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J Cardiovasc Dev Dis. 2015;2(2):48-65. Epub 2015 Apr 21.

Targeted Mybpc3 Knock-Out Mice with Cardiac Hypertrophy Exhibit Structural Mitral Valve Abnormalities.

Author information

1
Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Division of Cardiology, Johns Hopkins University, Baltimore, MD 21287, USA.
2
Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France; Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris 75016 France.
3
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29403, USA.
4
Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA.
5
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853 USA.
6
INSERM U582, University Pierre et Marie Curie-Paris 6, IFR14, Paris 75005 France.
7
Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris 75016 France.
8
Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Institut de recherche des Cordeliers, INSERM U652, Paris 75005, France.
9
Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France.
10
Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005 France; Paris Cardiovascular Research Center, INSERM U970, Paris 75016 France.
11
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
12
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.

Abstract

MYBPC3 mutations 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 compare Mybpc3-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 in Mybpc3-null mice (1.92 ± 0.08 vs. 1.72 ± 0.08 mm, p < 0.001), as was combined leaflet thickness (0.23 ± 0.04 vs. 0.15 ± 0.02 mm, p < 0.001). Micro-CT analyses of Mybpc3-null mice demonstrated increased MV volume (0.47 ± 0.06 vs. 0.15 ± 0.06 mm3, p = 0.018) and thickness (0.35 ± 0.04 vs. 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 with MYBPC3 mutation 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.

KEYWORDS:

TGFβ; hypertrophic cardiomyopathy; mitral valve

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