title: Calcific aortic valve stenosis: methods, models, and mechanisms.
abstract: Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, nonosseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High-resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research.
authors: Department of Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA. miller.jordan@mayo.edu
authors: Jordan D
authors: JD
authors: Miller
authors: Robert M
authors: RM
authors: Weiss
authors: Donald D
authors: DD
authors: Heistad
references: J Bone Miner Res. 2011 Feb;26(2):317-30
references: 20740684
references: Circ Res. 2009 May 8;104(9):1041-8
references: 19325147
references: Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):463-70
references: 18162610
references: J Vasc Res. 2011;48(3):227-35
references: 21099228
references: J Am Coll Cardiol. 2006 Jun 6;47(11):2303-9
references: 16750700
references: Dev Biol. 2010 Nov 1;347(1):167-79
references: 20804746
references: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4477-82
references: 15070743
references: Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2058-64
references: 17615383
references: N Engl J Med. 2005 Jun 9;352(23):2389-97
references: 15944423
references: J Microsc. 2005 May;218(Pt 2):171-9
references: 15857378
references: Hypertens Res. 2011 Jan;34(1):5-14
references: 20981034
references: Am J Cardiol. 2001 Jul 19;88(2A):16E-19E
references: 11473739
references: Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):936-42
references: 19304575
references: Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H569-77
references: 18539760
references: J Cardiovasc Magn Reson. 2009 Aug 11;11:27
references: 19671155
references: Circ Res. 2005 Apr 15;96(7):792-9
references: 15761200
references: PLoS One. 2010 Oct 11;5(10):e13254
references: 20949008
references: J Endocrinol Invest. 2009;32(4 Suppl):6-9
references: 19724159
references: Cell. 1997 Apr 18;89(2):309-19
references: 9108485
references: Nitric Oxide. 2007 Mar;16(2):197-201
references: 17126043
references: Am J Pathol. 2009 Feb;174(2):693-700
references: 19131590
references: J Am Coll Cardiol. 2006 Apr 18;47(8):1707-12
references: 16631011
references: Am J Pathol. 2001 Oct;159(4):1335-43
references: 11583961
references: Eur Heart J. 2005 Jul;26(13):1333-41
references: 15827062
references: Nat Clin Pract Cardiovasc Med. 2008 Jun;5(6):338-49
references: 18461048
references: J Int Med Res. 2009 May-Jun;37(3):847-54
references: 19589269
references: Arterioscler Thromb Vasc Biol. 2002 Jun 1;22(6):975-82
references: 12067907
references: Br J Pharmacol. 2011 Feb;162(3):722-32
references: 20958293
references: Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):708-15
references: 20110570
references: Circulation. 2005 Jun 21;111(24):3296-301
references: 15956138
references: Redox Rep. 2010;15(2):50-63
references: 20500986
references: Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1510-6
references: 16690876
references: Atherosclerosis. 2010 Jun;210(2):614-8
references: 20074734
references: Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):642-8
references: 17185617
references: Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1933-9
references: 20689078
references: Tissue Eng. 2007 Jan;13(1):41-9
references: 17518580
references: Arterioscler Thromb Vasc Biol. 2002 Jul 1;22(7):1225-31
references: 12117742
references: Hum Pathol. 2003 Aug;34(8):756-63
references: 14506635
references: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2576-81
references: 17962626
references: Cardiovasc Pathol. 2009 Mar-Apr;18(2):67-76
references: 18402835
references: Circulation. 1998 Aug 25;98(8):800-7
references: 9727551
references: Am J Physiol Endocrinol Metab. 2004 May;286(5):E686-96
references: 15102615
references: J Heart Valve Dis. 2008 Mar;17(2):187-93
references: 18512489
references: J Clin Invest. 2010 Jul;120(7):2292-306
references: 20551517
references: Cardiovasc Pathol. 2000 Sep-Oct;9(5):281-6
references: 11064275
references: Trends Cell Biol. 2010 Oct;20(10):609-17
references: 20810283
references: Circulation. 2007 Jan 23;115(3):377-86
references: 17224478
references: Arterioscler Thromb. 1991 Jul-Aug;11(4):947-57
references: 2065045
references: Circulation. 2007 May 15;115(19):2464-7
references: 17502586
references: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21790-4
references: 21098266
references: Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1104-11
references: 19407244
references: Cardiovasc Res. 2011 Feb 1;89(2):446-56
references: 20829218
references: J Am Coll Cardiol. 2007 Feb 6;49(5):554-61
references: 17276178
references: Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):489-94
references: 12615658
references: FEBS Lett. 2006 Jul 24;580(17):4121-5
references: 16828750
references: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18813-8
references: 16354837
references: Circ Res. 2005 Oct 28;97(9):900-7
references: 16179589
references: Circulation. 2010 Mar 2;121(8):1022-32
references: 20194875
references: J Am Coll Cardiol. 2005 Jul 5;46(1):134-41
references: 15992647
references: Cardiovasc Pathol. 2005 Mar-Apr;14(2):80-7
references: 15780799
references: Nature. 2005 Sep 8;437(7056):270-4
references: 16025100
references: Nature. 2010 Aug 12;466(7308):835-40
references: 20703300
references: Free Radic Biol Med. 2010 Mar 1;48(5):642-55
references: 20036736
references: Circ Res. 2011 Jan 21;108(2):219-34
references: 21252150
references: Curr Osteoporos Rep. 2009 Jul;7(2):42-6
references: 19631027
references: Annu Rev Immunol. 2009;27:165-97
references: 19302038
references: Hypertension. 2010 Feb;55(2):445-52
references: 20026757
references: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2589-96
references: 17932314
references: Trends Pharmacol Sci. 2008 Jul;29(7):367-74
references: 18579222
references: J Am Coll Cardiol. 1997 Mar 1;29(3):630-4
references: 9060903
references: J Heart Valve Dis. 2009 Mar;18(2):152-8
references: 19455889
references: J Clin Invest. 2010 Oct;120(10):3493-507
references: 20890042
references: J Clin Endocrinol Metab. 2010 Feb;95(2):592-600
references: 20061432
references: J Heart Valve Dis. 2005 May;14(3):365-75
references: 15974532
references: J Mol Cell Cardiol. 2004 Jan;36(1):57-66
references: 14734048
references: Eur J Pharmacol. 2008 Aug 20;590(1-3):290-6
references: 18585377
references: Antioxid Redox Signal. 2009 Jun;11(6):1415-52
references: 19061437
references: Circulation. 2009 Mar 17;119(10):1386-97
references: 19255345
references: J Cardiovasc Med (Hagerstown). 2011 Feb;12(2):96-101
references: 20625307
references: Arthritis Res Ther. 2007;9 Suppl 1:S1
references: 17634140
references: J Heart Valve Dis. 2001 May;10(3):371-4
references: 11380101
references: J Am Coll Cardiol. 2006 Feb 21;47(4):850-5
references: 16487855
references: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):225-31
references: 19926833
references: Hypertension. 2010 Apr;55(4):990-7
references: 20176996
references: Eur J Pharmacol. 2010 Sep 10;642(1-3):107-12
references: 20553922
references: Cell Cycle. 2010 Aug 1;9(15):2979-85
references: 20699646
references: J Am Coll Cardiol. 2008 Sep 2;52(10):843-50
references: 18755348
references: J Heart Valve Dis. 2010 Jul;19(4):441-52
references: 20845891
references: J Cardiovasc Magn Reson. 2009 May 19;11:16
references: 19454023
references: Cardiovasc Pathol. 2000 Jan-Feb;9(1):53-4
references: 10739908
references: J Clin Invest. 1991 Jan;87(1):221-8
references: 1845868
references: Nature. 1997 Mar 6;386(6620):78-81
references: 9052783
references: J Bone Miner Metab. 2005;23(4):275-9
references: 15981022
references: Blood. 2010 Oct 14;116(15):e66-73
references: 20551377
references: Am J Cardiol. 2010 Dec 1;106(11):1634-9
references: 21094366
references: Circulation. 2006 Nov 7;114(19):2065-9
references: 17075015
references: Hypertension. 2009 Sep;54(3):619-24
references: 19620507
references: Circ Res. 2005 Dec 9;97(12):1232-5
references: 16339495
references: J Am Coll Cardiol. 2004 Nov 2;44(9):1859-66
references: 15519020
references: Circulation. 2010 May 25;121(20):2200-10
references: 20458013
references: J Cardiovasc Med (Hagerstown). 2007 Dec;8(12):983-9
references: 18163008
references: J Am Soc Nephrol. 2004 Nov;15(11):2857-67
references: 15504939
references: Circulation. 2001 Mar 20;103(11):1522-8
references: 11257079
references: J Heart Valve Dis. 2010 Jul;19(4):466-70
references: 20845894
references: Circulation. 2002 Jun 4;105(22):2660-5
references: 12045173
references: Atherosclerosis. 2003 Oct;170(2):205-11
references: 14612199
references: Mod Pathol. 2007 Mar;20(3):357-66
references: 17334330
references: Free Radic Biol Med. 2009 Dec 15;47(12):1673-706
references: 19751821
references: Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15902-7
references: 18838683
references: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15877-82
references: 14673088
references: N Engl J Med. 2007 Dec 13;357(24):2482-94
references: 18077812
references: Med Clin North Am. 2009 May;93(3):621-35
references: 19427495
references: Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):689-95
references: 16410455
references: Nature. 1998 Jan 1;391(6662):79-82
references: 9422508
references: Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1478-80
references: 19592469
references: Arterioscler Thromb Vasc Biol. 2011 Mar;31(3):590-7
references: 21127288
references: Matrix Biol. 2005 Sep;24(6):428-37
references: 16055320
references: Curr Med Chem. 2006;13(17):1971-8
references: 16842191
references: J Mol Cell Cardiol. 2011 Mar;50(3):561-9
references: 21163264
references: Eur Heart J. 2006 Jun;27(12):1495-504
references: 16401677
references: Circulation. 2008 Oct 7;118(15):e523-661
references: 18820172
references: Ann N Y Acad Sci. 2006 Apr;1068:489-97
references: 16831946
references: J Biomed Mater Res A. 2009 Sep 15;90(4):1043-53
references: 18671262
references: Circulation. 1995 Feb 15;91(4):1129-34
references: 7850951
references: J Mol Cell Cardiol. 2009 Dec;47(6):828-34
references: 19695258
references: Hypertens Res. 2010 Mar;33(3):269-74
references: 20057483
references: Ageing Res Rev. 2010 Nov;9 Suppl 1:S59-66
references: 20708718
references: J Biol Chem. 2003 Dec 12;278(50):50195-202
references: 14504275
references: Biochem Biophys Res Commun. 2009 Nov 6;389(1):138-44
references: 19715669
references: Am J Pathol. 2001 Jul;159(1):321-7
references: 11438479
references: J Microsc. 2005 Apr;218(Pt 1):68-78
references: 15817065
references: Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2482-6
references: 20864669
references: Free Radic Biol Med. 2009 Jul 15;47(2):189-99
references: 19409483
references: Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):162-8
references: 19023094
references: Cell Metab. 2010 Feb 3;11(2):136-46
references: 20142101
references: Am J Nephrol. 2011;33(3):250-9
references: 21372560
references: Circulation. 2004 Sep 7;110(10):1291-5
references: 15337704
references: Arch Intern Med. 2005 Apr 25;165(8):858-62
references: 15851635
references: Bone. 2007 May;40(5):1370-7
references: 17320497
references: J Heart Valve Dis. 2004 Sep;13(5):866-9
references: 15473493
references: Nat Rev Cardiol. 2010 Sep;7(9):528-36
references: 20664518
references: J Am Coll Cardiol. 2007 Apr 3;49(13):1482-9
references: 17397679
references: J Magn Reson Imaging. 2010 Jan;31(1):110-6
references: 20027578
references: Cell. 2006 Aug 25;126(4):677-89
references: 16923388
references: Hypertension. 2005 May;45(5):840-4
references: 15738342
references: Int J Immunopathol Pharmacol. 2009 Oct-Dec;22(4):911-8
references: 20074454
references: Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H65-75
references: 19448146
references: Nat Genet. 2000 Feb;24(2):171-4
references: 10655064
references: Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):254-60
references: 19023092
references: Circulation. 1994 Aug;90(2):844-53
references: 7519131
references: J Heart Valve Dis. 2008 Nov;17(6):689-99
references: 19137803
references: Circ Res. 2010 Jul 9;107(1):106-16
references: 20448215
references: Arterioscler Thromb Vasc Biol. 2011 Mar;31(3):598-607
references: 21164078
references: Circulation. 2000 May 23;101(20):2345-8
references: 10821808
references: Adv Exp Med Biol. 2009;647:130-45
references: 19760071
references: J Clin Endocrinol Metab. 2010 Oct;95(10):4560-5
references: 20631021
references: Diabetes Care. 2008 May;31(5):845-51
references: 18223031
references: Eur Heart J. 2010 Aug;31(16):2049-57
references: 20304838
references: Circulation. 2007 Nov 6;116(19):2182-90
references: 17967777
references: Circulation. 2008 Jan 22;117(3):411-20
references: 18172035
references: J Vasc Res. 2009;46(6):572-80
references: 19571577
references: Circ Res. 2008 Feb 15;102(3):283-94
references: 18276926
references: Circ J. 2009 Feb;73(2):201-7
references: 19110503
references: Physiol Genomics. 2004 Jun 17;18(1):33-42
references: 15054141
references: Am Heart J. 1962 Sep;64:334-46
references: 14468738
references: Circ J. 2010 May;74(5):818-26
references: 20424337
references: Dev Biol. 2010 Feb 15;338(2):127-35
references: 19961844
references: Circulation. 2010 Feb 16;121(6):759-67
references: 20124122
references: Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1791-8
references: 16728655
references: Atherosclerosis. 2008 Aug;199(2):288-94
references: 18096165
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11201-6
references: 14500910
references: Am J Physiol Heart Circ Physiol. 2009 Jan;296(1):H220-5
references: 19028794
references: Toxicol Pathol. 2010 Dec;38(7):1011-25
references: 21030683
references: Blood. 2005 Aug 1;106(3):852-9
references: 15817678
references: Clin Sci (Lond). 2010 May 06;119(3):131-42
references: 20337596
references: Ann Thorac Cardiovasc Surg. 2001 Dec;7(6):378-80
references: 11888480
references: J Microsc. 2007 Oct;228(Pt 1):45-54
references: 17910697
references: Am J Cardiol. 2008 May 22;101(10A):14D-19D
references: 18474268
references: Circ Res. 2010 Aug 20;107(4):466-75
references: 20595654
references: J Bone Miner Res. 2010 Sep;25(9):1996-2005
references: 20499380
references: Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):653-61
references: 19910640
references: Hypertension. 2010 Mar;55(3):579-92
references: 20101002
references: J Heart Valve Dis. 2010 Jul;19(4):459-65
references: 20845893
references: Ann Thorac Surg. 2007 Mar;83(3):946-53
references: 17307438
references: Basic Res Cardiol. 1994 Sep-Oct;89(5):397-410
references: 7535519
references: Circ Res. 2007 Mar 16;100(5):738-46
references: 17293478
references: J Am Coll Cardiol. 2011 Jan 18;57(3):337-47
references: 21106318
references: Eur J Pharmacol. 2009 Jan 5;602(1):28-35
references: 19056377
references: Eur Heart J. 2010 Aug;31(16):1975-84
references: 20601388
references: Heart. 2006 Dec;92(12):1844-9
references: 16709694
references: Circulation. 2010 Jan 19;121(2):306-14
references: 20048204
references: Free Radic Biol Med. 2011 Apr 1;50(7):765-76
references: 21172428
references: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2480-8
references: 18390820
references: Atherosclerosis. 2010 Nov;213(1):8-20
references: 20494361
references: Circ Res. 2009 Sep 11;105(6):575-84
references: 19661459
references: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2117-24
references: 16840715
references: Circ Res. 2004 Aug 6;95(3):253-60
references: 15217906
references: Circ Res. 2006 Mar 17;98(5):690-6
references: 16456103
references: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13027-32
references: 18723672
references: J Biol Chem. 2008 May 30;283(22):15319-27
references: 18378684
references: Nat Med. 2006 Oct;12(10):1151-9
references: 16980969
references: Circulation. 2005 Jun 21;111(24):3316-26
references: 15967862
references: Circulation. 2009 May 26;119(20):2693-701
references: 19433756
references: Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1387-96
references: 21454810
references: J Heart Valve Dis. 2008 Jul;17(4):381-7
references: 18751467
references: Antioxid Redox Signal. 2009 May;11(5):1191-225
references: 19061441
references: Circulation. 1994 Apr;89(4):1810-8
references: 8149547
references: J Clin Invest. 2002 Aug;110(3):331-40
references: 12163452
references: J Biol Chem. 2004 Oct 1;279(40):41998-2007
references: 15292260
references: J Heart Valve Dis. 1999 May;8(3):254-60
references: 10399657
references: Z Kardiol. 2000;89 Suppl 2:28-35
references: 10769401
references: Circ Res. 2010 Aug 20;107(4):485-94
references: 20576934
references: Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2301-9
references: 20798379
references: Physiol Genomics. 2009 Nov 6;39(3):160-8
references: 19723774
references: J Clin Invest. 2004 Dec;114(11):1564-76
references: 15578089
references: J Biol Chem. 2009 Apr 3;284(14):9083-92
references: 19193641
references: Mech Ageing Dev. 2005 Dec;126(12):1274-83
references: 16144705
references: N Engl J Med. 2008 Sep 25;359(13):1343-56
references: 18765433
references: Tissue Eng. 2004 Sep-Oct;10(9-10):1368-75
references: 15588397
references: Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):237-9
references: 21248279
references: Atherosclerosis. 2010 Dec;213(2):385-91
references: 20850749
references: Nature. 1997 Nov 6;390(6655):45-51
references: 9363890
references: Cardiovasc Pathol. 2011 Nov-Dec;20(6):334-42
references: 21185747
references: Circulation. 2009 Apr 7;119(13):1785-94
references: 19307473
references: Lancet. 2006 Sep 16;368(9540):1005-11
references: 16980116
references: Circulation. 2003 May 6;107(17):2181-4
references: 12719282
references: Aging (Albany NY). 2010 Jun;2(6):353-60
references: 20606253
references: Heart. 2004 Aug;90(8):893-901
references: 15253962
references: J Am Coll Cardiol. 2002 Jan 2;39(1):96-101
references: 11755293
references: Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):337-44
references: 20966394
references: Heart. 2005 Jun;91(6):806-10
references: 15894785
references: Diabetes. 2009 Apr;58(4):813-9
references: 19136658
references: N Engl J Med. 2005 May 12;352(19):1959-66
references: 15888696
references: Ann Thorac Surg. 2003 Feb;75(2):457-65; discussion 465-6
references: 12607654
references: Z Kardiol. 2004 Feb;93(2):124-30
references: 14963678
references: Circulation. 2007 Dec 11;116(24):2841-50
references: 18040026
references: Circulation. 2005 Aug 30;112(9 Suppl):I229-34
references: 16159822
references: Free Radic Biol Med. 2001 Aug 15;31(4):509-19
references: 11498284
references: Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):246-53
references: 19023089