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Management of the No-Reflow Phenomenon

Joseph G. Salloum, MD; Richard W. Smalling, MD, PhD

Division of Cardiology, The University of Texas-Houston Medical School and
Memorial Hermann Hospital, Houston, TX, USA

   No-reflow describes the persistence of reduced flow and associated myocardial perfusion despite the removal of mechanical epicardial coronary occlusion. The term was first coined by Ames et al in their experimental work on cerebral ischemia [1]. Coronary no-reflow was also described first in an experimental setting [2] but was later noted to occur clinically as well [3]. No-reflow is mainly seen in acute myocardial infarction after catheter based or thrombolytic revascularization [4]. It is also seen during percutaneous intervention on old saphenous vein grafts [5] or on native coronary vessels in the setting of unstable angina [6].

   The exact pathophysiologic mechanism behind this phenomenon has not been identified. The epicardial vessel is patent and the flow impairment is the result of pathology in the microcirculation. This microvascular dysfunction usually follows a direct injury. This injury can result from ischemia-reperfusion, distal embolization, etc. Electron microscopy performed on animal experiments shows plugging of the capillaries with neutrophils, myocyte edema, and endothelial blistering [2]. Capillary resistance to flow is thus increased. Vasospasm, free radical generation and endothelial injury, debris/thrombus embolization, capillary plugging by neutrophils, and myocyte edema with intramural hemorrhage are all potential causes of no-reflow. It has also been postulated that activated platelets secrete potent vasoactive substances that promote distal microvascular constriction, thus impeding flow. In addition, particles from plaques or thrombi that are dislodged and embolized downstream by the revascularization procedure can lead to microvascular spasm. It is important to keep in mind that the responses of the endothelium of the distal microvasculature to these vasoactive substances may not be identical to those of intact endothelial cells. In other words, endothelium dependent vasoactive substances may lead to incomplete or even paradoxical responses once exposed to injured endothelium.

   In the reported experience of one catheterization laboratory, the no-reflow phenomenon was seen in about 2.0 percent of the total number of cases. The incidence varies with the clinical setting. Patients undergoing primary intervention for acute myocardial infarction show an incidence of 11.5 percent, compared to 1.5 percent of patients undergoing elective coronary intervention. Elective intervention performed on saphenous vein grafts carries a risk of 4.0 percent or higher.

   The risk of developing no-reflow depends also on the nature of the intervention since a higher trend is observed with stenting rotational atherectomy, and directional atherectomy than with conventional balloon angioplasty [7].

   Because no-reflow phenomenon occurs in different clinical settings, it is possible that different pathophysiological mechanisms operate in each setting. For instance, embolization of plaque material could be the culprit in saphenous vein graft interventions, while ischemia/reperfusion in acute myocardial infarction and activated platelets in unstable angina would play the major role. Different therapeutic strategies may therefore be needed in each situation.

   Patients who develop the No-reflow phenomenon during percutaneous revascularization for acute myocardial infarction have a worse prognosis than those who do not [8]. The same is true after thrombolytic agent administration [8]. Patients with no-reflow have a higher level of creatine kinase and have more severe wall motion abnormalities on ventriculography. Patients with no-reflow phenomenon have a higher incidence of myocardial wall or ventricular septal rupture compared to those who do not. Note also that serial coronary angiography performed twenty-four hours later has demonstrated the resolution of the no-reflow phenomenon in almost all patients [10].

   The best approach the No-reflow phenomenon is probably to avoid it altogether. Therefore, strategies aiming at reducing the risk of its occurrence are perhaps the most effective. Nevertheless, no-reflow can still occur in spite of all preventive measures. Treatment of established no-reflow phenomenon is mainly pharmacologic.

   Since the mechanism or mechanisms that lead to this phenomenon are not clear, we do not have a single infallible treatment that reverses its occurrence. Since spasm of the distal microvasculature appears to play an important role in the development of no-reflow, different vasodilating substances have been employed with varying degree of success. Platelet inhibiting agents have also been applied because activated platelets have been postulated to play an important role. Before going through each of the pharmacologic agents, let us review briefly the response of the coronary microvasculature to different medication.

   Different pharmacologic agents are used in the treatment of the no-reflow phenomenon. The response of the coronary circulation to these agents is altered by ischemia and reperfusion. It is useful to review the details of this response because ischemia probably plays a role in some of the clinical instances where the no-reflow phenomenon is seen.

   The normal coronary circulation shows significant heterogeneity. For instance, animal experiments have shown that arterioles 80-100 micrometers in diameter have a reduced response to nitroglycerin when compared to those >200 micrometers [11]. Serotonin, released upon platelet degranulation, is reported to dilate normal microvessels <90 micrometers in diameter while constricting larger vessels [12].

   Furthermore, the response of the coronary microvasculature to vasoactive substances varies with the location of the vascular bed. In general, subendocardial blood flow increases more so than subepicardial blood flow in response to endothelium dependent vasodilators like acetylcholine, adenosine triphosphate, and arachidonic acid [13,14]. Endothelium independent substances like sodium nitroprusside are equivalent in the two regions of myocardium.

   This heterogeneity of microvascular response is further increased by ischemia. Subendocardial layers are generally more susceptible to epicardial vessel occlusion and show greater vascular dysfunction. In general, the response of the coronary microvasculature to endothelium-dependent factors is reduced after ischemia-reperfusion [15].

   Before we review some of the agents that have been shown to improve no-reflow, it is important to keep in mind that no double-blind, randomized trial has been conducted to assess any of these agents. No trial has been conducted to determine the appropriate dosage either. The use of these drugs is mostly based on clinical experience and their administration limited by the resolution of no-reflow or the development of side effects. No formal study has evaluated any combination of these agents.

   Intracoronary verapamil has been reported to reverse no-reflow [5]. When compared to intracoronary nitroglycerine, verapamil is clearly superior, while nitroglycerine was essentially incapable of improving blood flow [16]. The mechanism of action of verapamil is most likely a direct effect on arteriolar smooth muscle cells that promotes relaxation and consequently eases spasm. In the canine model, verapamil has been shown to limit infarct size [17]. Verapamil is administered as intracoronary boluses of 100 µg each. Possible unwanted effects are development or progression of atrioventricular block, negative inotropy and hypotension. Nonetheless, clinical reports describing the usefulness of verapamil in the treatment of no-reflow do not mention any adverse effects.

   GPIIb/IIIa receptor antagonists have been found to improve procedural outcome and decrease the rate of adverse clinical events in those patients undergoing percutaneous interventions [18]. They also improve patient outcome in the setting of unstable angina or non-ST elevation myocardial infarction, especially when these patients undergo coronary interventions [19, 20].

   In view of the fact that GPIIb/IIIa antagonists improve percutaneous procedural outcome, one would suspect that they play a favorable role in the prevention of no-reflow, especially that no-reflow is more prone to occur in those situations where the integrin antagonists have proven their benefit. Studies that have evaluated coronary flow after percutaneous intervention have shown that GPIIb/IIIa blockade improves not only epicardial vessel patency, but also microvascular perfusion as well [21]. It appears that GPIIb/IIIa blockade maintains patency of recanalized coronary vessel and may prevent formation and embolization of platelet aggregates into the distal circulation [22].

   As we have discussed earlier, those patients who undergo interventions on saphenous vein grafts are prone to develop No-reflow phenomenon. The effects of GPIIb/IIIa antagonists on saphenous vein graft interventions per se have not been evaluated prospectively. Nevertheless, a review of the effects of Abciximab on outcome after vein graft procedures did not show a significant reduction in adverse clinical events [23]. This may indirectly imply that Abciximab does not necessarily improve coronary flow after percutaneous interventions on vein grafts. If this were the case, one would assume that no-reflow in this particular setting is mainly due to mechanisms that do not primarily involve platelet aggregation. In vitro experiments with the rotational atherectomy device have shown that abciximab inhibits platelet activation that results from rotablator use [24]. If these results remain true in vivo, GPIIb/IIIa inhibition may be able to play a role in improving blood flow during rotablation.

   Once No-reflow is established, isolated case reports have described reversal of flow impairment soon after GPIIb/IIIa administration [25]. Interestingly, these case reports involve situations whereby intervention was carried out on saphenous vein graft lesions.

   The use of GPIIb/IIIa antagonists is indicated in high-risk coronary interventions. They have proven their ability to improve patient procedural and clinical outcome. They are probably not best used as a treatment once no-reflow is established. Rather, they are probably more helpful if used to prevent epicardial vessel occlusion and microvascular dysfunction.

   Papaverine is an opiate derivative and is a potent microvessel dilator. It has been proven safe in the setting of acute myocardial infarction [26]. The reasoning behind the use of papaverine is that ischemia induces spasm, which, in turn, contributes to the development of no-reflow, thus perpetuating ischemia and tissue injury [27]. Papaverine would break the ischemia-spasm cycle and thus help resolve No-reflow.

   In at least one report, papaverine was administered intracoronary at doses of 10 mg in the setting of intervention for acute myocardial infarction complicated by no-reflow. It was noted to significantly improve blood flow as estimated by cine frame count (41 ± 17 frames down to 18 ± 8 frames) [28]. Care must be taken though because papaverine may lead to QT segment prolongation and has been known to cause Torsades de Pointes.

   Adenosine is generally considered an endothelium-independent vasodilator. It is secreted locally, binds to purinergic receptors and causes relaxation by activating adenylate cyclase. Nonetheless, it has been shown that canine coronary arteries have a reduced relaxation in response to adenosine when denuded from their endothelium [29]. Adenosine is considered a possible autoregulator of coronary blood flow.

   In addition to its vasoactive properties, adenosine has been shown to inhibit various neutrophil functions and reduce neutrophil-mediated endothelial damage in vitro [30]. Adenosine has also been noted to decrease the generation of oxygen free radicals by activated neutrophils [31]. It has been demonstrated experimentally that adenosine decreases the degradation of ATP during ischemia and facilitates its repletion with reperfusion [32].

   In the coronary occlusion/reperfusion animal model, adenosine has been found to reduce infarct size. Adenosine treated animals showed preservation of the endothelial structure and function. Obstruction of capillary vessels by neutrophils or swollen endothelial cells was rarely seen [33].

   In the setting of percutaneous intervention in acute myocardial infarction, adenosine has been found to decrease the incidence of no-reflow by fourfold. Adenosine is administered in the form of intracoronary boluses before and after balloon inflation distal to the point of coronary occlusion [34]. During percutaneous intervention on saphenous vein grafts, intra-graft adenosine has been show to reverse the no-reflow phenomenon [35]. In contrary to intervention during acute myocardial infarction, adenosine does not prevent but reverses no-reflow with saphenous vein graft procedures [36]. The difference in the effect of adenosine could reflect different pathophysiologic mechanisms that lead to no-reflow in these two situations.

   In the setting of rotational atherectomy of complex lesions in the native coronary vessels, intracoronary adenosine administration was again noted to decrease the incidence of no-reflow phenomenon.

   Adenosine is a readily available agent, has a very low incidence of untoward effects and is very easy to use during percutaneous intervention. It is probably the only agent that has been reported to prevent the development no-reflow altogether. It can also be used in conjunction with other medication and/or mechanical devices to avoid or treat no-reflow.

   The fact that the no-reflow phenomenon can be seen in those patients treated with thrombolytic agents suggests that these agents are not the ideal treatment for this phenomenon. In fact, streptokinase and tissue-type plasminogen activator have been observed to be unable to fully prevent the occurrence of no-reflow [37,38]. The failure of these agents probably reflects the fact that they are unable to dissolve microthrombi that can still injure the microcirculation. Alternatively, this may indicate that factors other than fibrin clots take part in the pathophysiology of no-reflow.

Intraaortic balloon counterpulsation
The intraaortic balloon pump (IABP) has never been evaluated as a tool to reverse the no-reflow phenomenon per se. Nevertheless, this device is known to increase cardiac output in those patients suffering from hemodynamic instability resulting from cardiogenic shock and consequently it can increase coronary flow. In the context of coronary intervention in those patients without cardiogenic shock, Kern et al have found that the IABP does increase coronary flow in the target vessel only after the epicardial occlusion is relieved. In the absence of a patent epicardial vessel, the IABP was not able to increase distal coronary flow [39]. One may consider the use of the IABP in situations of no-reflow phenomenon to increase flow although one must bear in mind that there exists no conclusive evidence in favor of its effectiveness in this scenario. Evidently, if the patient shows signs of hemodynamic instability in the setting of a percutaneous intervention complicated by the no-reflow phenomenon, then the use of the IABP is primarily indicated to correct the hemodynamic picture and may aid in increasing distal coronary flow.

Distal protection devices
   Embolization into the microcirculation of plaque material and/or of platelet aggregates appears to play an important role in the development of no-reflow. If this can be prevented, no-reflow would be avoided and patient outcome improved. This is most relevant in the context of intervention on degenerated saphenous vein grafts and in the setting of acute myocardial infarction when intracoronary thrombus is present more often than not and platelets are in a state of activation.

  Multiple devices are in different stages of development and evaluation for the purpose of distal protection during percutaneous intervention. It is conceivable that one day all catheter-based interventions will involve distal protection of some sort.

   An example of such devices is the Guard Wire system by PercuSurge. It involves a distal occlusion balloon mounted on a wire that is used as the angioplasty wire. After distal occlusion, the procedure is performed and debris is aspirated. The distal balloon is then deflated and blood flow reestablished. This device was evaluated in the SAFE study. This study involved saphenous vein graft interventions, where distal embolization is presumed to play a very detrimental role. The GuardWire system resulted in a 73 percent reduction in adverse clinical events when compared to traditional procedures on vein graft disease. TIMI III flow was attained in 98.9 percent of cases and mortality at 30 days was 1 percent [40].

   These promising results indicate that distal protection devices could probably be the best available means to insure procedural success and improve patient outcome.

  In conclusion, no-reflow is a significant complication of interventional coronary procedures. The best strategy is to avoid its occurrence by the use of distal protection devices. Platelet glycoprotein IIb/IIIa antagonists can be concomitantly used when indicated, although definitive data demonstrating their benefit in no-reflow situations is lacking at the time. Further preventive measures include the administration of intracoronary adenosine, which has been shown to be safe and effective in the prevention and treatment of no-reflow. In the situation where no-reflow occurs, in addition to intracoronary adenosine, vasodilator agents like verapamil or sodium nitroprusside can be administered intracoronary to relieve the element of spasm in the microcirculation in an attempt at breaking the cycle of continued microvascular injury. The use of the intraaortic balloon pump is probably the last measure. Clearly beneficial when hemodynamic instability is present, it may help improve flow after the epicardial occlusion is successfully relieved.


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