title: Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice.
abstract: OBJECTIVE
  We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice.
  
  
  RESULTS
  At 1.5 months of age, before development of valve fibrosis and calcification, aortic regurgitation, but not aortic stenosis, was common in Wave mice. Aortic valve fibrosis, profibrotic signaling, calcification, osteogenic markers, lipid deposition, and apoptosis increased dramatically by 6 and 12 months of age in Wave mice. Aortic regurgitation remained prevalent, however, and aortic stenosis was rare, at all ages. Proteoglycan content was abnormally increased in aortic valves of Wave mice at all ages. Treatment with pioglitazone prevented abnormal valve calcification, but did not protect valve function. There was significant left ventricular volume overload, hypertrophy, and fetal gene expression, at all ages in Wave mice with aortic regurgitation. Left ventricular systolic function was normal until 6 months of age in Wave mice, but became impaired by 12 months of age. Myocardial transverse tubules were normal in the presence of left ventricular hypertrophy at 1.5 and 3 months of age, but became disrupted by 12 months of age.
  
  
  CONCLUSIONS
  We present the first comprehensive phenotypic and molecular characterization of spontaneous aortic regurgitation and volume-overload cardiomyopathy in an experimental model. In Wave mice, fibrocalcific changes are not linked to valve dysfunction and are epiphenomena arising from structurally incompetent myxomatous valves.
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Georges P
authors.initials: GP
authors.lastname: Hajj
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Lund
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Magida
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Funk
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brooks
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Baumbach
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Zimmerman
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Melissa K
authors.initials: MK
authors.lastname: Davis
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Ramzi N
authors.initials: RN
authors.lastname: El Accaoui
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Tariq
authors.initials: T
authors.lastname: Hameed
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Hardik
authors.initials: H
authors.lastname: Doshi
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: BiYi
authors.initials: B
authors.lastname: Chen
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder.
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder. robert-weiss@uiowa.edu donald-heistad@uiowa.edu.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
authors.affiliation: From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder. robert-weiss@uiowa.edu donald-heistad@uiowa.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001022:Aortic Valve Insufficiency / Q000473:pathology* / Q000503:physiopathology*; D002114:Calcinosis / Q000473:pathology / Q000517:prevention & control; D016923:Cell Death; D018450:Disease Progression; D005355:Fibrosis; D015870:Gene Expression; D006349:Heart Valve Diseases / Q000473:pathology* / Q000503:physiopathology*; D050356:Lipid Metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D015675:Osteocalcin / Q000378:metabolism; D000077205:Pioglitazone; D011509:Proteoglycans / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D013599:Systole; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D011509:Proteoglycans; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D045162:Thiazolidinediones; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; D000077205:Pioglitazone
keywords: aortic regurgitation; aortic stenosis; aortic valve disease; cardiomyopathy