title: Cellular, structural and functional cardiac remodelling following pressure overload and unloading.
abstract: BACKGROUND
  The cardiac remodelling process in advanced heart failure due to pressure overload has not been clearly defined but likely involves mechanisms of cardiac fibrosis and cardiomyocyte hypertrophy. The aim of this study was to examine pressure overload (PO)-induced cardiac remodelling processes and their reversibility after unloading in both humans with heart failure and a mouse model of PO induced by aortic constriction.
  
  
  RESULTS
  Speckle tracking echocardiography showed PO-induced cardiac dysfunction in mice was reversible after removal of aortic constriction to unload. Masson's Trichrome staining suggested that PO-induced myocardial fibrosis was reversible, however detailed analysis of 3-dimensional collagen architecture by scanning electron microscopy demonstrated that matrix remodelling was not completely normalised as a disorganised network of thin collagen fibres was evident. Analysis of human left ventricular biopsy samples from HF patients revealed increased presence of large collagen fibres which were greatly reduced in paired samples from the same individuals after unloading by left ventricular assist device implantation. Again, an extensive network of small collagen fibres was still clearly seen to closely surround cardiomyocytes after unloading. Other features of PO-induced remodelling including increased myofibroblast content, cardiomyocyte disarray and hypertrophy were largely reversed upon unloading in both humans and mouse model. Previous work in humans demonstrated that receptors for adiponectin, an important mediator of cardiac fibrosis and hypertrophy, decreased in heart failure patients and returned to normal after unloading. Here we provide novel data showing a similar trend for adiponectin receptor adaptor protein APPL1, but not APPL2 isoform.
  
  
  CONCLUSIONS
  LV unloading diminishes PO-induced cardiac remodelling and improves function. These findings add new insights into the cardiac remodelling process, and provide novel targets for future pharmacologic therapies.
authors.affiliation: Department of Biology, York University, Toronto, Canada.
authors.forename: Keith
authors.initials: K
authors.lastname: Dadson
authors.affiliation: Department of Biology, York University, Toronto, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Kovacevic
authors.affiliation: Department of Biology, York University, Toronto, Canada.
authors.forename: Palanivel
authors.initials: P
authors.lastname: Rengasamy
authors.affiliation: Department of Biology, York University, Toronto, Canada.
authors.forename: Grace Ha Eun
authors.initials: GH
authors.lastname: Kim
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Canada.
authors.forename: Stellar
authors.initials: S
authors.lastname: Boo
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.affiliation: Department of Internal Medicine I, Division of Cardiology, Friedrich Schiller University Jena, Jena, Germany; Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: George
authors.affiliation: Department of Internal Medicine I, Division of Cardiology, Friedrich Schiller University Jena, Jena, Germany; Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, USA.
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Canada.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.affiliation: Department of Biology, York University, Toronto, Canada. Electronic address: gsweeney@yorku.ca.
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications*; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism; D003094:Collagen / Q000648:ultrastructure*; D004195:Disease Models, Animal; D004452:Echocardiography; D006333:Heart Failure / Q000473:pathology*; D006352:Heart Ventricles / Q000000981:diagnostic imaging* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D020257:Ventricular Remodeling
chemical_list: C464801:APPL1 protein, human; C528555:APPL2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D003094:Collagen
keywords: Adiponectin; Autophagy; Extracellular matrix; Fibrosis; Pressure overload; Reverse remodelling