title: Caspase-3 inhibition preserves myocardial geometry and long-term function after infarction.
abstract: BACKGROUND
  Cardiac remodeling after infarction is characterized by progressive ventricular dilation and functional impairment. Although surgical and percutaneous revascularization strategies may prevent remodeling, not all patients are candidates for these procedures. Apoptosis in the border-zone myocardium is thought to be critical to the remodeling process, and caspase-3 is a downstream effector of apoptosis. We hypothesized that inhibition of caspase-3 activity might limit dysfunction and remodeling after permanent coronary artery ligation.
  
  
  METHODS
  FVB male mice underwent permanent ligation of the left anterior descending coronary artery. Immediately before surgery and for 7 subsequent days, animals were treated daily with 3 mg/kg DEVD-CHO, a cell-permeable inhibitor of caspase-3 (n = 16), or vehicle (n = 28). At 2 weeks and 6 weeks, echocardiography was performed and ventricular dimensions and function were assessed. At 8 weeks, invasive hemodynamic measurements were made and the animals were sacrificed.
  
  
  RESULTS
  There was a trend toward improved survival in the inhibitor-treated group compared to the vehicle-treated group (56.3% versus 21.4%, P = 0.07). Infarct size at the time of sacrifice was comparable in both groups. At both 2 and 6 weeks, left ventricular dimensions, including end-diastolic and end-systolic diameters, were less in inhibitor-treated animals. Fractional shortening was higher at 6 weeks in the inhibitor-treated animals (22.1 +/- 6.0% versus 15.0 +/- 6.0%, P = 0.02). Invasive hemodynamic parameters at 8 weeks were comparable, with the exception of diastolic blood pressure, which was less in the inhibitor group.
  
  
  CONCLUSIONS
  Treatment with a caspase-3 inhibitor improved survival and prevented ventricular dilation and dysfunction after permanent coronary artery occlusion.
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. lbalsam@stanford.edu
authors.forename: Leora B
authors.initials: LB
authors.lastname: Balsam
authors.forename: Theo
authors.initials: T
authors.lastname: Kofidis
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C108637:aspartyl-glutamyl-valyl-aspartal; C505409:Casp3 protein, mouse; D053148:Caspase 3