title: A Preclinical Translational Study of the Cardioprotective Effects of Plasma-Derived Alpha-1 Anti-trypsin in Acute Myocardial Infarction.
abstract: BACKGROUND
  The area of myocardial infarction continues to expand for hours after reperfusion. The injured but viable myocardium may be salvaged if the signals leading to cell death are interrupted. Activation of the caspase-1 inflammasome in the heart shortly after ischemia-reperfusion contributes to the final infarct size. Plasma-derived α-1 anti-trypsin (AAT) has shown to inhibit inflammasome formation in vitro and in vivo. To explore the potential translational clinical value of AAT as a therapeutic, we conducted a series of preclinical experiments designed to simulate clinically relevant scenarios.
  
  
  METHODS
  Adult male CD1 mice were used. The left anterior descending coronary artery was ligated for 30 or 75 minutes followed by reperfusion, to explore different severity of ischemic injury. Plasma-derived AAT (Prolastin C) was administered intraperitoneally after reperfusion, without pretreatment, exploring 3 different doses (60, 120, and 180 mg/kg). In a subgroup of mice, we administered Prolastin C with a delay of 30 minutes after reperfusion to simulate the clinical context of delayed administration, and we also used a model of permanent coronary artery ligation without reperfusion. Finally, we tested whether a single dose at reperfusion was sufficient to maintain a benefit in the longer term (7 days). Infarct size was measured by 3 different and independent methodologies: pathology, plasma levels of troponin I, and wall motion abnormalities at echocardiography.
  
  
  RESULTS
  Prolastin C given at reperfusion after 30 minutes of ischemia provided a powerful reduction in infarct size (>50% reduction in all methodology used, all P < 0.01) without a clear dose-dependent response. Prolongation of ischemia to 75 minutes nor a delay in treatment by 30 minutes after reperfusion had any negative impact on Prolastin C effects. A single dose given at reperfusion was as effective as multiple daily doses. When given to the mouse without reperfusion, Prolastin C failed to reduce infarct size.
  
  
  CONCLUSIONS
  Plasma-derived AAT (Prolastin C) given as an adjunct to reperfusion powerfully limits the final infarct size across a wide range of experiments in the mouse reproducing clinically relevant scenarios, such as variable duration of ischemia, delay in administration in the drug, and a large therapeutic index.
authors.affiliation: *VCU Pauley Heart Center; †VCU Johnson Research Center; ‡Department of Pharmacotherapy and Outcome Sciences, School of Pharmacy; and §Department of Surgery, Virginia Commonwealth University, Richmond, VA.
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Mauro
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.forename: Pratyush
authors.initials: P
authors.lastname: Narayan
authors.forename: Marco G
authors.initials: MG
authors.lastname: Del Buono
authors.forename: Marialessia
authors.initials: M
authors.lastname: Capuano
authors.forename: Andrea
authors.initials: A
authors.lastname: Prestamburgo
authors.forename: Simone
authors.initials: S
authors.lastname: Catapano
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology*; D013997:Time Factors; D014022:Tissue Survival; D019210:Troponin I / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage* / Q000097:blood
chemical_list: D002317:Cardiovascular Agents; D019210:Troponin I; D000515:alpha 1-Antitrypsin