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In Vivo Effects of Contrast Media on Coronary Thrombolysis

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In Vivo Effects of Contrast Media on Coronary Thrombolysis View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 1102 JACC Vol. 32, No. 4 October 1998:1102–8 In Vivo Effects of Contrast Media on Coronary Thrombolysis SORIN PISLARU, MD, PHD,*† CRISTINA PISLARU, MD,* MONIKA SZILARD, MD,* JEF ARNOUT, PHD,‡ FRANS VAN DE WERF, MD, PHD, FACC* Leuven, Belgium and Bucharest, Romania Objectives. The aim of the present study was to evaluate the associated with longer reperfusion delays (time to optimal reper- influence of radiographic contrast media (CM) on alteplase- fusion: 67 6 48 min and 65 6 49 min, respectively, vs. 21 6 11 min induced coronary thrombolysis. after placebo; p < 0.05) and shorter periods of coronary perfusion Background. Contrast media inhibit fibrinolysis in vitro and (optimal perfusion time: 21 6 26 min and 21 6 28 min, respec- interact with endothelial cells, platelets and the coagulation tively, vs. 58 6 40 min after placebo; p < 0.05). No significant system. The in vivo effects of CM on thrombolysis are not known. differences were observed between groups with regard to activated Methods. Occlusive coronary artery thrombosis was induced in partial thromboplastin times, circulating thrombin-antithrombin 4 groups of 10 dogs by the copper coil technique. After 70 min of III complex concentrations and fibrinogen. occlusion the dogs were randomized to intracoronary injection of Conclusions. In this animal model administration of iohexol 2 2mlkg 1 of either saline, a low-osmolar ionic CM (ioxaglate), a and amidotrizoate before thrombolysis significantly delayed low-osmolar nonionic CM (iohexol) or a high-osmolar ionic CM reperfusion. This interaction should be considered in the design of (amidotrizoate). Thrombolysis with alteplase and co-therapy with clinical trials of thrombolytic therapy that evaluate coronary aspirin and heparin was initiated after 90 min of occlusion. The artery patency and in patients receiving local infusions of fibrino- coronary artery flow was monitored with an electromagnetic lytic agents. flowmeter throughout the experiment. (J Am Coll Cardiol 1998;32:1102–8) Results. Iohexol and amidotrizoate, but not ioxaglate, were ©1998 by the American College of Cardiology The interaction between radiographic contrast media (CM) CM) but not ioxaglate (low-osmolar, ionic CM) delayed and hemostasis has been a subject of intense debate during the alteplase-induced thrombolysis (15). last decade. Since Robertson’s first report (1) of clots being Administration of thrombolytic agents for acute myocardial more likely formed in syringes containing nonionic than ionic infarction has profound effects on hemostasis, activating both CM, numerous studies have addressed the “clotting issue.” lytic and prothrombotic mechanisms. Since CM may interact Much has been learned about the interaction of CM with with all factors involved in these reactions (i.e., platelets, endothelial cells (2–4), platelets (5–7) and coagulation pro- endothelial cells and coagulation and fibrinolytic proteins), it is teins (8–11). The effect of CM on endogenous fibrinolysis has difficult to predict the result of CM administration at the time also been described (12,13), but little is known about the of thrombolytic therapy from in vitro experiments. The aim of interaction of CM with pharmacologic thrombolysis. In vitro our study was twofold: 1) to evaluate the interaction between studies have shown CM-induced inhibition of clot dissolution different CM and the process of coronary artery thrombolysis (14,15) and plasminogen activation (16). However, the mech- and 2) to test the relative importance of biophysical properties anisms proposed are contradictory, one study suggesting that (osmolality, electrical charge) for their effects in vivo. the inhibitory effect is due to the electrical charge of CM molecules (16), while another showed that iohexol (low- osmolar, nonionic CM) and diatrizoate (high-osmolar, ionic Methods Coronary artery thrombosis. Mongrel dogs weighing 18 to 2 30 kg were sedated with 2.5 mg kg 1 xylazin (Rompun, Bayer AG, Leverkusen, Germany), anesthetized with sodium pento- From the *Department of Cardiology, University Hospitals Leuven, Leuven, 21 21 21 Belgium; †“Carol Davila” University of Medicine, Bucharest, Romania; ‡Center barbital (15 mg kg bolus and 0.1 mg kg min infusion; for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. Nembutal, Sanofi, France), intubated and artificially ventilated This study was supported in part by the research grant G.0304.97N from the (Mark 7A respirator, Bird Corporation, Palm Springs, CA, National Fund for Scientific Research—Flanders (Fonds voor Wettenschapelijk Onderzoek—Vlanderen). USA). A left thoracotomy was performed in the fifth intercos- Manuscript received March 13, 1998; revised manuscript received June 5, tal space, and the heart was suspended in a pericardial cradle. 1998, accepted June 12, 1998. The left anterior descending (LAD) coronary artery was Address for correspondence: Dr. Frans Van de Werf, Department of Cardiology, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: dissected free distal to the first diagonal branch. An electro- [email protected]. magnetic coronary flow probe (Skalar MDL1401, Skalar Med- ©1998 by the American College of Cardiology 0735-1097/98/$19.00 Published by Elsevier Science Inc. PII S0735-1097(98)00326-X JACC Vol. 32, No. 4 PISLARU ET AL. 1103 October 1998:1102–8 CONTRAST MEDIA AND THROMBOLYSIS Venous blood samples. Venous blood samples were col- Abbreviations and Acronyms lected on 4% citrate at baseline (sample 1), 70 min after aPTT 5 activated partial thromboplastin time coronary occlusion (before the administration of contrast CM 5 radiographic contrast media media, sample 2), after 90 min of occlusion (sample 3), at the 5 LAD left anterior descending coronary end of the alteplase infusion (sample 4) and at the end of artery 5 experiment (sample 5). The samples were cooled on ice, TAT thrombin-antithrombin III complex 2 TIMI 5 Thrombolysis In Myocardial Infarction centrifuged and stored at 20°C for analysis of activated partial thromboplastin time ([aPTT]; using Synthasil, ORTHO Diagnostics, Raritan, New Jersey, USA) and fibrinogen ac- cording to the Clauss method. Both assays were run on a KC10 ical BV, Delft, The Netherlands) was positioned around the coagulometer (Amelung, Germany) employing a mechanical artery, distal to a silk snare. Coronary thrombosis was induced end point. We have also measured a2-antiplasmin with a by placing a 3- to 5-mm long copper coil over an intracoronary chromogenic assay (Chromogenix, Sweden) and circulating wire into the LAD, as previously described (17). There were no thrombin-antithrombin III (TAT) complexes with enzyme- visible diagonal branches between the copper coil and the flow linked immunosorbent assay (Behringwerke, Germany). probe. An occlusive thrombus was formed in 2 to 104 min Data acquisition and analysis. The aortic pressure, lead II (mean 26 6 25 SD). The coronary thrombus was allowed to electrocardiogram and coronary flow analog signals were dig- 2 grow for 90 min before initiation of thrombolysis with alteplase itized online at 1.000 Hz channel 1 and recorded on a PC with (recombinant tissue plasminogen activator; Actilyse, Boehr- a commercially available software package (Windaq, Dataq 2 inger Ingelheim GmbH, Ingelheim, Germany; 0.1 mg kg 1 Instruments, Akron, Ohio, USA). The software stores the intravenous bolus followed by a continuous infusion of 0.01 mg digital input of each channel together with the time reference 2 2 2 kg 1 min 1 for 30 min) and co-therapy with aspirin (5 mg kg 1 in binary format (i.e., the signal intensity at each sampling of acetylsalicylic acid intravenous bolus; Aspegic, Synthe´labo, point together with its time reference taken from the internal France) and heparin (heparin naturium; Heparine Rorer, clock of the computer) and displays it on a screen resembling 2 Rhoˆne-Poulenc Rorer, Belgium; 100 IU kg 1 bolus plus 25 IU the millimetric paper. The advantage over classical paper 2 2 kg 1 h 1 infusion). Ventricular arrhythmias were treated with recording is that at playback, the operator can choose the lidocaine boluses (Xylocaine, Astra Pharmaceuticals, Brussels, number of data-points that will be displayed between two Belgium). The ventilation was adjusted to maintain the pH and consecutive grids on the screen. Typically, we have first used a arterial blood gases within a physiologic range. Blood loss was low compression level (0.04 s of digital recording displayed on 2 compensated with a saline infusion adjusted according to the 1 mm of the screen, corresponding to the 25 mm s 1 speed of hematocrit. Body temperature was kept constant with a heat- paper recorders). This level of data compression allowed the ing pad. All experiments conformed with the “Position of best evaluation of the coronary flow pattern (phasic or not). American Heart Association on Research Animal Use” and The occurrence of cyclic flows was easier to identify at higher were conducted with the approval of the Ethics Committee of compression levels (1 to 5 min of digital recording displayed on the University of Leuven. 1 cm on the screen). Coronary zero flow was confirmed Contrast media. After 70 min of coronary artery occlusion, whenever needed by occluding the coronary artery for a few the dogs were randomized to an intracoronary injection of one seconds with the proximal snare. We have performed qualita- of the following: placebo (normal saline solution); the low- tive and quantitative analysis of the flow curve. The qualitative osmolar, ionic CM ioxaglate (Hexabrix 320, Laboratories analysis was focused on identification of events (reperfusion, Guerbet, France); the low-osmolar, nonionic CM iohexol cyclic flow and reocclusion; Fig. 1). The definitions of events (Omnipaque 350, Nycomed, Belgium); or the high-osmolar, and of the derived time indexes are given in Table 1. Another ionic CM amidotrizoate (Urographin 76%, Schering AG, blinded investigator performed a second reading of the flow Germany). A 5F catheter was positioned in the proximal LAD curves.
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