CLINICAL RESEARCH: EDITORIAL COMMENT
Glycoprotein IIb/IIIa inhibitors and no-reflow*
Robert A. Kloner, MD, PhD, FACC  ,* and
Wangde Dai, MD
Heart Institute, Good Samaritan Hospital, Los Angeles, California, USA
Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
* Reprint requests and correspondence: Dr. Robert A. Kloner, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, California 90017, USA.
rkloner{at}goodsam.org
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Definition and biology of no-reflow
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The no-reflow phenomenon is the inability to perfuse a portion of the myocardium after re-establishment of patency of a previously occluded epicardial coronary artery (1–3). This phenomenon has been described in experimental animal models in which the coronary artery is occluded with a mechanical occluder or snare (1). In animal models no-reflow has been detected by using the fluorescent dye Thioflavin S that stains endothelium receiving flow, radioactive microspheres, carbon black, echocardiographic contrast, and magnetic resonance imaging (MRI) techniques.
The phenomenon also has been observed in humans after reperfusion therapy for acute myocardial infarction (MI) in which the occlusion is thrombus mediated, and it has been measured using myocardial contrast echocardiography, nuclear tracers, and MRI (4–6). Perfusion at the tissue level can be severely compromised even when the epicardial coronary artery appears to be fully patent by coronary angiography.
In previous experimental studies we observed the development of the no-reflow phenomenon when the proximal coronary artery was occluded for 90 min or 3 hrs but not 40 min, followed by reperfusion therapy (1). In our models the zone of no-reflow is usually confined to areas of necrotic myocardium (1,2,7–9). There is a tight coupling between infarct size and no-reflow. Outside the zone of no-reflow, there may be an area that is necrotic but that contains an infarct that can be reperfused. Although there is ongoing discussion whether reducing no-reflow can then reduce infarct size, in most of our analyses, myocardial cell death occurs before the disruption of the microvasculature. Thus, in our opinion, no-reflow probably does not exacerbate myocardial cell death but occurs after the myocytes in the area are already dead. This does not mean that no-reflow should be ignored. A large zone of no-reflow may impede the ability of the infarct to heal and prevent delivery of pharmaceutical agents (such as anti-arrhythmics) into the infarct zone. Recently, we observed that a large area of no-reflow predicts worse infarct expansion and left ventricular (LV) dilation (Reffelmann T, Hale SL, Dow JS, Kloner RA, submitted for publication). In humans, the no-reflow phenomenon predicts worse outcome in the post-MI patient (5,10).
In this issue of the Journal, Kunichika et al. (11) clearly show that quantitative myocardial contrast echocardiography (QMCE) is a useful non-invasive tool for measuring myocardial perfusion and diagnosing and quantitating no-reflow in real time. Myocardial blood flow velocity is measured by the rapid destruction of echo contrast microbubbles using ultrasound and then determining the rate at which they refill the myocardium. Findings with QMCE paralleled their measures of regional myocardial blood flow made with fluorescent microspheres. The beauty of the echo contrast technique is that it can be used repeatedly to measure the success (or failure) of myocardial perfusion by a non-invasive technique. It can be used to track perfusion over time, measuring the ability of pharmacologic therapy to affect perfusion of the tissue.
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Therapy for no-reflow
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A reduction in the size of the anatomic zone of no-reflow might limit infarct expansion, enhance healing, and reduce long-term LV dilation. In our models, any agent that reduces MI size will secondarily reduce no-reflow. We have observed this coupling with agents such as cariporide, preconditioning (12), and hypothermia (13). We have not observed any benefit of thrombolytic agents on infarct size or no-reflow in a mechanical (non-thrombotic) model of coronary artery occlusion. In the present study by Kunichika et al. (11), a fascinating observation was made. Tirofiban, a platelet glycoprotein (GP) IIb/IIIa inhibitor, reduced infarct size and no-reflow in a non-thrombotic coronary occlusion model in the dog. Previous studies in patients with thrombotic coronary occlusions have shown that GP IIb/IIIa inhibitors can enhance reperfusion as would be expected in the setting of a thrombus. GP IIb/IIIa inhibitors were shown to decrease coronary thrombus, improve TIMI flow grade, enhance epicardial reperfusion when combined with thrombolysis, improve 30-day clinical outcomes post MI, speed resolution of ST-segment elevation, and in one study of elective percutaneous coronary intervention improve coronary artery flow reserve and myocardial blush grade. The later two findings support improved microvascular reperfusion (14–17). Kunichika et al.'s (11) observation has an important implication related to the role of platelets in no-reflow. No-reflow in the setting of a thrombotic occlusion may be related in part to micro-emboli, and platelet aggregates could play a significant role (18). However, the exact cause of no-reflow in a non-thrombotic model has remained difficult to trace definitively. Within the zone of no-reflow, discrete ultrastructural abnormalities are observed, suggesting anatomic damage to the microvasculature (Fig. 1). Diffuse and regional endothelial swelling with bleb-like structures appear to occlude the capillaries. Endothelial gaps, fibrin tactoids, rouleaux formation, neutrophil plugging, and compression of capillaries from adjacent swollen myocytes have been identified (1–3). Spasm of the microvasculature at the pre-capillary level also has been implicated (19). However, in our studies of mechanical non-thrombotic occlusion of the coronary artery, ultrastructural identification of platelet or platelet plugs within the microvasculature was an extremely rare finding (1). In the present study, the authors also indicated to me that on histologic analysis they did not observe platelet plugging of the microvasculature either in control or treated animals. If this is the case, then why should a GP IIb/IIIa inhibitor work? One explanation is that inhibition of platelet activation prevents or reduces the release of injurious vasoactive and chemotactic mediators from platelets that may exacerbate tissue injury (11). For example, inhibition of chemotactic mediators might prevent neutrophils from entering the area, thereby reducing damage due to neutrophil-mediated oxygen free-radical release. Of note, in one previous study from our laboratory, Przyklenk et al. (20) showed that oxygen free-radical scavengers given at the time of reperfusion reduced no-reflow as assessed by radioactive microspheres. Inhibiting platelet release of vasoactive mediators theoretically could reduce microvascular spasm, although recently we observed that two agents known to reduce vascular spasm, adenosine and verapamil, did not prevent no-reflow in a similar non-thrombotic model (21). Another possible explanation is that GP IIb/IIIa inhibitors reduce infarct size by some mechanism independent of platelet inhibition and that this is followed by a secondary reduction in no-reflow.
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Figure 1 Potential mechanisms of the no-reflow phenomenon based on ultrastructural and other observations. Micro-emboli and platelet plugs would be more relevant to the clinical situation in which a percutaneous coronary intervention is performed with disruption of an atherosclerotic plaque and/or thrombus. All of the other findings have been described in experimental non-atherosclerotic models of coronary artery occlusion and reperfusion. Reprinted, with permission, from Reffelmann and Kloner (3). RBCs = red blood cells.
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Nevertheless, the fact that Kunichika et al. (11) found that GP IIb/IIIa inhibition reduced no-reflow as well as infarct size in this non-thrombotic model is a fascinating observation. It suggests that the role of platelets in inducing no-reflow, even in a model in which the coronary artery occlusion is created with a mechanical device or snare rather than thrombus, may be far more important than previously appreciated.
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Footnotes
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Jonathan R. Lindner, MD, FACC, acted as guest editor for this comment.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- Reffelmann T, Kloner RA. The "no-reflow" phenomenon: basic science and clinical correlates. Heart. 2002;87:162–168[Free Full Text]
- Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction. Circulation. 1996;93:1993–1999[Abstract/Free Full Text]
- Kenner MD, Zajac EJ, Kondos GT, et al. Ability of the no-reflow phenomenon during an acute myocardial infarction to predict left ventricular dysfunction at one-month follow-up. Am J Cardiol. 1995;76:861–868[CrossRef][Medline]
- Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation. 1998;97:765–772[Abstract/Free Full Text]
- Kloner RA, Alker KJ. Effect of streptokinase on intramyocardial hemorrhage, infarct size, and the no-reflow phenomenon during coronary reperfusion. Circulation. 1984;70:513–521[Abstract/Free Full Text]
- Kloner RA, Alker KA, Campbell C, Figures G, Eisenhauer A, Hale S. Does tissue plasminogen activator have direct beneficial effects on the myocardium independent of its ability to lyse intracoronary thrombi? Circulation. 1989;79:1125–1136[Abstract/Free Full Text]
- Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LWV, Braunwald E. Ultrastructural evidence of microvascular damage and myocardial cell injury following coronary artery occlusion: which comes first? Circulation. 1980;62:178–184
- Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the "no reflow" phenomenon: a predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation. 1996;93:223–228[Abstract/Free Full Text]
- Kunichika H, Ben-Yehuda O, Lafitte S, Kunichika N, Peters B, DeMaria AN. Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion: a quantitative myocardial contrast echocardiography study. J Am Coll Cardiol 2004;43:276–83
- Reffelmann T, Kloner RA. Is microvascular protection by cariporide and ischemic preconditioning causally linked to myocardial salvage? Am J Physiol Heart Circ Physiol. 2003;284:H1134–1141[Abstract/Free Full Text]
- Hale SL, Dae MW, Kloner RA. Hypothermia during reperfusion limits "no-reflow" injury in a rabbit model of acute myocardial infarction. Cardiovasc Res. 2003;59:715–722[Abstract/Free Full Text]
- Zhao X-Q, Theroux P, Snapinn SM, et al. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non–Q-wave myocardial infarction: angiographic results from the PRISM-PLUS trial (platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). Circulation. 1999;100:1609–1615[Abstract/Free Full Text]
- de Lemos JA, Antman EM, Gibson CM, et al. Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction: observation from the TIMI 14 trial. Circulation. 2000;101:239–243[Abstract/Free Full Text]
- Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation. 1998;98:2695–2701[Abstract/Free Full Text]
- Gibson CM, Cohen DJ, Cohen EA, et al. Effect of eptifibatide on coronary flow reserve following coronary stent implantation (an ESPRIT substudy). Am J Cardiol. 2001;87:1293–1295[CrossRef][Medline]
- Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation. 2000;101:570–580[Free Full Text]
- Hellstrom HR. The injury-spasm (ischemia-based hemostatic vasoconstrictive) and vascular autoregulatory hypothesis of ischemic disease: resistance vessel-spasm hypothesis of ischemic disease. Am J Cardiol. 1982;49:802–810[CrossRef][Medline]
- Przyklenk K, Kloner RA. Reperfusion injury by oxygen-free radicals? Effect of superoxide dismutase plus catalase, given at the time of reperfusion, on myocardial infarct size, contractile function, coronary microvasculature, and regional myocardial blood flow. Circ Res. 1989;64:86–96[Abstract/Free Full Text]
- Reffelmann T, Kloner RA. Can anatomic no-reflow be prevented by pharmacologic treatment with adenosine and verapamil (abstr)? J Am Coll Cardiol. 2003;41(Suppl A):401A
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Definition and biology of...
Therapy for no-reflow