title: A Novel Murine Model of Marfan Syndrome Accelerates Aortopathy and Cardiomyopathy.
abstract: BACKGROUND
  Marfan syndrome (MFS) represents a genetic disorder with variable phenotypic expression. The main cardiovascular sequelae of MFS include aortic aneurysm/dissection and cardiomyopathy. Although significant advances in the understanding of transforming growth factor beta signaling have led to promising therapeutic targets for the treatment of aortopathy, clinical studies have tempered this optimism. In particular, these studies suggest additional signaling pathways that play a significant role in disease progression. To date, studies aimed at elucidating molecular mechanisms involved in MFS-induced disease progression have been hampered by the lack of an accelerated disease model.
  
  
  METHODS
  Wild-type B6.129 mice and MFS Fbn1C1039G/+mice underwent subcutaneous, cervical osmotic minipump installation with sodium chloride (wild-type mice, n = 39; MFS mice, n = 12) or angiotensin II, 4.5 mg/kg daily (wild-type mice, n = 11; MFS mice; n = 35) for as long as 28 days. Hemodynamic measurements were obtained throughout the experiment. Aortas and hearts were analyzed by transthoracic echocardiography and histopathology study.
  
  
  RESULTS
  This accelerated murine MFS model replicates increased mortality from MFS-related maladies (20.0%, 39.3%, and 52.9% at 10, 14, and 28 days, respectively). Aortic diameters in accelerated MFS mice were significantly enlarged at 10 days after minipump implantation and correlated with a higher degree of elastin fragmentation. Accelerated MFS mice also demonstrated dilated cardiomyopathy at 14 days, even without aortic insufficiency, suggesting an intrinsic etiology.
  
  
  CONCLUSIONS
  A novel in vivo model consisting of subcutaneously delivered angiotensin II in MFS mice reproducibly causes accelerated aortic aneurysm formation and cardiomyopathy. This model allows for better investigation of MFS sequelae by rapid experimental processes.
authors.affiliation: Department of Cardiothoracic Surgery, Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Cavanaugh
authors.affiliation: Department of Cardiothoracic Surgery, Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Cardiothoracic Surgery, Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Westergaard
authors.affiliation: Department of Internal Medicine, Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kutschke
authors.affiliation: Department of Cardiothoracic Surgery, Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Ella J
authors.initials: EJ
authors.lastname: Born
authors.affiliation: Department of Cardiothoracic Surgery, Francois M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa. Electronic address: joseph-turek@uiowa.edu.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Turek
mesh_terms: D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000175:diagnosis / Q000209:etiology*; D009202:Cardiomyopathies / Q000175:diagnosis / Q000209:etiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D006352:Heart Ventricles / Q000000981:diagnostic imaging*; D008382:Marfan Syndrome / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta