title: Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction.
abstract: BACKGROUND
  We investigated the potential contributions of tumor necrosis factor-alpha (TNF-alpha) on the incidence of acute myocardial rupture and subsequent chronic cardiac dysfunction after myocardial infarction (MI) in TNF knockout (TNF-/-) mice compared with C57/BL wild-type (WT) mice.
  
  
  RESULTS
  Animals were randomized to left anterior descending ligation or sham operation and killed on days 3, 7, 14, and 28. We monitored cardiac rupture rate, cardiac function, inflammatory response, collagen degradation, and net collagen formation. We found the following: (1) within 1 week after MI, 53.3% (n=120) of WT mice died of cardiac rupture, in contrast to 2.5% (n=80) of TNF-/- mice; (2) inflammatory cell infiltration and cytokine expression were significantly higher in the infarct zone in WT than TNF-/- mice on day 3; (3) matrix metalloproteinase-9 and -2 activity in the infarcted myocardium was significantly higher in WT than in TNF-/- mice on day 3; (4) on day 28 after MI compared with sham, there was a significant decrease in LV developed pressure (74%) and +/-dP/dt(max) (68.3%/65.3%) in WT mice but a less significant decrease in +/-dP/dt(max) (25.8%/28.8%) in TNF-/- mice; (5) cardiac collagen volume fraction was lower in WT than in TNF-/- mice on days 3 and 7 but higher on day 28 compared with TNF-/- mice; and (6) a reduction in myocyte apoptosis in TNF-/- mice occurred on day 28 compared with WT mice.
  
  
  CONCLUSIONS
  Elevated local TNF-alpha in the infarcted myocardium contributes to acute myocardial rupture and chronic left ventricle dysfunction by inducing exuberant local inflammatory response, matrix and collagen degradation, increased matrix metalloproteinase activity, and apoptosis.
authors.affiliation: Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, and University Health Network, Toronto, Ontario, Canada.
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Fayez
authors.initials: F
authors.lastname: Dawood
authors.forename: Wen-Hu
authors.initials: WH
authors.lastname: Wen
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.forename: Ian
authors.initials: I
authors.lastname: Dixon
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D003094:Collagen / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006341:Heart Rupture / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications*; D009205:Myocarditis / Q000473:pathology; D009206:Myocardium / Q000737:chemistry* / Q000473:pathology; D016328:NF-kappa B / Q000032:analysis; D011897:Random Allocation; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D020257:Ventricular Remodeling
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9