title: TargetedMybpc3Knock-Out Mice with Cardiac Hypertrophy Exhibit Structural Mitral Valve Abnormalities.
abstract: MYBPC3mutations cause hypertrophic cardiomyopathy, which is frequently associated with mitral valve (MV) pathology. We reasoned that increased MV size is caused by localized growth factors with paracrine effects. We used high-resolution echocardiography to compareMybpc3-null, heterozygous, and wild-type mice (n= 84, aged 3-6 months) and micro-CT for MV volume (n= 6, age 6 months).Mybpc3-null mice showed left ventricular hypertrophy, dilation, and systolic dysfunction compared to heterozygous and wild-type mice, but no systolic anterior motion of the MV or left ventricular outflow obstruction. Compared to wild-type mice, echocardiographic anterior leaflet length (adjusted for left ventricular size) was greatest inMybpc3-null mice (1.92 ± 0.08vs. 1.72 ± 0.08 mm,p< 0.001), as was combined leaflet thickness (0.23 ± 0.04vs. 0.15 ± 0.02 mm,p< 0.001). Micro-CT analyses ofMybpc3-null mice demonstrated increased MV volume (0.47 ± 0.06vs. 0.15 ± 0.06 mm3,p= 0.018) and thickness (0.35 ± 0.04vs. 0.12 ± 0.04 mm,p= 0.002), coincident with increased markers of TGFβ activity compared to heterozygous and wild-type littermates. Similarly, excised MV from a patient withMYBPC3mutation showed increased TGFβ activity. We conclude that MYBPC3 deficiency causes hypertrophic cardiomyopathy with increased MV leaflet length and thickness despite the absence of left ventricular outflow-tract obstruction, in parallel with increased TGFβ activity. MV changes in hypertrophic cardiomyopathy may be due to paracrine effects, which represent targets for therapeutic studies.
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Division of Cardiology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.affiliation: Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France; Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris 75016 France.
authors.forename: Hany
authors.initials: H
authors.lastname: Neamatalla
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29403, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Levine
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853 USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Butcher
authors.affiliation: INSERM U582, University Pierre et Marie Curie-Paris 6, IFR14, Paris 75005 France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignier
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853 USA.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Kang
authors.affiliation: Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris 75016 France.
authors.forename: Quangtung
authors.initials: Q
authors.lastname: Nguyen
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Institut de recherche des Cordeliers, INSERM U652, Paris 75005, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Perier
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Messas
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29403, USA.
authors.forename: Annemarieke
authors.initials: A
authors.lastname: de Vlaming
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29403, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Markwald
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France; Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris 75016 France.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Hagège
keywords: TGFβ; hypertrophic cardiomyopathy; mitral valve
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