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

Calcific aortic valve disease (CAVD) encompasses the range of disease from initial alterations in the cell biology of the leaflets to end-stage calcification resulting in left ventricular outflow obstruction. The first detectable macroscopic changes in the leaflets, seen as calcification, or focal leaflet thickening with normal valve function, is termed aortic valve sclerosis, but it is likely that the initiating events in the disease process occur much earlier. Disease progression is characterized by a process of thickening of the valve leaflets and the formation of calcium nodules – often including the formation of actual bone – and new blood vessels, which are concentrated near the aortic surface. End stage disease, e.g. calcific aortic stenosis, is characterized pathologically by large nodular calcific masses within the aortic cusps that protrude through the outflow surfaces into the sinuses of Valsalva, interfering with opening of the cusps. For decades, this disease was thought to be a passive process in which the valve degenerates with age in association with calcium accumulation. Moreover, although calcific aortic valve disease is more common with age, it is not an inevitable consequence of aging. Instead, CAVD appears to be an actively regulated disease process that cannot be characterized exclusively as “senile” or “degenerative.” The NHLBI convened a group of scientists from different fields of study, including cardiac imaging, molecular biology, cardiovascular pathology, epidemiology, cell biology, endocrinology, bioengineering, and clinical outcomes, to review the scientific studies from the past decade in the field of CAVD. The purpose was to develop a consensus statement on the current state of translational research related to CAVD. Herein, we summarize recent scientific studies and define future directions for research to diagnose, treat and potentially prevent this complex disease process.

[1]  N. Rajamannan.  Bicuspid aortic valve disease: the role of oxidative stress in Lrp5 bone formation. , 2011, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

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

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

[4]  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.

[5]  N. Rajamannan.  Mechanisms of aortic valve calcification: the LDL-density-radius theory: a translation from cell signaling to physiology. , 2010, American journal of physiology. Heart and circulatory physiology.

[6]  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.

[7]  K. Masters,et al.  Role of the MAPK/ERK pathway in valvular interstitial cell calcification. , 2009, American journal of physiology. Heart and circulatory physiology.

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

[9]  Craig A Simmons,et al.  Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. , 2009, The American journal of pathology.

[10]  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.

[11]  K. Masters,et al.  Efficacy of Simvastatin Treatment of Valvular Interstitial Cells Varies With the Extracellular Environment , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[12]  J. Chambers,et al.  Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. , 2009, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

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

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

[15]  B. Popescu,et al.  Stage-related effect of statin treatment on the progression of aortic valve sclerosis and stenosis. , 2008, The American journal of cardiology.

[16]  R. Brooks,et al.  Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. , 2008, Journal of the American College of Cardiology.

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

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

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

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

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

[22]  H. Jakubowski,et al.  Letter by Undas and Jakubowski regarding article, "Relationship between homocysteine and mortality in chronic kidney disease". , 2006, Circulation.

[23]  F. Schoen,et al.  Human Pulmonary Valve Progenitor Cells Exhibit Endothelial/Mesenchymal Plasticity in Response to Vascular Endothelial Growth Factor-A and Transforming Growth Factor-&bgr;2 , 2006, Circulation research.

[24]  M. Amrani,et al.  Role of Human Valve Interstitial Cells in Valve Calcification and Their Response to Atorvastatin , 2006, Circulation.

[25]  L. D. Cas,et al.  Epidemiology and cardiovascular risk factors of aortic stenosis , 2006, Cardiovascular ultrasound.

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

[27]  R. Kronmal,et al.  Features of the Metabolic Syndrome and Diabetes Mellitus as Predictors of Aortic Valve Calcification in the Multi-Ethnic Study of Atherosclerosis , 2006, Circulation.

[28]  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.

[29]  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.

[30]  R. Kronmal,et al.  Reproducibility of CT measurements of aortic valve calcification, mitral annulus calcification, and aortic wall calcification in the multi-ethnic study of atherosclerosis. , 2006, Academic radiology.

[31]  D. Newby,et al.  Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both? , 2005, Heart.

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

[33]  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.

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

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

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

[37]  W. Edwards,et al.  Calcified Rheumatic Valve Neoangiogenesis Is Associated With Vascular Endothelial Growth Factor Expression and Osteoblast-Like Bone Formation , 2005, Circulation.

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

[39]  R O Bonow,et al.  Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve , 2005, Heart.

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

[41]  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.

[42]  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.

[43]  E. Mohler,et al.  Paradoxical Effects of Statins on Aortic Valve Myofibroblasts and Osteoblasts: Implications for End-Stage Valvular Heart Disease , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[44]  S. Hagl,et al.  Influence of receptor activator of nuclear factor kappa B on human aortic valve myofibroblasts. , 2005, Experimental and molecular pathology.

[45]  Zhaoming He,et al.  Cyclic Pressure Affects the Biological Properties of Porcine Aortic Valve Leaflets in a Magnitude and Frequency Dependent Manner , 2004, Annals of Biomedical Engineering.

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

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

[48]  Catherine M. Otto,et al.  Textbook of Clinical Echocardiography , 2004 .

[49]  R. Autschbach,et al.  The amount of calcium-deficient hexagonal hydroxyapatite in aortic valves is influenced by gender and associated with genetic polymorphisms in patients with severe calcific aortic stenosis. , 2004, European heart journal.

[50]  K. Watson,et al.  Multilineage Potential of Cells From the Artery Wall , 2003, Circulation.

[51]  B. Griffin,et al.  Association Between Apolipoprotein E Alleles and Calcific Valvular Heart Disease , 2003, Circulation.

[52]  S. Hagl,et al.  Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. , 2003, Atherosclerosis.

[53]  W. Edwards,et al.  Hypercholesterolemic aortic-valve disease. , 2003, The New England journal of medicine.

[54]  R. Lorentzon,et al.  Oestrogen receptor α gene polymorphism is related to aortic valve sclerosis in postmenopausal women , 2003, Journal of internal medicine.

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

[56]  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.

[57]  C. Tribouilloy,et al.  Relation between cardiovascular risk factors and nonrheumatic severe calcific aortic stenosis among patients with a three-cuspid aortic valve. , 2003, The American journal of cardiology.

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

[59]  F. Parhami,et al.  High-Density Lipoprotein Regulates Calcification of Vascular Cells , 2002, Circulation research.

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

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

[62]  L. Demer.  Cholesterol in vascular and valvular calcification. , 2001, Circulation.

[63]  S. Achenbach,et al.  Progression of Aortic Valve Calcification: Association with Coronary Progression of Aortic Valve Calcification Association with Coronary Atherosclerosis and Cardiovascular Risk Factors , 2022 .

[64]  F. Schoen,et al.  Aortic Valve Endothelial Cells Undergo Transforming Growth Factor-β-Mediated and Non-Transforming Growth Factor-β-Mediated Transdifferentiation in Vitro , 2001 .

[65]  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.

[66]  K. Chan,et al.  Case-controlled study to assess risk factors for aortic stenosis in congenitally bicuspid aortic valve. , 2001, The American journal of cardiology.

[67]  R. Levy,et al.  Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. , 2001, The American journal of pathology.

[68]  F. Ohme,et al.  The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis , 2001, Heart.

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

[70]  D. Newby,et al.  Association between calcific aortic stenosis and hypercholesterolemia: Is there a need for a randomized controlled trial of cholesterol‐lowering therapy? , 2001, Clinical cardiology.

[71]  R. Choudhury,et al.  New insights into the progression of aortic stenosis: implications for secondary prevention. , 2000, Circulation.

[72]  F. Schoen,et al.  Aortic valve endothelial cells undergo transforming growth factor-beta-mediated and non-transforming growth factor-beta-mediated transdifferentiation in vitro. , 2001, The American journal of pathology.

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

[74]  R. Pai,et al.  New insights into the progression of aortic stenosis: implications for secondary prevention. , 2000, Circulation.

[75]  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.

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

[77]  C. Yutani,et al.  Characteristic cardiovascular manifestation in homozygous and heterozygous familial hypercholesterolemia. , 1999, American heart journal.

[78]  D. Harrison,et al.  Vascular expression of extracellular superoxide dismutase in atherosclerosis. , 1998, The Journal of clinical investigation.

[79]  J. Lodder,et al.  Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve , 1997, Heart.

[80]  H. Griffiths,et al.  A case-control investigation of the relation between hyperlipidaemia and calcific aortic valve stenosis , 1997, Heart.

[81]  F. Parhami,et al.  Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

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

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

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

[85]  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.

[86]  M. Ferguson,et al.  Osteopontin is expressed in human aortic valvular lesions. , 1995, Circulation.

[87]  T. Strandberg,et al.  Factors associated with calcific aortic valve degeneration in the elderly. , 1994, European heart journal.

[88]  W. P. Harvey,et al.  Development and progression of aortic valve stenosis: Atherosclerosis risk factors—a causal relationship? a clinical morphologic study , 1991, Clinical cardiology.

[89]  C. Otto,et al.  Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. , 1989, Journal of the American College of Cardiology.

[90]  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.

[91]  E. Cook,et al.  Case-control analysis of risk factors for presence of aortic stenosis in adults (age 50 years or older). , 1985, The American journal of cardiology.

[92]  B. McManus,et al.  Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. , 1984, The American journal of cardiology.

[93]  H. Rockette,et al.  Diabetes and hypercholesterolemia among patients with calcific aortic stenosis. , 1984, Journal of chronic diseases.

[94]  M. Brown,et al.  Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. , 1973, Proceedings of the National Academy of Sciences of the United States of America.