Pathology of Aortic Stenosis
Nikolaus Gassler MD, MA
Professor of Pathology
Institute of Pathology, RWTH Aachen University, Aachen, Germany
Search for more papers by this authorPhilipp A. Schnabel MD
Professor of Medicine
Institute of Pathology, University Clinics Heidelberg, Heidelberg, Germany
Search for more papers by this authorNikolaus Gassler MD, MA
Professor of Pathology
Institute of Pathology, RWTH Aachen University, Aachen, Germany
Search for more papers by this authorPhilipp A. Schnabel MD
Professor of Medicine
Institute of Pathology, University Clinics Heidelberg, Heidelberg, Germany
Search for more papers by this authorJürgen Haase MD, PhD, FESC, FACC
Professor of Medicine Consultant Cardiologist
Kardiocentrum Frankfurt, Klinik Rotes Kreuz, Frankfurt/Main, Germany
Search for more papers by this authorHans-Joachim Schäfers MD, PhD
Professor of Surgery Chair
Department of Thoracic and Cardiovascular Surgery, University Hospital Saarland, Homburg/Saar, Germany
Search for more papers by this authorHorst Sievert MD, FESC, FACC
Professor of Medicine Head
Department of Cardiology, CardioVascular Center Frankfurt, Frankfurt, Germany
Search for more papers by this authorRon Waksman MD, FACC
Professor of Medicine Associate Director Director
Division of Cardiology, Washington, DC, USA
Experimental Cardiology, Washington Hospital Center, Washington, DC, USA
Search for more papers by this authorSummary
This chapter contains sections titled:
-
Types of aortic stenosis
-
Pathologic evaluation of the aortic valve
-
Etiology and pathogenesis of aortic valve stenosis
-
Pathophysiology of aortic valve stenosis
-
Acknowledgment
-
References
References
- Patanè S, Marte F, & Di Bella G (2009) Asymptomatic double site of left ventricular outflow tract obstruction: subvalvular aortic stenosis associated with valvular aortic stenosis. Int J Cardiol 133: e30–e32.
- Fernandes SM, Sanders SP, Khairy P, et al. (2004) Morphology of bicuspid aortic valve in children and adolescents. J Am Coll Cardiol 44: 1648–1651.
- Roberts WC & Ko JM (2003) Weights of operatively-excised stenotic unicuspid, bicuspid, and tricuspid aortic valves and their relation to age, sex, body mass index, and presence or absence of concomitant coronary artery bypass grafting. Am J Cardiol 92: 1057–1065.
- Roberts WC (1970) The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol 26: 72–83.
- Phillips D (2006) Aortic stenosis: a review. AANA J 74: 309–315.
- Lindroos M, Kupari M, Heikkila J, et al. (1993) Prevalence of aortic valve abnormalities in the elderly: an echocardio-graphic study of a random population sample. J Am Coll Cardiol 21: 1220–1225.
- Stewart BF, Siscovick D, Lind BK, et al. (1997) Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 29: 630–634.
- Chan KL (2003) Is aortic stenosis a preventable disease? J Am Coll Cardiol 42: 593–599.
- Matsumura T, Ohtaki E, Misu K, et al. (2002) Etiology of aortic valve disease and recent changes in Japan: a study of 600 valve replacement cases. Int J Cardiol 86: 217–223.
- Dare AJ, Veinot JP, Edwards WD, et al. (1993) New observations on the etiology of aortic valve disease: a surgical pathologic study of 236 cases from 1990. Hum Pathol 24: 1330–1338.
- Butany J, Collins MJ, Demellawy DE, et al. (2005) Morphological and clinical findings in 247 surgically excised native aortic valves. Can J Cardiol 21: 747–755.
- Davies MJ, Treasure T, & Parker DJ (1996) Demographic characteristics of patients undergoing aortic valve replacement for stenosis: relation to valve morphology. Heart 75: 174–178.
- Roberts WC, Ko JM, & Hamilton C (2005) Comparison of valve structure, valve weight, and severity of the valve obstruction in 1849 patients having isolated aortic valve replacement for aortic valve stenosis (with or without associated aortic regurgitation) studied at 3 different medical centers in 2 different time periods. Circulation 112: 3919–3929.
- Roberts WC & Ko JM (2005) 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. Circulation 111: 920–925.
- Stephan PJ, Henry AC, Hebeler RF, et al. (1997) Comparison of age, gender, number of aortic valve cusps, concomitant coronary artery bypass grafting, and magnitude of left ventricular-systemic arterial peak systolic gradient in adults having aortic valve replacement for isolated aortic valve stenosis. Am J Cardiol 79: 166–172.
- Collins MJ, Butany J, Borger MA, et al. (2008) Implications of a congenitally abnormal valve: a study of 1025 consecutively excised aortic valves. J Clin Pathol 61: 530–536.
- Chuangsuwanich T, Warnnissorn M, Leksrisakul P, et al. (2004) Pathology and etiology of 110 consecutively removed aortic valves. J Med Assoc Thai 87: 921–934.
- Ward C (2000) Clinical significance of the bicuspid aortic valve. Heart 83: 81–85.
- Timperley J, Milner R, Marshall AJ, & Gilbert TJ (2002) Quadricuspid aortic valves. Clin Cardiol 25: 548–552.
- Cemri M, Cengel A, & Timurkaynak T (2000) Pentacuspid aortic valve diagnosed by transoesophageal echocardiography. Heart 84: E9.
- Martin LJ, Ramachandran V, Cripe LH, et al. (2007) Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum Genet 121: 275–284.
- Osler W (1886) The bicuspid condition of the aortic valve. Trans Assoc Am Physicians 2: 185–192.
- Sievers HH & Schmidtke C (2007) A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 133: 1226–1233.
- Wallby L, Janerot-Sjöberg B, Steffensen T, et al. (2002) T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves. Heart 88: 348–351.
- Mazzone A, Venneri L, & Berti S (2007) Aortic valve stenosis and coronary artery disease: pathophysiological and clinical links. J Cardiovasc Med (Hagerstown) 8: 983–989.
- Agmon Y, Khandheria BK, Meissner I, et al. (2001) Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study. J Am Coll Cardiol 38: 827–834.
- Otto CM & O'Brien KD (2001) Why is there discordance between calcific aortic stenosis and coronary artery disease? Heart 85: 601–602.
- Hughes BR, Chahoud G, & Mehta JL (2005) Aortic stenosis; is it simply a degenerative process or an active atherosclerotic process? Clin Cardiol 28: 111–114.
- Helske S, Kupari M, Lindstedt KA, et al. (2007) Aortic valve stenosis: an active atheroinflammatory process. Curr Opin Lipidol 18: 483–491.
- Mazzone A, Epistolato MC, De Caterina R, et al. (2004) 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 43: 1670–1676.
- Sanchez PL, Santos JL, Kaski JC, et al. (2006) Relation of circulating C-reactive protein to progression of aortic valve stenosis. Am J Cardiol 97: 90–93.
- Otto CM, Kuusisto J, Reichenbach DD, et al. (1994) Charac terization of the early lesion of “degenerative” valvular aortic stenosis. Histological and immunohistochemical studies. Circulation 90: 844–853.
- Aikawa E, Nahrendorf M, Sosnovik D, et al. (2007) Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation 23: 377–386.
- Mirzaie M, Meyer T, Schwarz P, et al. (2002) Ultrastructural alterations in acquired aortic and mitral valve disease as revealed by scanning and transmission electron microscopical investigations. Ann Thorac Cardiovasc Surg 8: 24–30.
- Thubrikar MJ, Aouad J, & Nolan SP (1986) Patterns of calcific deposits in operatively excised stenotic or purely regurgitant aortic valves and their relation to mechanical stress. Am J Cardiol 58: 304–308.
- Butcher JT, Penrod AM, Garcia AJ, et al. (2004) Unique morphology and focal adhesion development of valvular endothelial cells in static und fluid flow environments. Arterioscler Thromb Vasc Biol 24: 1429–1434.
- Poggianti E, Venneri L, Chubuchny V, et al. (2003) Aortic valve sclerosis is associated with systemic endothelial dysfunction. J Am Coll Cardiol 41: 136–141.
- Goland S, Trento A, Czer LS, et al. (2008) Thoracic aortic arteriosclerosis in patients with degenerative aortic stenosis with and without coexisting coronary artery disease. Ann Thorac Surg 85: 113–119.
- Helske S, Oksjoki R, Lindstedt KA, et al. (2008) Complement system is activated in stenotic aortic valves. Atherosclerosis 196: 190–200.
- Oksjoki R, Laine P, Helske S, et al. (2007) Receptors for the anaphylatoxins C3a and C5a are expressed in human athero-sclerotic coronary plaques. Atherosclerosis 195: 90–99.
- Tedgui A & Mallat Z (2001) Anti-inflammatory mechanisms in the vascular wall. Circ Res 88: 877–887.
- Ghaisas NK, Foley JB, O'Briain DS, et al. (2000) Adhesion molecules in nonrheumatic aortic valve disease: endothelial expression, serum levels and effects of valve replacement. J Am Coll Cardiol 36: 2257–2262.
- Helske S, Lindstedt KA, Laine M, et al. (2004) Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol 44: 1859–1866.
- Wallby L, Steffensen T, & Broqvist M (2007) Role of inflammation in nonrheumatic, regurgitant heart valve disease. A comparative, descriptive study regarding apolipoproteins and inflammatory cells in nonrheumatic heart valve disease. Cardiovasc Pathol 16: 171–178.
- Olsson M, Dalsgaard CJ, Haegerstrand A, et al. (1994) Accumulation of T lymphocytes and expression of interleukin-2 receptors in non rheumatic stenotic aortic valves. J Am Coll Cardiol 23: 1162–1170.
- Meng X, Ao L, Song Y, et al. (2008) Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis. Am J Physiol Cell Physiol 294: C29–C35.
- Kaden JJ, Bickelhaupt S, Grobholz R, et al. (2003) Pathogenetic role of Chlamydia pneumoniae in calcific aortic stenosis: immunohistochemistry study and review of the literature. J Heart Valve Dis 12: 447–453.
- Helske S, Syväranta S, Kupari M, et al. (2006) Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves. Eur Heart J 27: 1495–1504.
- Kaden JJ, Kilic R, Sarikoc A, et al. (2005) Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. Int J Mol Med 16: 869–872.
- Soini Y, Salo T, & Satta J (2003) Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis. Hum Pathol 34: 756–763.
- Fondard O, Detaint D, Iung B, et al. (2005) Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. Eur Heart J 26: 1333–1341.
- Mathieu P, Després JP, & Pibarot P (2007) The “valvulo-metabolic” risk in calcific aortic valve disease. Can J Cardiol 23(Suppl. B): 32B–39B.
- Yilmaz MB, Guray U, Guray Y, et al. (2004) Lipid profile of patients with aortic stenosis might be predictive of rate of progression. Am Heart J 147: 915–918.
- Rossebo AB & Pedersen TR (2004) Hyperlipidaemia and aortic valve disease. Curr Opinion Lipidol 15: 447–451.
- Otto CM (2004) Aortic stenosis and hyperlipidemia: establishing a cause-effect relationship. Am Heart J 147: 761–763.
- Wenk MR (2005) The emerging field of lipidomics. Nat Rev Drug Discov 4: 594–610.
- O'Brien KD, Reichenbach DD, Marcovina SM, et al. (1996) Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of “degenerative” valvular aortic stenosis. Arterioscler Thromb Vasc Biol 16: 523–532.
- Tanaka K, Sata M, Fukuda D, et al. (2005) Age-associated aortic stenosis in apolipoprotein E-deficient mice. J Am Coll Cardiol 46: 134–141.
- Mohty D, Pibarot P, Després JP, et al. (2008) Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol 28: 187–193.
- Drolet MC, Roussel E, Deshaies Y, et al. (2006) A high fat/high carbohydrate diet induces aortic valve disease in C57BL/6J mice. J Am Coll Cardiol 47: 850–855.
- Demer LL (2001) Cholesterol in vascular and valvular calcification. Circulation 104: 1881–1883.
- Abedin M, Lim J, Tang TB, et al. (2006) N-3 fatty acids inhibit vascular calcification via the p38-mitogen-activated protein kinase and peroxisome proliferator-activated receptor-gamma pathways. Circ Res 98: 727–729.
- Jacob MP (2003) Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother 57: 195–202.
- Cote C, Pibarot P, Despres JP, et al. (2008) Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis. Heart 94: 1175–1180.
- Kaden JJ, Dempfle CE, Grobholz R, et al. (2005) Inflammatory regulation of extracellular matrix remodelling in calcific aortic valve stenosis. Cardiovasc Pathol 14: 80–87.
- Merryman WD, Lukoff HD, Long RA, et al. (2007) Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast. Cardiovasc Pathol 16: 268–276.
- Galis ZS & Khatri JJ (2002) Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90: 251–262.
- Wilton E, Bland M, Thompson M, et al. (2008) Matrix metalloproteinase expression in the ascending aorta and aortic valve. Interact Cardiovasc Thorac Surg 7: 37–40.
- Satta J, Oiva J, Salo T, et al. (2003) Evidence for an altered balance between matrix metalloproteinase-9 and its inhibitors in calcific aortic stenosis. Ann Thorac Surg 76: 681–688.
- Yeghiazaryan K, Skowasch D, Bauriedel G, et al. (2007) Could activated tissue remodeling be considered as early marker for progressive valve degeneration? Comparative analysis of checkpoint and ECM remodeling gene expression in native degenerating aortic valves and after bioprosthetic replacement. Amino Acids 32: 109–114.
- Stephens EH & Grande-Allen KJ (2007) Age-related changes in collagen synthesis and turnover in porcine heart valves. J Heart Valve Dis 16: 672–682.
- Basta G (2008) Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis 196: 9–21.
- Ahmed SH, Clark LL, Pennington WR, et al. (2006) Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 113: 2089–2096.
- Edep ME, Shirani J, Wolf P, et al. (2000) Matrix metalloproteinase expression in nonrheumatic aortic stenosis. Cardiovasc Pathol 9: 281–286.
- Jian B, Jones PL, Li Q, et al. (2001) Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. Am J Pathol 159: 321–327.
- Olsson M, Rosenqvist M, & Nilsson J (1994) Expression of HLADR antigen and smooth muscle cell differentiation markers by valvular fibroblasts in degenerative aortic stenosis. J Am Coll Cardiol 24: 1664–1671.
- Eriksen HA, Satta J, Risteli J, et al. (2006) Type I and type III collagen synthesis and composition in the valve matrix in aortic valve stenosis. Atherosclerosis 189: 91–98.
- Kurz DJ, Kloeckener-Gruissem B, Akhmedov A, et al. (2006) Degenerative aortic valve stenosis, but not coronary disease, is associated with shorter telomere length in the elderly. Arterioscler Thromb Vasc Biol 26: e114–117.
- Cushing MC, Mariner PD, Liao JT, et al. (2008) Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells. FASEB J 22: 1769–1777.
- O'Brien KD, Shavelle DM, Caulfield MT, et al. (2002) Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma. Circulation 106: 2224–2230.
- Mehta PK & Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292: C82–C97.
- Helske S, Laine M, Kupari M, et al. (2007) Increased expression of profibrotic neutral endopeptidase and bradykinin type 1 receptors in stenotic aortic valves. Eur Heart J 28: 1894–1903.
- Rosenhek R, Binder T, Porenta G, et al. (2000) Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 343: 611–617.
- Strickberger SA, Schulman SP, & Hutchins GM (1987) Association of Paget's disease of bone with calcific aortic valve disease. Am J Med 82: 953–956.
- Palta S, Pai AM, Gill KS, et al. (2000) New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation 101: 2497–2502.
- Maher ER, Pazianas M, & Curtis JR (1987) Calcific aortic stenosis: a complication of chronic uraemia. Nephron 47: 119–122.
- Rajamannan NM & Otto CM (2004) Targeted therapy to prevent progression of calcific aortic stenosis. Circulation 110: 1180–1182.
- Skowasch D, Schrempf S, Preusse CJ, et al. (2006) Tissue resident C reactive protein in degenerative aortic valves: correlation with serum C reactive protein concentrations and modification by statins. Heart 92: 495–498.
- Mathieu P, Voisine P, Pépin A, et al. (2005) Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity. J Heart Valve Dis 14: 353–357.
- Aikawa E, Nahrendorf M, Fiqueiredo JL, et al. (2007) Osteo-genesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 116: 2841–2850.
- Mohler ER (2004) Mechanisms of aortic valve calcification. Am J Cardiol 94: 1396–1402.
- Radcliff K, Tang TB, Lim J, et al. (2005) Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways. Circ Res 96: 398–400.
- Annes JP, Munger JS, & Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116: 217–224.
- Watson KE, Boström K, Ravindranath R, et al. (1994) TGF-beta1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest 93: 2106–2113.
- Clark-Greuel JN, Connolly JM, Sorichillo E, et al. (2007) Transforming growth factor-beta1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. Ann Thorac Surg 83: 946–953.
- Jian B, Xu J, Connolly J, et al. (2002) Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol 161: 2111–2121.
- Xu J, Jian B, Chu R, et al. (2002) Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. Am J Pathol 161: 2209–2218.
- Perco P, Wilflingseder J, Bernthaler A, et al. (2008) Biomarker candidates for cardiovascular disease and bone metabolism disorders in chronic kidney disease: a systems biology perspective. J Cell Mol Med 12: 1177–1187.
- Jian B, Narula N, Li QY, et al. (2003) Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg 75: 457–465.
- Guerraty M & Mohler ER (2007) Models of aortic valve calcification. J Investig Med 55: 278–283.
- Warrier B, Mallipeddi R, Karla PK, et al. (2005) The functional role of C-reactive protein in aortic wall calcification. Cardiology 104: 57–64.
- Satta J, Melkko J, Pöllänen R, et al. (2002) Progression of human aortic valve stenosis is associated with tenascin-C expression. J Am Coll Cardiol 39: 96–101.
- Majumdar R, Miller DV, Ballman KV, et al. (2007) Elevated expressions of osteopontin and tenascin C in ascending aortic aneurysms are associated with trileaflet aortic valves as compared with bicuspid aortic valves. Cardiovasc Pathol 16: 144–150.
- Kaden JJ, Bickelhaupt S, Grobholz R, et al. (2004) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol 36: 57–66.
- Ix JH, Chertow GM, Shlipak MG, et al. (2007) Association of fetuin-A with mitral annular calcification and aortic stenosis among persons with coronary heart disease: data from the heart and soul study. Circulation 115: 2533–2539.
- Mohler ER, Chawla MK, Chang AW, et al. (1999) Identification and characterization of calcifying valve cells from human and canine aortic valves. J Heart Valve Dis 8: 254–260.
- Liberman M, Bassi E, Martinatti MK, et al. (2008) Oxidant generation predominates around calcifying foci and enhances progression of aortic valve calcification. Arterioscler Thromb Vasc Biol 28: 463–470.
- Shen M, Kara-Mostefa A, Chen L, et al. (2001) Effect of ethanol and ether in the prevention of calcification of bioprostheses. Ann Thorac Surg 71: S413–S416.
- Levy RJ (1997) Strategies to mitigate mineralization in the bio-prosthetic or homograft cusp and aortic wall. J Heart Valve Dis 6: 7–8.
- Li AC & Glass CK (2002) The macrophage foam cell as a target for therapeutic intervention. Nat Med 8: 1235–1242.
- Morony S, Tintut Y, Zhang Z, et al. (2008) Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(-/-) mice. Circulation 117: 411–420.
- Mohler ER, Gannon F, Reynolds C, et al. (2001) Bone formation and inflammation in cardiac valves. Circulation 103: 1522–1528.
- Leskelä HV, Satta J, Oiva J, et al. (2006) Calcification and cellularity in human aortic heart valve tissue determine the differentiation of bone-marrow-derived cells. J Mol Cell Cardiol 41: 642–649.
- Caira FC, Stock SR, Gleason TG, et al. (2006) Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol 47: 1707–1712.
- Boland GM, Perkins G, Hall DJ, et al. (2004) Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem 93: 1210–1230.
- Baksh D, Boland GM, & Tuan RS (2007) Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation. J Cell Biochem 101: 1109–1124.
- Garg V, Muth AN, Ransom JF, et al. (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437: 270–274.
- O'Brien KD (2006) Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more). Arterioscler Thromb Vasc Biol 26: 1721–1728.
- Novaro GM, Sachar R, Pearce GL, et al. (2003) Association between apolipoprotein E alleles and calcific valvular heart disease. Circulation 108: 1804–1808.
- Ortlepp JR, Pillich M, Mevissen V, et al. (2006) APOE alleles are not associated with calcific aortic stenosis. Heart 92: 1463–1466.
- Ortlepp JR, Hoffmann R, Ohme F, et al. (2001) The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis. Heart 85: 635–638.
- Araújo-Vilar D, Lado-Abeal J, Palos-Paz F, et al. (2008) A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy. Clin Endocrinol (Oxf.) 69: 61–68.
- Salo T, Soini Y, Oiva J, et al. (2006) Chemically modified tetracyclines (CMT-3 and CMT-8) enable control of the pathologic remodellation of human aortic valve stenosis via MMP-9 and VEGF inhibition. Int J Cardiol 111: 358–364.
- Yoshioka M, Yuasa S, Matsumura K, et al. (2006) Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. Nat Med 12: 1151–1159.
- Goldbarg SH, Elmariah S, Miller MA, et al. (2007) Insights into degenerative aortic valve disease. J Am Coll Cardiol 50: 1205–1213.
- Rajamannan NM, Subramaniam M, Springett M, et al. (2002) Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 105: 2660–2665.
- Osman L, Yacoub MH, Latif N, et al. (2006) Role of human valve interstitial cells in valve calcification and their response to atorvastatin. Circulation 114(1 Suppl.): I547–I552.
- Rajamannan NM, Subramaniam M, Caira F, et al. (2005) Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation 112(9 Suppl.): I229–I234.
- Osman L, Chester AH, Amrani M, et al. (2006) A novel role of extracellular nucleotides in valve calcification: a potential target for atorvastatin. Circulation 114(1 Suppl.): I566–I572.
- Osman L, Chester AH, Sarathchandra P, et al. (2007) A novel role of the sympatho-adrenergic system in regulating valve calcification. Circulation 116(11 Suppl.): I282–I287.
- Arishiro K, Hoshiga M, Negoro N, et al. (2007) Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits. J Am Coll Cardiol 49: 1482–1489.
- Brown ML, Pellikka PA, Schaff HV, et al. (2008) The benefits of early valve replacement in asymptomatic patients with severe aortic stenosis. J Thorac Cardiovasc Surg 135: 308–315.
- Han RK, Gurofsky RC, Lee KJ, et al. (2007) Outcome and growth potential of left heart structures after neonatal intervention for aortic valve stenosis. J Am Coll Cardiol 50: 2406–2414.
- Avakian SD, Grinberg M, Ramires JA, et al. (2008) Outcome of adults with asymptomatic severe aortic stenosis. Int J Cardiol 123: 322–327.
- Morgan-Hughes GJ, Roobottom CA, Owens PE, et al. (2004) Dilation of the aorta in pure, severe, bicuspid aortic valve stenosis. Am Heart J 147: 736–740.
- Bauer M, Gliech V, Siniawski H, et al. (2006) Configuration of the ascending aorta in patients with bicuspid and tricuspid aortic valve disease undergoing aortic valve replacement with or without reduction aortoplasty. J Heart Valve Dis 15: 594–600.