title: Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans.
abstract: BACKGROUND
  Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding.
  
  
  METHODS
  To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1(C1039G/+) mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction.
  
  
  RESULTS
  Fbn1(C1039G/+) mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort.
  
  
  CONCLUSIONS
  In analogy with what is observed in the majority of MFS patients, the Fbn1(C1039G/+) mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS.
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Campens
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.affiliation: IBiTech-bioMMeda, Ghent University, Ghent, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Trachet
authors.affiliation: IBiTech-bioMMeda, Ghent University, Ghent, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Segers
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Muino Mosquera
authors.affiliation: Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: De Sutter
authors.affiliation: Shriners Hospital for Children, Oregon Health & Science University, Portland, Oregon.
authors.forename: Lynn
authors.initials: L
authors.lastname: Sakai
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Julie
authors.identifier: 0000000188781507
authors.initials: J
authors.lastname: De Backer
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000150:complications* / Q000473:pathology; D015331:Cohort Studies; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D008297:Male; D008382:Marfan Syndrome / Q000150:complications* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left; D016277:Ventricular Function, Left; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D016023:Integrins; D008840:Microfilament Proteins; D053773:Transforming Growth Factor beta1; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse