Accelerated intravenous dosing of recombinant tissue-type plasminogen activator causes rapid but unstable reperfusion in a canine model of acute myocardial infarction.
BACKGROUND
Accelerated intravenous dosing is currently the preferred regimen for administering recombinant tissue-type plasminogen activator (rt-PA) in acute myocardial infarction (AMI). This regimen is recommended on the basis of clinical angiographic studies that reported superior 60 and 90 min patency rates. However, continuous infarct-vessel flow characteristics after reperfusion following this regimen are poorly described. The aim of our study was an improved definition of the characteristics of infarct-vessel flow induced by intravenous accelerated rt-PA using an animal model of acute coronary artery thrombosis.


METHODS
We studied the characteristics of reperfusion induced by an accelerated intravenous rt-PA dosing regimen in a canine coronary artery thrombosis model that simulates AMI. We created a critical stenosis in the left anterior descending coronary artery (LAD) of 24 open-chest dogs. Thrombosis was caused immediately proximal to the stenosis by injection of a blood and thrombin mixture into a segment of the LAD which had intimal damage. Hemodynamics and distal LAD blood flow velocity were recorded continuously. Six animals did not complete the protocol. Animals in the treatment group (n = 10) received an intravenous accelerated rt-PA regimen (1.25 mg/kg total dose) and were observed for 150 min. Eight animals served as controls.


RESULTS
None of the control animal arteries reperfused. In the treatment group, reperfusion occurred 31.5 +/- 7.3 min after starting rt-PA dosing in two general patterns. In one pattern, reperfusion onset was gradual and linear; in the other pattern, reperfusion was sudden. LAD flow was cyclical in all animals, with marked variations in magnitude compared with baseline (0-173% of baseline). Reocclusion was common and occurred 30.3 +/- 6.3 min after the initial reperfusion. There were 1.9 +/- 0.4 reocclusions per animal, and two distinct patterns were noted. In one, flow ceased abruptly and, in the second, flow declined gradually in a linear fashion before stopping. Infarct-vessel flow was evident for 103.1 +/- 14.1 min of the 150 min observation period.


CONCLUSIONS
Reperfusion occurs rapidly after an accelerated dosing regimen of rt-PA. However, the infarct-vessel flow resulting from this therapy is unstable and is associated with early reocclusion and marked variation in flow magnitude. Analysis of continuous infarct-vessel flow velocity patterns suggests at least two different mechanisms for the onset of reperfusion and reocclusion after this therapy. Recognizing several mechanisms of arterial opening and closing may have important implications for methods of stabilizing infarct vessels after reperfusion by accelerated dosing of rt-PA.
Gurbel
P A
PA
Department of Medicine, University of Maryland Medical Center, Baltimore 21201.
Anderson
R D
RD
MacCord
C S
CS
Scott
H
H
Serebruany
V
V
Herzog
W R
WR
D000054:Acceleration; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015425:Myocardial Reperfusion / Q000379:methods*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012008:Recurrence; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator