Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries

Abstract

Background-Recent studies suggest that patients with angina before myocardial infarction exhibit improved recovery of coronary perfusion after thrombolysis by an as-yet-unknown mechanism. We therefore proposed that brief antecedent ischemia/reperfusion may, via release of adenosine, improve vessel patency in damaged and stenotic coronary arteries. Methods and Results-Anesthetized dogs underwent coronary injuryϩstenosis, resulting in repeated cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgment of platelet-rich thrombi. Vessel patency was assessed for 3 hours after stenosis by quantification of the nadir of the CFVs, duration of total thrombotic occlusion (flowϭ0), and area of the flow-time profile (expressed as percent of baseline flowϫ180 minutes). In protocol 1, dogs received 10 minutes of coronary occlusionϩ10 minutes of reflow or a comparable 20-minute control period before injuryϩstenosis. The median nadir of the CFVs was higher (4.0 versus 0.3 mL/min), median zero flow duration per 30-minute time interval was shorter (0.4 versus 15.1 minutes), and mean percent flow-time area was greater (54Ϯ8% versus 28Ϯ9%) in dogs that received antecedent ischemia versus controls (PϽ.05). These benefits of antecedent ischemia/reperfusion were largely mimicked by a 10-minute intracoronary adenosine infusion (400 g/min) in lieu of brief ischemia (protocol 2) and were abolished by administration of the adenosine A 1 /A 2 receptor antagonist PD 115,199 (3 mg/kg IV) before brief antecedent coronary occlusion (protocol 3). Conclusions-Brief antecedent ischemia attenuates subsequent platelet-mediated thrombosis in damaged and stenotic canine coronary arteries, due, in large part, to an adenosine-mediated mechanism. (Circulation. 1998;97:692-702.)

Brief Antecedent Ischemia Enhances Recombinant Tissue Plasminogen Activator–Induced Coronary Thrombolysis by Adenosine-Mediated Mechanism

“…[3][4][5][6] This is supported by our recent observation that 10 minutes of coronary artery occlusion attenuated the subsequent spontaneous formation/dislodgment of platelet thrombi in damaged and stenotic canine coronary arteries, which is due largely to the release of adenosine (a potent inhibitor of platelet aggregation 7,8 ) during the PC stimulus. 3 Clinical reports further suggest that the benefits of antecedent ischemia on coronary patency may extend to the setting of persistent thrombotic occlusion: in patients with acute myocardial infarction, preinfarct angina was associated with more rapid thrombolysis 6 and lower rates of reocclusion after initial lysis. 5 However, the effect of antecedent ischemia on the efficacy of coronary thrombolysis has, to date, not been rigorously assessed.…”

“…3,9 All samples were evaluated by using bright-field illumination to confirm the expected loss of endothelium and tearing of the tunica media and to document the presence or absence of adventitial exposure. Identification of thrombotic components was facilitated by viewing picrosirius red-stained sections with polarized light; fibrin fibers are birefringent and appear green when this method is used, whereas platelets and erythrocytes are not birefringent and thus appear dark.…”

“…However, rather than causing deep arterial injury, we damaged the tunica media without adventitial exposure by compressing the LAD with cushioned hemostats, thereby initiating cyclic variations in coronary flow (CFVs) caused by formation/ dislodgment of platelet thrombi 3,11,14 rather than persistent thrombotic occlusion.…”

“…Coronary patency after lysis (protocols 2 and 3) and after injury plus stenosis (protocol 4) was assessed by measuring the duration (in minutes) of reocclusion (CBFϭ0) and percent flow-time area (defined as the area of the flow-time profile throughout each 2-hour observation period) and normalized for each dog to the baseline flowϫ120 minutes. 3,4,9 Total duration of thrombotic occlusion (protocols 2 and 3) was calculated as ⌺ (1-hour test occlusionϩtime to achieve reperfusionϩduration of reocclusion after initial lysis). RMBF (protocols 2 and 3) was measured in subendocardial and subepicardial tissue blocks cut from the center of the LAD territory with the use of routine methods.…”

“…5 However, the effect of antecedent ischemia on the efficacy of coronary thrombolysis has, to date, not been rigorously assessed. By use of a canine model of occlusive coronary thrombosis, our objectives were to (1) establish whether brief PC ischemia is associated with accelerated recombinant tissue plasminogen activator (rtPA)-induced thrombolysis and better maintenance of patency after initial restoration of blood flow and (2) determine whether, as in models of recurrent plateletmediated occlusion, 3,4 adenosine receptor stimulation may play a role.…”