title: Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway.
abstract: OBJECTIVE
  Myocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction. However, the effects of caspase activation on left ventricular geometry post-myocardial infarction remain unclear. This project applied broad-spectrum caspase inhibition to a chronic porcine model of myocardial infarction.
  
  
  METHODS
  Coronary snares and sonomicrometry crystals in remote and area-at-risk regions were placed in pigs (n = 22, 34 kg). Geometric measurements at end diastole and end systole, including left ventricular area by echocardiography and interregional distance by sonomicrometry, were obtained at baseline. Coronary occlusion was instituted for 60 minutes, followed by reperfusion and repeated geometric measurements at 7 days, including left ventriculography. At reperfusion, pigs were randomized to saline (n = 12) or caspase inhibition (n = 10, IDN6734, 2 mg/kg intravenously, then 2 mg x kg x h for 24 hours) at a dose that achieved desired plasma concentrations (790 +/- 142 ng/mL) as predicted by prior pharmacokinetic studies.
  
  
  RESULTS
  Infarct size and 24-hour troponin-I values were not significantly different between the saline and caspase inhibition groups (51% +/- 8% vs 42% +/- 6% and 189 +/- 20 ng/mL vs 152 +/- 26 ng/mL, respectively, P >.10). At 7 days, end-diastole volume was increased in both groups compared with reference control values (47 +/- 1 mL, P <.05), but it was decreased with caspase inhibition (72 +/- 4 mL) compared with saline (84 +/- 4 mL, P <.05). Similarly, end-diastole and end-systole areas increased by 32% +/- 3% and 81% +/- 16% in the saline group but were attenuated with caspase inhibition (19% +/- 3% and 31% +/- 10%, respectively, P <.05). End-diastole interregional distance increased by 30% +/- 7% in the saline group but was attenuated with caspase inhibition (12% +/- 5%, P <.05).
  
  
  CONCLUSIONS
  Despite equivalent degrees of myocardial injury, caspase inhibition reduced post-myocardial infarction left ventricular remodeling as evidenced by multiple, independent assessments of left ventricular dilation. Thus, caspase activation alters left ventricular geometry in the absence of significant effects on myocardial injury.
authors.affiliation: Division of Thoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Yarbrough
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: G Patricia
authors.initials: GP
authors.lastname: Escobar
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sample
authors.forename: Julie E
authors.initials: JE
authors.lastname: McLean
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Dowdy
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Hendrick
authors.forename: William C
authors.initials: WC
authors.lastname: Gibson
authors.forename: Amy E
authors.initials: AE
authors.lastname: Hardin
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Mingoia
authors.forename: Patrick C
authors.initials: PC
authors.lastname: White
authors.forename: Ann
authors.initials: A
authors.lastname: Stiko
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.forename: Fred A
authors.initials: FA
authors.lastname: Crawford
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D003326:Coronary Circulation; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology*; D013552:Swine; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D020169:Caspases