title: Enhanced myocardial salvage by maintenance of microvascular patency following initial thrombolysis with recombinant tissue plasminogen activator.
abstract: OBJECTIVE
  The aim was to examine the value of a subthrombolytic maintenance infusion of recombinant double chain tissue plasminogen activator (BW t-PA, Duteplase) in preserving microvascular coronary flow following initial thrombolysis.
  
  
  METHODS
  Coronary arterial thrombi were induced by a copper coil (placed under fluoroscopic control) in the canine left anterior descending coronary artery. Complete vessel occlusion occurred within 10-15 min of coil placement. Following 90 min of thrombotic occlusion, animals received one of three treatments: group 1, vehicle 0.9% saline; group 2, t-PA 1.0 X 10(6) IU.kg-1.h-1 for 1 h; group 3, t-PA 1.0 X 10(6) IU.kg-1.h-1 for 1 h followed by 0.12 X 10(6) IU.kg-1.h-1 throughout the 2 h reperfusion period. Radiolabelled microspheres were administered to assess microvascular coronary flow at various time points throughout the experimental period.
  
  
  METHODS
  Experimental subjects were beagle dogs of either sex (n = 30), weight 8.9-14.3 kg.
  
  
  RESULTS
  Main vessel patency (assessed fluoroscopically) was achieved within 40.0(SEM 4.0) min and 37.0(3.1) min for group 2 and group 3 animals respectively. Group 1 animals did not reperfuse. Full microvascular coronary flow was achieved following the lytic infusion of t-PA. However, microvascular flow to the ischaemic zone was significantly reduced at the end of the 2 h reperfusion phase in group 2 animals despite "aggressive" anticoagulation with heparin throughout the reperfusion period: subendocardial flow decreased from 0.74(0.14) to 0.24(0.08) ml.min-1.g-1; subepicardial flow decreased from 0.82(0.13) to 0.36(0.09) ml.min-1.g-1, p less than 0.05. Microvascular coronary flow to the ischaemic zone was better preserved following the maintenance infusion of t-PA given throughout the reperfusion phase: subendocardial flow decreased from 0.95(0.07) to 0.50(0.10) ml.min-1.g-1; subepicardial flow decreased from 0.73(0.04) to 0.52(0.08) ml.min-1.g-1. Thrombolytic reperfusion led to salvage of the ischaemic myocardium, with infarct/risk ratio decreasing from 75.0(10.0)% in group 1 to 46.3(11.0)% in group 2, p less than 0.05. Further salvage of the ischaemic myocardium followed a lytic plus maintenance infusion of t-PA, with infarct/risk ratio decreasing to 35.5(6.7)% but this did not reach statistical significance.
  
  
  CONCLUSIONS
  t-PA consistently achieved main vessel reperfusion within 40 min (mean) of instituting therapy in our model, leading to marked salvage of ischaemic myocardium. The data also suggest that maintenance infusion of t-PA helps preserve microvascular coronary flow throughout reperfusion and tends to reduce infarct size further.
authors.affiliation: Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
authors.forename: D J
authors.initials: DJ
authors.lastname: Longridge
authors.forename: M J
authors.initials: MJ
authors.lastname: Follenfant
authors.forename: M P
authors.initials: MP
authors.lastname: Maxwell
authors.forename: A J
authors.initials: AJ
authors.lastname: Ford
authors.forename: B
authors.initials: B
authors.lastname: Hughes
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D007262:Infusions, Intravenous; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009203:Myocardial Infarction / Q000097:blood / Q000628:therapy*; D015425:Myocardial Reperfusion; D010314:Partial Thromboplastin Time; D011994:Recombinant Proteins / Q000008:administration & dosage; D015912:Thrombolytic Therapy / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000627:therapeutic use; D014654:Vascular Patency / Q000187:drug effects*
chemical_list: D011994:Recombinant Proteins; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator