russjcardiolРоссийский кардиологический журналRussian Journal of Cardiology1560-40712618-7620«SILICEA-POLIGRAF» LLC10.15829/1560-4071-2015-10-99-106russjcardiol-325Research ArticleОБЗОРЫ ЛИТЕРАТУРЫREVIEWМОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКИЕ ФАКТОРЫ, АССОЦИИРОВАННЫЕ С РАЗВИТИЕМ АОРТАЛЬНОГО СТЕНОЗАMOLECULAR-GENETIC FACTORS, ASSOCIATED WITH AORTIC STENOSIS DEVELOPMENTТиптеваТ. А.TiptevaT. A.

Аспирант кафедры терапии, кардиологии и функциональной диагностики с курсом нефрологии

dz@bk.ruЧумаковаО. С.ChumakovaO. S.

Кандидат медицинских наук, доцент кафедры терапии, кардиологии и функциональной диагностики с курсом нефрологии

dz@bk.ruЗатейщиковД. А.ZateyshchikovD. A.

Доктор медицинских наук, руководитель первичного сосудистого отделения, профессор кафедры терапии, кардиологии и функциональной диагностики с курсом нефрологии, ведущий научный сотрудник лаборатории генетики

dz@bk.ruЦентральная государственная медицинская академия Управления делами Президента РФ, МоскваРоссияCentral state medical Academy of the administrative Department of the President of the Russian Federation, MoscowRussian FederationГородская клиническая больница №51, Москва; Центральная государственная медицинская академия Управления делами Президента РФ, Москва; Федеральный научно-клинический центр специализированных видов клинической помощи и медицинских технологий ФМБА России, МоскваРоссияCity Clinical Hospital №51, Moscow; Central state medical Academy of the administrative Department of the President of the Russian Federation, Moscow; Federal scientific-clinical center of specialized types of clinical care and medical technologies of FMBA of Russia, MoscowRussian Federation20152810201501099106Copyright © Типтева Т.А., Чумакова О.С., Затейщиков Д.А., 20152015Типтева Т.А., Чумакова О.С., Затейщиков Д.А.Tipteva T.A., Chumakova O.S., Zateyshchikov D.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://russjcardiol.elpub.ru/jour/article/view/325

Аортальный стеноз (АС) является одним из наиболее частых клапанных поражений сердца у больных старше 65 лет. Несмотря на изученность молекулярных механизмов развития и прогрессирования АС, хирургическое лечение в настоящее время остается единственным возможным лечением порока. В связи с коморбидностью пожилых больных, остаются препятствия для рекомендации таким пациентам хирургической замены клапана, несмотря на очевидный неблагоприятный прогноз консервативной терапии. Поиск новых подходов для ранней оценки неблагоприятных факторов риска, скорости прогрессирования заболевания позволит оценить необходимость более раннего лечения, а также позволит выявить возможности замедления прогрессирования заболевания. Одним из направлений изучения остается поиск генетических маркеров. В обзоре представлены основные исследованные молекулярные механизмы и связанные с ними генетические маркеры, ассоциированные с развитием АС. 

Aortic stenosis (AS) is one of the most prevalent valvular heart disorders in patients older than 65 years. Regardless the studied molecular mechanisms of development and progression of the disease, surgical treatment is recently the only successful method of help. Due to lots of comorbidities of older patients, there are obstacles to recommend surgical valve replacement, even knowing an adverse prognosis of conservative treatment. Search for new approaches to earlier assessment of adverse risk factors, speed of progression of this disease, would help to evaluate the necessity of earlier treatment and could make to slow down the progression of the disease. One of directions for this — is a search for genetic markers. This review focuses on the main known molecular mechanisms and genetic markers related to them, that are associated with AS. 

аортальный стенозгенетическая предрасположенностьaortic stenosishereditary predispositionReferencesIivanainen AM, Lindroos M, Tilvis R, et al. Natural history of aortic valve stenosis of varying severity in the elderly. Am J Cardiol 1996, 78(1): 97-101.Iivanainen AM, Lindroos M, Tilvis R, et al. Natural history of aortic valve stenosis of varying severity in the elderly. Am J Cardiol 1996, 78(1): 97-101.Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997, 29(3): 630-4.Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997, 29(3): 630-4.Le Gal G, Bertault V, Bezon E, et al. Heterogeneous geographic distribution of patients with aortic valve stenosis: arguments for new aetiological hypothesis. Heart 2005, 91(2): 247-9.Le Gal G, Bertault V, Bezon E, et al. Heterogeneous geographic distribution of patients with aortic valve stenosis: arguments for new aetiological hypothesis. Heart 2005, 91(2): 247-9.Horne BD, Camp NJ, Muhlestein JB, et al. Evidence for a heritable component in death resulting from aortic and mitral valve diseases. Circulation 2004, 110(19): 3143-8.Horne BD, Camp NJ, Muhlestein JB, et al. Evidence for a heritable component in death resulting from aortic and mitral valve diseases. Circulation 2004, 110(19): 3143-8.Probst V, Le Scouarnec S, Legendre A, et al. Familial aggregation of calcific aortic valve stenosis in the western part of France. Circulation 2006, 113(6): 856-60.Probst V, Le Scouarnec S, Legendre A, et al. Familial aggregation of calcific aortic valve stenosis in the western part of France. Circulation 2006, 113(6): 856-60.Bella JN, Tang W, Kraja A, et al. Genome-wide linkage mapping for valve calcification susceptibility loci in hypertensive sibships: the Hypertension Genetic Epidemiology Network Study. Hypertension 2007, 49(3): 453-60.Bella JN, Tang W, Kraja A, et al. Genome-wide linkage mapping for valve calcification susceptibility loci in hypertensive sibships: the Hypertension Genetic Epidemiology Network Study. Hypertension 2007, 49(3): 453-60.Rajamannan NM, Subramaniam M, Rickard D, et al. Human Aortic Valve Calcification Is Associated With an Osteoblast Phenotype. Circulation 2003, 107(17): 2181-4.Rajamannan NM, Subramaniam M, Rickard D, et al. Human Aortic Valve Calcification Is Associated With an Osteoblast Phenotype. Circulation 2003, 107(17): 2181-4.Ducy P, Zhang R, Geoffroy V, et al. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997, 89(5): 747-54.Ducy P, Zhang R, Geoffroy V, et al. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997, 89(5): 747-54.Kern B, Shen J, Starbuck M, et al. Cbfa1 Contributes to the Osteoblast-specific Expression of type I collagen Genes. J Biol Chem 2001, 276(10): 7101-7.Kern B, Shen J, Starbuck M, et al. Cbfa1 Contributes to the Osteoblast-specific Expression of type I collagen Genes. J Biol Chem 2001, 276(10): 7101-7.Franceschi R, Xiao G. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J Cell Biochem 2003, 88(3): 446-54.Franceschi R, Xiao G. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J Cell Biochem 2003, 88(3): 446-54.Gordon K, Blobe G. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta 2008, 1782(4): 197-228.Gordon K, Blobe G. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta 2008, 1782(4): 197-228.Osman L, Yacoub MH, Latif N, et al. Role of Human Valve Interstitial Cells in Valve Calcification and Their Response to Atorvastatin. Circulation 2006, 114(1_suppl): I-547-52.Osman L, Yacoub MH, Latif N, et al. Role of Human Valve Interstitial Cells in Valve Calcification and Their Response to Atorvastatin. Circulation 2006, 114(1_suppl): I-547-52.Walker GA, Masters KS, Shah DN, et al. Valvular Myofibroblast Activation by Transforming Growth Factor-{beta}: Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease. Circ Res 2004, 95(3): 253-60.Walker GA, Masters KS, Shah DN, et al. Valvular Myofibroblast Activation by Transforming Growth Factor-{beta}: Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease. Circ Res 2004, 95(3): 253-60.Chua CC, Chua BH, Chen Z, et al. TGF-beta1 inhibits multiple caspases induced by TNFalpha in murine osteoblastic MC3T3-E1 cells. Biochim Biophys Acta 2002, 1593(1): 1-8.Chua CC, Chua BH, Chen Z, et al. TGF-beta1 inhibits multiple caspases induced by TNFalpha in murine osteoblastic MC3T3-E1 cells. Biochim Biophys Acta 2002, 1593(1): 1-8.Chambers T. Regulation of the differentiation and function of osteoclasts. J. pathology 2000, 192(1): 4-13.Chambers T. Regulation of the differentiation and function of osteoclasts. J. pathology 2000, 192(1): 4-13.Jian B, Narula N, Li Q-y, et al. Progression of aortic valve stenosis: TGF-{beta}1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg 2003, 75(2): 457-65.Jian B, Narula N, Li Q-y, et al. Progression of aortic valve stenosis: TGF-{beta}1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg 2003, 75(2): 457-65.Khan R, Sheppard R. Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology 2006, 118(1): 10-24.Khan R, Sheppard R. Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology 2006, 118(1): 10-24.Clark-Greuel JN, Connolly JM, Sorichillo E, et al. Transforming growth factor-?1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. The Annals of thoracic surgery 2007, 83(3): 946-53.Clark-Greuel JN, Connolly JM, Sorichillo E, et al. Transforming growth factor-?1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. The Annals of thoracic surgery 2007, 83(3): 946-53.Nordstrom P, Glader CA, Dahlen G, et al. Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women. J Intern Med 2003, 254(2): 140-6.Nordstrom P, Glader CA, Dahlen G, et al. Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women. J Intern Med 2003, 254(2): 140-6.Gaudreault N, Ducharme V, Lamontagne M, et al. Replication of genetic association studies in aortic stenosis in adults. Am J Cardiol 2011, 108(9): 1305-10.Gaudreault N, Ducharme V, Lamontagne M, et al. Replication of genetic association studies in aortic stenosis in adults. Am J Cardiol 2011, 108(9): 1305-10.Bosse Y, Miqdad A, Fournier D, et al. Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves. Circ Cardiovasc Genet 2009, 2(5): 489-98.Bosse Y, Miqdad A, Fournier D, et al. Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves. Circ Cardiovasc Genet 2009, 2(5): 489-98.Yang X, Meng X, Su X, et al. Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: Role of Smad1 and extracellular signalregulated kinase 1/2. J Thorac Cardiovasc Surg 2009, 138(4): 1008-15.Yang X, Meng X, Su X, et al. Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: Role of Smad1 and extracellular signalregulated kinase 1/2. J Thorac Cardiovasc Surg 2009, 138(4): 1008-15.Hruska KA, Mathew S, Saab G. Bone Morphogenetic Proteins in Vascular Calcification. Circ Res 2005, 97(2): 105-14.Hruska KA, Mathew S, Saab G. Bone Morphogenetic Proteins in Vascular Calcification. Circ Res 2005, 97(2): 105-14.Kaden J, Bickelhaupt S, Grobholz R, et al. Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J Heart Valve Dis 2004, 13(4): 560-6.Kaden J, Bickelhaupt S, Grobholz R, et al. Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J Heart Valve Dis 2004, 13(4): 560-6.Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis 2008, 4(2): 68-75.Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis 2008, 4(2): 68-75.Pandur P, Maurus D, K?hl M. Increasingly complex: new players enter the Wnt signaling network. Bioessays 2002, 24(10): 881-4.Pandur P, Maurus D, K?hl M. Increasingly complex: new players enter the Wnt signaling network. Bioessays 2002, 24(10): 881-4.Rajamannan NM, Subramaniam M, Caira F, et al. Atorvastatin Inhibits HypercholesterolemiaInduced Calcification in the Aortic Valves via the Lrp5 Receptor Pathway. Circulation 2005, 112(9_suppl): I-229-34.Rajamannan NM, Subramaniam M, Caira F, et al. Atorvastatin Inhibits HypercholesterolemiaInduced Calcification in the Aortic Valves via the Lrp5 Receptor Pathway. Circulation 2005, 112(9_suppl): I-229-34.Kaden J, Bickelhaupt S, Grobholz R, et al. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol 2004, 36(1): 57-66.Kaden J, Bickelhaupt S, Grobholz R, et al. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol 2004, 36(1): 57-66.Engin F, Yao Z, Yang T, et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 2008, 14(3): 299-305.Engin F, Yao Z, Yang T, et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 2008, 14(3): 299-305.Meier-Stiegen F, Schwanbeck R, Bernoth K, et al. Activated Notch1 target genes during embryonic cell differentiation depend on the cellular context and include lineage determinants and inhibitors. PLoS One 2010, 5(7): e11481.Meier-Stiegen F, Schwanbeck R, Bernoth K, et al. Activated Notch1 target genes during embryonic cell differentiation depend on the cellular context and include lineage determinants and inhibitors. PLoS One 2010, 5(7): e11481.Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005, 437(7056): 270-4.Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005, 437(7056): 270-4.Shimizu T, Tanaka T, Iso T, et al. Notch Signaling Induces Osteogenic Differentiation and Mineralization of Vascular Smooth Muscle Cells Role of Msx2 Gene Induction via Notch-RBP-Jk Signaling. Arteriosclerosis, thrombosis, and vascular biology 2009, 29(7): 1104-11.Shimizu T, Tanaka T, Iso T, et al. Notch Signaling Induces Osteogenic Differentiation and Mineralization of Vascular Smooth Muscle Cells Role of Msx2 Gene Induction via Notch-RBP-Jk Signaling. Arteriosclerosis, thrombosis, and vascular biology 2009, 29(7): 1104-11.Ducharme V, Guauque-Olarte S, Gaudreault N, et al. NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. J Heart Valve Dis 2013, 22(2): 142-9.Ducharme V, Guauque-Olarte S, Gaudreault N, et al. NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. J Heart Valve Dis 2013, 22(2): 142-9.Maher ER, Young G, Smyth-Walsh B, et al. Aortic and mitral valve calcification in patients with end-stage renal disease. Lancet 1987, 2(8564): 875-7. 35. McFalls EO, Archer SL. Rapid progression of aortic stenosis and secondary hyperparathyroidism. Am Heart J 1990, 120(1): 206-8.Maher ER, Young G, Smyth-Walsh B, et al. Aortic and mitral valve calcification in patients with end-stage renal disease. Lancet 1987, 2(8564): 875-7. 35. McFalls EO, Archer SL. Rapid progression of aortic stenosis and secondary hyperparathyroidism. Am Heart J 1990, 120(1): 206-8.Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 2004, 286(5): E686-96.Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 2004, 286(5): E686-96.Lindroos M, Kupari M, Valvanne J, et al. Factors associated with calcific aortic valve degeneration in the elderly. European heart journal 1994, 15(7): 865-70.Lindroos M, Kupari M, Valvanne J, et al. Factors associated with calcific aortic valve degeneration in the elderly. European heart journal 1994, 15(7): 865-70.Linhartova K, Veselka J, Sterbakova G, et al. Parathyroid hormone and vitamin D levels are independently associated with calcific aortic stenosis. Circ J 2008, 72(2): 245-50.Linhartova K, Veselka J, Sterbakova G, et al. Parathyroid hormone and vitamin D levels are independently associated with calcific aortic stenosis. Circ J 2008, 72(2): 245-50.Ortlepp JR, Hoffmann R, Ohme F, et al. The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis. Heart 2001, 85(6): 635-8.Ortlepp JR, Hoffmann R, Ohme F, et al. The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis. Heart 2001, 85(6): 635-8.Imai K, Okura H, Kume T, et al. C-Reactive protein predicts severity, progression, and prognosis of asymptomatic aortic valve stenosis. Am Heart J 2008, 156(4): 713-8.Imai K, Okura H, Kume T, et al. C-Reactive protein predicts severity, progression, and prognosis of asymptomatic aortic valve stenosis. Am Heart J 2008, 156(4): 713-8.Shavelle DM, Katz R, Takasu J, et al. Soluble intercellular adhesion molecule-1 (sICAM-1) and aortic valve calcification in the multi-ethnic study of atherosclerosis (MESA). J Heart Valve Dis 2008, 17(4): 388-95.Shavelle DM, Katz R, Takasu J, et al. Soluble intercellular adhesion molecule-1 (sICAM-1) and aortic valve calcification in the multi-ethnic study of atherosclerosis (MESA). J Heart Valve Dis 2008, 17(4): 388-95.Basta G, Corciu AI, Vianello A, et al. Circulating soluble receptor for advanced glycation end-product levels are decreased in patients with calcific aortic valve stenosis. Atherosclerosis 2010, 210(2): 614-8.Basta G, Corciu AI, Vianello A, et al. Circulating soluble receptor for advanced glycation end-product levels are decreased in patients with calcific aortic valve stenosis. Atherosclerosis 2010, 210(2): 614-8.Kaden JJ, Dempfle CE, Grobholz R, et al. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis 2003, 170(2): 205-11.Kaden JJ, Dempfle CE, Grobholz R, et al. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis 2003, 170(2): 205-11.Csiszar A, Ungvari Z. Endothelial dysfunction and vascular inflammation in Type 2 diabetes: interaction of AGE/RAGE and TNF-? signaling. Am J Physiol Heart Circ Physiol 2008, 295(2): H475-6.Csiszar A, Ungvari Z. Endothelial dysfunction and vascular inflammation in Type 2 diabetes: interaction of AGE/RAGE and TNF-? signaling. Am J Physiol Heart Circ Physiol 2008, 295(2): H475-6.Yu Z, Seya K, Daitoku K, et al. Tumor Necrosis Factor-? Accelerates the Calcification of Human Aortic Valve Interstitial Cells Obtained from Patients with Calcific Aortic Valve Stenosis via the BMP2-Dlx5 Pathway. Journal of Pharmacology and Experimental Therapeutics 2011, 337(1): 16-23.Yu Z, Seya K, Daitoku K, et al. Tumor Necrosis Factor-? Accelerates the Calcification of Human Aortic Valve Interstitial Cells Obtained from Patients with Calcific Aortic Valve Stenosis via the BMP2-Dlx5 Pathway. Journal of Pharmacology and Experimental Therapeutics 2011, 337(1): 16-23.Warnock JN, Nanduri B, Pregonero Gamez CA, et al. Gene profiling of aortic valve interstitial cells under elevated pressure conditions: modulation of inflammatory gene networks. International journal of inflammation 2011, 2011.Warnock JN, Nanduri B, Pregonero Gamez CA, et al. Gene profiling of aortic valve interstitial cells under elevated pressure conditions: modulation of inflammatory gene networks. International journal of inflammation 2011, 2011.Mazzone A, Epistolato MC, De Caterina R, et al. Neoangiogenesis, T-lymphocyte infiltration, and heat shock protein-60 are biological hallmarks of an immunomediated inflammatory process in end-stage calcified aortic valve stenosis. J Am Coll Cardiol 2004, 43(9): 1670-6.Mazzone A, Epistolato MC, De Caterina R, et al. Neoangiogenesis, T-lymphocyte infiltration, and heat shock protein-60 are biological hallmarks of an immunomediated inflammatory process in end-stage calcified aortic valve stenosis. J Am Coll Cardiol 2004, 43(9): 1670-6.Aikawa E, Aikawa M, Libby P, et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 2009, 119(13): 1785-94.Aikawa E, Aikawa M, Libby P, et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 2009, 119(13): 1785-94.Attaran S, Sherwood R, Dastidar MG, et al. Identification of low circulatory transforming growth factor beta-1 in patients with degenerative heart valve disease. Interact Cardiovasc Thorac Surg 2010, 11(6): 791-3.Attaran S, Sherwood R, Dastidar MG, et al. Identification of low circulatory transforming growth factor beta-1 in patients with degenerative heart valve disease. Interact Cardiovasc Thorac Surg 2010, 11(6): 791-3.Fondard O, Detaint D, Iung B, et al. Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. European heart journal 2005, 26(13): 1333-41.Fondard O, Detaint D, Iung B, et al. Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. European heart journal 2005, 26(13): 1333-41.Kaden JJ, Dempfle CE, Grobholz R, et al. Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc Pathol 2005, 14(2): 80-7.Kaden JJ, Dempfle CE, Grobholz R, et al. Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc Pathol 2005, 14(2): 80-7.Jian B, Jones PL, Li Q, et al. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. Am J Pathol 2001, 159(1): 321-7.Jian B, Jones PL, Li Q, et al. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. Am J Pathol 2001, 159(1): 321-7.Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013, 368(6): 503-12.Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013, 368(6): 503-12.Novaro GM, Sachar R, Pearce GL, et al. Association Between Apolipoprotein E Alleles and Calcific Valvular Heart Disease. Circulation 2003, 108(15): 1804-8.Novaro GM, Sachar R, Pearce GL, et al. Association Between Apolipoprotein E Alleles and Calcific Valvular Heart Disease. Circulation 2003, 108(15): 1804-8.Avakian S, Annicchino-Bizzac J, Grinberg M, et al. Apolipoproteins AI, B, and E polymorphisms in severe aortic valve stenosis. Clin Genet 2001, 60(5): 381-4.Avakian S, Annicchino-Bizzac J, Grinberg M, et al. Apolipoproteins AI, B, and E polymorphisms in severe aortic valve stenosis. Clin Genet 2001, 60(5): 381-4.Moura LM, Faria S, Brito M, et al. Relationship of PON1 192 and 55 gene polymorphisms to calcific valvular aortic stenosis. Am J Cardiovasc Dis 2012, 2(2): 123-32.Moura LM, Faria S, Brito M, et al. Relationship of PON1 192 and 55 gene polymorphisms to calcific valvular aortic stenosis. Am J Cardiovasc Dis 2012, 2(2): 123-32.Chalajour F, Treede H, Ebrahimnejad A, et al. Angiogenic activation of valvular endothelial cells in aortic valve stenosis. Exp Cell Res 2004, 298(2): 455-64.Chalajour F, Treede H, Ebrahimnejad A, et al. Angiogenic activation of valvular endothelial cells in aortic valve stenosis. Exp Cell Res 2004, 298(2): 455-64.Soini Y, Salo T, Satta J. Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis. Hum Pathol 2003, 34(8): 756-63.Soini Y, Salo T, Satta J. Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis. Hum Pathol 2003, 34(8): 756-63.Charest A, Pepin A, Shetty R, et al. Distribution of SPARC during neovascularisation of degenerative aortic stenosis. Heart 2006, 92(12): 1844-9.Charest A, Pepin A, Shetty R, et al. Distribution of SPARC during neovascularisation of degenerative aortic stenosis. Heart 2006, 92(12): 1844-9.Yoshioka M, Yuasa S, Matsumura K, et al. Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. Nat Med 2006, 12(10): 1151-9.Yoshioka M, Yuasa S, Matsumura K, et al. Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. Nat Med 2006, 12(10): 1151-9.Syvaranta S, Helske S, Laine M, et al. Vascular endothelial growth factor-secreting mast cells and myofibroblasts: a novel self-perpetuating angiogenic pathway in aortic valve stenosis. Arterioscler Thromb Vasc Biol 2010, 30(6): 1220-7.Syvaranta S, Helske S, Laine M, et al. Vascular endothelial growth factor-secreting mast cells and myofibroblasts: a novel self-perpetuating angiogenic pathway in aortic valve stenosis. Arterioscler Thromb Vasc Biol 2010, 30(6): 1220-7.Zhao W, Wang J, Shen J, et al. A nonsense variation p.Arg325X in the vascular endothelial growth factor-A gene may be associated with congenital tricuspid aortic valve stenosis. Cardiol Young 2012, 22(3): 316-22.Zhao W, Wang J, Shen J, et al. A nonsense variation p.Arg325X in the vascular endothelial growth factor-A gene may be associated with congenital tricuspid aortic valve stenosis. Cardiol Young 2012, 22(3): 316-22.Ellis S, Dushman-Ellis S, Luke M, et al. Pilot candidate gene analysis of patients? 60 years old with aortic stenosis involving a tricuspid aortic valve. Am J Cardiol 2012, 110(1): 88-92.Ellis S, Dushman-Ellis S, Luke M, et al. Pilot candidate gene analysis of patients? 60 years old with aortic stenosis involving a tricuspid aortic valve. Am J Cardiol 2012, 110(1): 88-92.Tang Y, Urs S, Boucher J, et al. Notch and Transforming Growth Factor-{beta} (TGF{beta}) Signaling Pathways Cooperatively Regulate Vascular Smooth Muscle Cell Differentiation. J Biol Chem 2010, 285(23): 17556-63.Tang Y, Urs S, Boucher J, et al. Notch and Transforming Growth Factor-{beta} (TGF{beta}) Signaling Pathways Cooperatively Regulate Vascular Smooth Muscle Cell Differentiation. J Biol Chem 2010, 285(23): 17556-63.Zamurovic N, Cappellen D, Rohner D, et al. Coordinated Activation of Notch, Wnt, and Transforming Growth Factor-? Signaling Pathways in Bone Morphogenic Protein 2-induced Osteogenesis Notch TARGET GENE Hey1 INHIBITS MINERALIZATION AND Runx2 TRANSCRIPTIONAL ACTIVITY. Journal of Biological Chemistry 2004, 279(36): 37704-15.Zamurovic N, Cappellen D, Rohner D, et al. Coordinated Activation of Notch, Wnt, and Transforming Growth Factor-? Signaling Pathways in Bone Morphogenic Protein 2-induced Osteogenesis Notch TARGET GENE Hey1 INHIBITS MINERALIZATION AND Runx2 TRANSCRIPTIONAL ACTIVITY. Journal of Biological Chemistry 2004, 279(36): 37704-15.Chen JH, Chen WL, Sider KL, et al. Beta-catenin mediates mechanically regulated, transforming growth factor-beta1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol 2011, 31(3): 590-7.Chen JH, Chen WL, Sider KL, et al. Beta-catenin mediates mechanically regulated, transforming growth factor-beta1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol 2011, 31(3): 590-7.de Ruijter AJ, van Gennip AH, Caron HN, et al. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003, 370(Pt 3): 737-49.de Ruijter AJ, van Gennip AH, Caron HN, et al. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003, 370(Pt 3): 737-49.Schroeder TM, Kahler RA, Li X, et al. Histone Deacetylase 3 Interacts with Runx2 to Repress the Osteocalcin Promoter and Regulate Osteoblast Differentiation. Journal of Biological Chemistry 2004, 279(40): 41998-2007.Schroeder TM, Kahler RA, Li X, et al. Histone Deacetylase 3 Interacts with Runx2 to Repress the Osteocalcin Promoter and Regulate Osteoblast Differentiation. Journal of Biological Chemistry 2004, 279(40): 41998-2007.Stein S, Schafer N, Breitenstein A, et al. SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/mice. Aging (Albany NY) 2010, 2(6): 353-60.Stein S, Schafer N, Breitenstein A, et al. SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/mice. Aging (Albany NY) 2010, 2(6): 353-60.de Oca AM, Madue?o JA, Martinez-Moreno JM, et al. High-phosphate-induced calcification is related to SM22? promoter methylation in vascular smooth muscle cells. J. Bone and Mineral Research 2010, 25(9): 1996-2005.de Oca AM, Madue?o JA, Martinez-Moreno JM, et al. High-phosphate-induced calcification is related to SM22? promoter methylation in vascular smooth muscle cells. J. Bone and Mineral Research 2010, 25(9): 1996-2005.

The authors declare that there are no conflicts of interest present.