title: Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage.
abstract: BACKGROUND
  Granulation tissue cells at the subacute stage of myocardial infarction (MI) are eliminated by apoptosis to finally make a scar at the chronic stage. We hypothesized that postinfarct inhibition of apoptosis might preserve myofibroblasts and endothelial cells in granulation and modulate chronic left ventricular (LV) remodeling and heart failure.
  
  
  RESULTS
  A pancaspase inhibitor, Boc-Asp-fmk (BAF, 10 micromol/kg per day), or vehicle (control) was given to rats with experimental large MI. The treatment was started on the third day after MI and continued until 4-week-old MI. Two weeks later, the apoptosis of granulation tissue cells was significantly reduced and conversely, the cell population was greater in BAF. Twelve weeks later, BAF showed significantly greater survival rates (84% versus 42%) with significantly smaller LV cavity, lower LV end-diastolic pressure and central venous pressure, and higher LV dP/dt, which indicated improvement of LV remodeling and dysfunction. A scar was established in old infarct of control subjects, but in BAF, the infarct wall was thicker because of greater old infarct area, which contained abundant myofibroblasts and vessels. Surprisingly, many of the alpha-smooth muscle actin-positive myofibroblast-like cells in BAF, making bundles and running parallel to the survived cardiomyocytes, were ultrastructurally mature smooth muscle cells with contractile phenotype. Cardiomyocyte apoptosis in the infarct area was equally rare in each group.
  
  
  CONCLUSIONS
  The postinfarct treatment with BAF improved LV remodeling and dysfunction through inhibition of granulation tissue cell apoptosis. These findings imply a new therapeutic strategy against postinfarct heart failure.
authors.affiliation: Second Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-Machi, Gifu 500-8705, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Motoo
authors.initials: M
authors.lastname: Kanoh
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kawase
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D002908:Chronic Disease; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D006097:Granulation Tissue / Q000187:drug effects / Q000473:pathology*; D006321:Heart / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D018754:Ventricular Dysfunction / Q000188:drug therapy / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C417985:butyloxycarbonyl-aspartyl-fluoromethyl ketone