Coronary thrombosis/thrombolysis in pigs: effects of heparin, asa, and the thrombin inhibitor inogatran

Abstract

The aim of the present study was to develop a coronary thrombolysis model using the copper coil technique in closed-chest pigs. The first goal (protocol I) was to obtain a reproducible size of myocardial infarction by controlling the coronary occlusion period, a prerequisite for evaluation of myocardioprotective interventions. The second goal (protocol II) was to study if thrombin and platelet aggregation inhibitors influence the rate of thrombolysis, the degree of reocclusion, and the time of coronary patency when added to a thrombolytic regimen (recombinant tissue-type plasminogen activator, rt-PA). Coronary thrombosis was produced by insertion of a thrombogenic copper coil into the LAD of 40 anesthetized pigs. The animals were divided into six groups as follows: Protocol I, group 1: Open-chest, lysis initiated with intracoronary rt-PA (50 mg) concomitant with intravenous heparin and acetylsalicylic acid (ASA) ( n = 6). Group 2: Closed-chest, lysis initiated with intracoronary rt-PA concomitant with intravenous heparin and ASA ( n = 10). Protocol II, group 3: Closed-chest, lysis initiated with intravenous rt-PA ( n = 6). Group 4: Closed-chest, lysis initiated with intravenous rt-PA concomitant with heparin ( n = 6). Group 5: Closed-chest, lysis initiated with intravenous rt-PA concomitant with inogatran, a low molecular weight thrombin inhibitor ( n = 6). Group 6: Closed-chest, lysis initiated with intravenous rt-PA immediately after intravenous administration of ASA ( n = 6). Protocol 1; Reperfusion was achieved in all closed- and open-chest pigs. The time to thrombolysis was 5 ± 1.6 and 6 ± 3.0 min (mean ± SD) for closed- and open-chest pigs, respectively. Reocclusions were rare (one in group 1). The size of the ischemic myocardial area was 21 ± 11% of the left ventricular area in group 1 and 22 ± 6% in group 2. The corresponding values for infarct size as a proportion of the ischemic area were 58 ± 10% and 68 ± 14%, respectively. The closed-chest model was subsequently used to study the effect of the thrombin and platelet aggregation inhibitors (inogatran, heparin, and ASA) as conjunctive agents to rt-PA-induced thrombolysis (groups 3–6). To mimic its clinical use, rt-PA was administered intravenously. Time to lysis after rt-PA only (group 3) was 33 ± 24 min. Concomitant treatment with heparin (group 4), inogatran (group 5), and ASA (group 6) did not significantly influence time to lysis. All adjunctive compounds did, however, prolong the time to reocclusion, which occurred in 100%, 75%, 67%, and 20% of the animals in groups 3, 4, 5, and 6. Thus, concomitant treatment with heparin and inogatran did not shorten time to lysis or reduce the reocclusion rate, and ASA turned out to be the only effective adjunct to rt-PA, significantly reducing both time to and frequency of reocclusion ( p < 0.05). Conclusion: The described closed-chest pig model was feasible as regards the induction and lysis of a thrombus in the left coronary artery, giving reproducible areas of myocardial ischemia and infarction. This model was useful for the evaluation of pharmacological interventions in the thrombolysis process.