title: Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction.
abstract: BACKGROUND
  The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF.
  
  
  RESULTS
  We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-β. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-β, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-β resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction.
  
  
  CONCLUSIONS
  Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.
authors.affiliation: Department of Cardiology and Pneumology, Charité, Universititäts-Medizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Germany. dirk.westermann@web.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Diana
authors.initials: D
authors.lastname: Lindner
authors.forename: Mario
authors.initials: M
authors.lastname: Kasner
authors.forename: Christine
authors.initials: C
authors.lastname: Zietsch
authors.forename: K
authors.initials: K
authors.lastname: Savvatis
authors.forename: F
authors.initials: F
authors.lastname: Escher
authors.forename: J
authors.initials: J
authors.lastname: von Schlippenbach
authors.forename: C
authors.initials: C
authors.lastname: Skurk
authors.forename: Paul
authors.initials: P
authors.lastname: Steendijk
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D013318:Stroke Volume / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D020781:Matrix Metalloproteinase 1