Hagl,et al.  Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. , 2004, The Journal of heart valve disease.

[136]  P. Dijke,et al.  New insights into TGF-β–Smad signalling , 2004 .

[137]  F. Baaijens,et al.  Collagen fibers reduce stresses and stabilize motion of aortic valve leaflets during systole. , 2004, Journal of biomechanics.

[138]  K. Alitalo,et al.  Specific Induction of tie1 Promoter by Disturbed Flow in Atherosclerosis-Prone Vascular Niches and Flow-Obstructing Pathologies , 2004, Circulation research.

[139]  G. De Visscher,et al.  Molecular and functional characterization of ovine cardiac valve-derived interstitial cells in primary isolates and cultures. , 2003, Tissue engineering.

[140]  P. Raggi,et al.  Valvular calcification in hemodialysis patients randomized to calcium-based phosphorus binders or sevelamer. , 2004, The Journal of heart valve disease.

[141]  C. Hill,et al.  New insights into TGF-beta-Smad signalling. , 2004, Trends in biochemical sciences.

[142]  S. Hagl,et al.  Receptor activator of nuclear factor κB ligand and osteoprotegerin regulate aortic valve calcification , 2004 .

[143]  M. Nanes.  Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. , 2003, Gene.

[144]  K. Rogers,et al.  Smoothelin-positive cells in human and porcine semilunar valves , 2003, Histochemistry and Cell Biology.

[145]  T. Salo,et al.  Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis. , 2003, Human pathology.

[146]  Philippe Ravaud,et al.  A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. , 2003, European heart journal.

[147]  M. Schultz,et al.  Evidence of woven bone formation in heart valve disease. , 2003, Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia.

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

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

[150]  R. Levy,et al.  Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. , 2003, The Annals of thoracic surgery.

[151]  P. Faggiano,et al.  Progression of aortic valve sclerosis to aortic stenosis. , 2003, The American journal of cardiology.

[152]  E. Picano,et al.  Aortic valve sclerosis is associated with systemic endothelial dysfunction. , 2003, Journal of the American College of Cardiology.

[153]  M. Enriquez-Sarano,et al.  Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. , 2002, Journal of the American College of Cardiology.

[154]  I. Kronzon,et al.  The risk of the development of aortic stenosis in patients with "benign" aortic valve thickening. , 2002, Archives of internal medicine.

[155]  C. Otto,et al.  Association of Angiotensin-Converting Enzyme With Low-Density Lipoprotein in Aortic Valvular Lesions and in Human Plasma , 2002, Circulation.

[156]  P. Raggi,et al.  Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. , 2002, Kidney international.

[157]  R. Bonow,et al.  Atorvastatin Inhibits Hypercholesterolemia-Induced Cellular Proliferation and Bone Matrix Production in the Rabbit Aortic Valve , 2002, Circulation.

[158]  Stephen W Carmichael,et al.  Localization of Caveolin 1 in Aortic Valve Endothelial Cells Using Antigen Retrieval , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[159]  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.

[160]  M. Budoff,et al.  HMG CoA reductase inhibitor (statin) and aortic valve calcium , 2002, The Lancet.

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

[162]  M. Lauer,et al.  Effect of Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors on the Progression of Calcific Aortic Stenosis , 2001, Circulation.

[163]  W. Aronow,et al.  Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. , 2001, The American journal of cardiology.

[164]  R. Natarajan,et al.  Diabetes-induced accelerated atherosclerosis in swine. , 2001, Diabetes.

[165]  Y. Soini,et al.  Expression of MMP2, MMP9, MT1‐MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart , 2001, The Journal of pathology.

[166]  C. Otto,et al.  Why is there discordance between calcific aortic stenosis and coronary artery disease? , 2001, Heart.

[167]  A. Tajik,et al.  Experimental hypercholesterolemia induces apoptosis in the aortic valve. , 2001, The Journal of heart valve disease.

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

[169]  W G Henderson,et al.  Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. , 2000, Journal of the American College of Cardiology.

[170]  M. Schemper,et al.  Predictors of outcome in severe, asymptomatic aortic stenosis. , 2000, The New England journal of medicine.

[171]  Jianglin Fan,et al.  Cholesterol-fed and transgenic rabbit models for the study of atherosclerosis. , 2000, Journal of atherosclerosis and thrombosis.

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

[173]  K. Müller,et al.  Expression of endothelial cell adhesion molecules on heart valves: up‐regulation in degeneration as well as acute endocarditis , 2000, The Journal of pathology.

[174]  M. Yacoub,et al.  Asymmetric redirection of flow through the heart , 2000, Nature.

[175]  M. Sturek,et al.  Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[176]  Bonnie K. Lind,et al.  Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. , 1999, The New England journal of medicine.

[177]  R. Levy,et al.  Identification and characterization of calcifying valve cells from human and canine aortic valves. , 1999, The Journal of heart valve disease.

[178]  J. Thyberg,et al.  Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[179]  W. Edwards,et al.  Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases. , 1999, Mayo Clinic proceedings.

[180]  H. Hultgren.  Osteitis deformans (Paget's disease) and calcific disease of the heart valves. , 1998, The American journal of cardiology.

[181]  C M Otto,et al.  Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. , 1997, Circulation.

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

[183]  E. Mohler,et al.  Detection of osteopontin in calcified human aortic valves. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

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

[185]  J. Taipale,et al.  Latent transforming growth factor-beta 1 and its binding protein are components of extracellular matrix microfibrils. , 1996, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

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

[187]  C. Otto,et al.  Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

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

[189]  Y Imai,et al.  Regulation of the aortic valve opening. In vivo dynamic measurement of aortic valve orifice area. , 1995, The Journal of thoracic and cardiovascular surgery.

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

[191]  J. Heikkilä,et al.  Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. , 1993, Journal of the American College of Cardiology.

[192]  J Rapacz,et al.  Development of complex atherosclerotic lesions in pigs with inherited hyper-LDL cholesterolemia bearing mutant alleles for apolipoprotein B. , 1991, The American journal of pathology.

[193]  D J Wheatley,et al.  Twelve-year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. , 1991, The New England journal of medicine.

[194]  M. Kirby,et al.  Role of Neural Crest in Congenital Heart Disease , 1990, Circulation.

[195]  M. Simionescu,et al.  Cellular events in the development of valvular atherosclerotic lesions induced by experimental hypercholesterolemia. , 1987, Atherosclerosis.

[196]  W. Aronow,et al.  Correlation of serum lipids, calcium, and phosphorus, diabetes mellitus and history of systemic hypertension with presence or absence of calcified or thickened aortic cusps or root in elderly patients. , 1987, The American journal of cardiology.

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

[198]  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.

[199]  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.

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

[201]  H. Hultgren,et al.  Noninvasive evaluation of the severity of aortic stenosis in adult patients. , 1984, American heart journal.

[202]  M. Thubrikar,et al.  Patterns and pathogenesis of calcification in pathologic human aortic valves. , 1984, Current surgery.

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

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

[205]  N. Fowler,et al.  Clinical aspects of acquired valvular heart disease. , 1979, Seminars in roentgenology.

[206]  W. Roberts,et al.  The Structure of the Aortic Valve in Clinically Isolated Aortic Stenosis: An Autopsy Study of 162 Patients Over 15 Years of Age , 1970, Circulation.

[207]  O. Jaffee.  The development of the arterial outflow tract in the chick embryo heart , 1967, The Anatomical record.

[208]  A. PelaezGomez.  Calcific aortic stenosis , 1959 .

[209]  H. A. Braun,et al.  The importance of high-pitched squeaking systolic murmur in the diagnosis of aortic stenosis and calcification of the aortic valve. , 1951, The New England journal of medicine.