Microvascular Dysfunction following Primary Percutaneous Coronary Intervention

In the Setting of ST-Elevation Myocardial Infarction

ABSTRACT: Primary percutaneous coronary intervention (PCI) is an established reperfusion strategy in the treatment of acute myocardial infarction with ST-segment elevation (STEMI). Nevertheless, myocardial damage is not terminated immediately, even with successful primary PCI, which eliminates the epicardial occlusion. Despite the success of contemporary reperfusion therapy and effective restoration of epicardial coronary flow, many patients have suboptimal flow at the tissue level within the myocardium. Studies indicate that these patients have a decreased recovery of left ventricular function and poor long-term prognosis. This could be due to reperfusion injury, embolization of epicardial thrombus or plaque debris jeopardizing tissue-level perfusion. This article attempts to review the process of microvascular dysfunction following reperfusion of STEMI with primary PCI and different strategies tried thus far to improve this. J INVASIVE CARDIOL 2008;20:603–614 The pathogenesis of an acute myocardial infarction (AMI) is a sudden thrombotic coronary occlusion following the rupture or erosion of an atherosclerotic plaque. Even before the full understanding of the underlying pathophysiology, studies performed four decades ago showed that nonselective intracoronary fibrinolysis can restore perfusion to the jeopardized vascular territory.1 Primary percutaneous coronary intervention (PCI) performed within 90 minutes of the first medical contact has emerged as the best mode of reperfusion therapy. Recent research emphasizes the ubiquitous occurrence of distal embolization of atheromatous and thrombotic debris after PCI. This results in microcirculatory dysfunction, abnormal myocardial metabolism and increased myonecrosis.2–4 Mechanisms that contribute to ischemia after restoring circulation in coronary arteries are reperfusion injury, which comprises the production of oxygen free radicals, neutrophil activation, endothelial and myocyte edema, the loss of antioxidant enzymes and cardiomyocyte apoptosis. By preventing microvascular dysfunction, one might be able to improve the success of reperfusion, reduce infarct size and enhance event-free survival. In this review, reasons for microvascular dysfunction after PCI and strategies to prevent them are explained. Search Strategy and Selection Criteria Literature including Medline, the Cochrane library and PubMed were searched for articles from 1988 to 2008. The keywords used for the search were “microvascular dysfunction”, “microvascular circulation”, “myocardial infarction”, “primary percutaneous intervention” and “reperfusion” in relation to etiology, pathophysiology, measurements and outcomes. For the factors contributing to microvascular dysregulation, a complete Medline database search was performed and, when appropriate, publications from before 1988 were also considered if they were commonly referenced or highly-regarded older publications. The search also included the reference list for these articles and selected additional articles and Web pages that were judged to be relevant. Role of Microvascular Dysfunction After an AMI, early and successful myocardial reperfusion with the use of PCI is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. In recent years, optimal outcome of reperfusion treatment includes not only sustained coronary arterial patency, but also reperfusion of myocardium supplied by the affected coronary artery.5 Randomized studies have failed to show a beneficial effect of distal protection devices on microvascular perfusion during primary PCI, despite effective retrieval of thrombus and plaque content from epicardial coronary arteries.6,7 This could either be due to earlier thromboembolism of proximal origin, which may limit microvascular perfusion2,8 or formation of thrombus in the microvasculature itself. The process of restoring blood flow to the ischemic myocardium by PCI can itself induce injury termed as myocardial reperfusion injury, thereby paradoxically reducing the beneficial effects of myocardial reperfusion. This phenomenon induces the death of cardiac myocytes that were viable immediately before myocardial reperfusion.9 This form of myocardial injury can by itself induce cardiomyocyte death and increase infarct size. This may in part explain why, despite optimal myocardial reperfusion, the rate of death after an AMI approaches 10%, and the incidence of cardiac failure after an AMI is almost 25%.10 The extent of microvascular dysfunction has been shown to be an important and independent contributor to subsequent changes in left ventricular geometry and performance.11,12 Factors Influencing Microvascular Dysfunction Generally, primary PCI is successful in clearing the coronary arterial occlusion, but a significant proportion of patients have microvascular dysfunction. This can be assessed either by angiographic capillary opacification (myocardial blush) or electrocardiographic ST-segment resolution (STR).7 Microvascular dysfunction in the presence of open coronary arteries is thought to be caused by microvascular obstruction/resistance and/or reperfusion injury. The former, in turn, is caused by adrenergic neural reflexes, spasm, thromboembolic occlusion of microvessels or procoagulant cascade activation.13 The latter could be due to the formation of oxygen-free radicals, endothelial dysfunction, increased myocardial cell calcium levels, cellular and interstitial edema and vasoconstriction.14,15 Both of these contribute to increased infarct size and reduced survival. Gregorini et al16 proposed that epicardial coronary vasoconstriction soon after percutaneous coronary angioplasty may be due to alpha-adrenergic activation that can be reversed by alpha-adrenergic receptor antagonists given before the procedure. This reversible constriction of coronary microvessels may be a reason for the delayed improvement in exercise-induced myocardial ischemia after PCI.17 A similar type of delayed recovery of coronary microvascular function has also been demonstrated after bypass surgery.18 One important factor leading to microvascular dysfunction is embolization of soft plaque and/or thrombotic material into the downstream bed of the infarct-related artery5 either spontaneously or after mechanical dilatation of the culprit lesion. Injury to the endothelium promotes a procoagulant cascade, then the red-cell and platelet aggregation contributes to microvascular dysfunction and increases the resistance in the microvasculature.19 It is also well recognized that the inflammatory response accompanying myocardial ischemia and reperfusion plays a significant role in myocardial malperfusion and that activation of complement is a key component of this response.20 The various possible causes of microvascular dysfunction are listed in Table 1. There are four different types of cardiac dysfunction demonstrated during myocardial reperfusion. The first type is mechanical dysfunction that persists after reperfusion in the absence of irreversible damage and restoration of normal or near-normal coronary flow, which is otherwise called myocardial stunning.21 The second type is called the no-reflow phenomenon, which is the inability to reperfuse a previously ischemic region.22,23 The third type is reperfusion arrhythmia, which is a potentially deleterious type.24 The last type is lethal reperfusion injury, which is defined as myocardial injury caused by the restoration of coronary blood flow after an ischemic episode. Even with normal epicardial thrombolysis in myocardial infarction (TIMI) blood flow, approximately 15% of patients have inadequate myocardial perfusion called “no-reflow” phenomenon. This may be due to microvascular damage after myocardial ischemia or cell necrosis and regional inflammatory responses induced by reperfusion, or both.25 The no-reflow phenomenon can in turn be classified into structural and functional forms as proposed by Galiuto.26 In the structural type of no-reflow phenomenon, the cellular components of the microvessels are confined within necrotic myocardium and exhibit irreversible damage. In the functional form, the patency of intact microvessel is compromised by the loss of endothelium-mediated vasomotion, alteration of sympathetic innervation, and external compression by interstitial edema and the plugging of platelets and neutrophils.27,28 Measurements for Microvascular Dysfunction Distal microvascular dysfunction is largely heterogeneous, not only between patients, but also between neighboring vascular territories. Ideally, a combination of intracoronary pressure and flow-velocity measurements are required to interpret the complexity of the coronary microvasculature.29 Measurements can be performed by both noninvasive and invasive techniques. i) Noninvasive techniques (Table 2) Routine assessment of perfusion includes the electrocardiographic (ECG) analysis of ST-segment resolution, which evaluates the efficacy of myocardial tissue reperfusion. The percentage of ST-segment resolution30 normally is categorized as: 1. Complete: > 70%, 2. Partial: 30–70%, or 3. Absent: Methods to Improve Microvascular Circulation By improving microvascular circulation one can decrease infarct size and increase survival. Various modes to enhance microvascular circulation have been tried including pharmacotherapy and mechanical devices. Pharmacological Intervention (Tables 4 and 5) Reducing oxidative injury. During myocardial reperfusion, oxidative stress decreases the bioavailability of nitric oxide (NO), an intracellular signaling molecule, thereby reducing its cardioprotective effects which include the inhibition of neutrophil accumulation, inactivation of superoxide radicals and improvement of coronary blood flow.46 According to Zhao et al,47 the marked myocardial hyperoxygenation in reperfused myocardium may be a critical factor that triggers post ischemic remodeling. NO production is increased in post ischemic myocardium, and hence leads to marked myocardial hyperoxygenation on reperfusion. AMIHOT (Acute Myocardial Infarction with Hyperoxemic Therapy) trial (Presented at the TCT Meeting, Washington, D.C., September 2004), assessed the effectiveness of this reperfusion technique in 134 patients and 135 controls. ST-segment resolution was significantly better in the anterior MI group and showed a favorable trend in the cohort as a whole. Recent insights into the potential role of excess NO production in the pathogenesis and adverse outcomes from cardiogenic shock on the one hand, and clinical benefits associated with attenuation of NO production on the other, point toward potentially new pathways for enhancing patient outcomes.48 In a recent international, multicenter, randomized trial TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients with Cardiogenic Shock), isoform-nonselective NO synthetase inhibition with tilarginine (L-NMMA) did not reduce 30-day or 6-month mortality rates in patients with MI complicated by cardiogenic shock persisting after the infarct artery was patent, either in the overall group or when stratified by age.49 Clinical studies using the antianginal NO donor nicorandil have reported benefit only in terms of improved myocardial reperfusion; results in terms of clinical outcomes after an AMI are mixed.50,51 Regulation of intracellular calcium. A sudden intracellular Ca2+ influx occurs secondary to sarcolemmal-membrane damage and oxidative stress-induced dysfunction of the sarcoplasmic reticulum at the time of myocardial reperfusion. Few experimental studies have demonstrated that reducing intracellular Ca2+ overload using pharmacologic antagonists of the sarcolemmal Ca2+ ion channel, the mitochondrial Ca2+ uniporter, or the sodium-hydrogen exchanger decreases myocardial infarct size by up to 50%.52–54 However, the results of the clinical studies have been negative.55,56 Acid-base balance. There is a rapid restoration of physiologic pH during myocardial reperfusion, which follows the washout of lactic acid. This activates the sodium-hydrogen exchanger and the sodium-bicarbonate symporter contributing to lethal reperfusion injury.57 Experimental studies have shown that reoxygenation with acidic buffer is cardioprotective.58 This cardiac protection can be explained by the inhibition of mitochondrial permeability transition pore (PTP) opening.59 Improving the oxygen-carrying capacity of hemoglobin has also been found to improve microvascular dysfunction and reduce infarct size.60 Specific benzoyl-guanidine Na+/H+ exchange (NHE1) inhibitor HOE-642 (cariporide) has been shown to reduce myocardial injury after ischemia and reperfusion in clinical studies.61,62 Na+/H+ exchange inhibition through HOE-642 delays intracellular alkalinization in the myocardium in situ during reperfusion, and this is associated with improved diastolic function and high-energy phosphate preservation.63 However, in other clinical studies, delaying the restoration of physiologic pH during myocardial reperfusion using sodium-hydrogen exchange inhibition did not have any cardiac protection.56,64 Reducing inflammation. Several experimental interventions aimed at neutrophils during myocardial reperfusion have shown reductions in infarct size of up to 50%. These interventions include depletion of leukocytes in blood;65 antibodies against the cell-adhesion molecules P-selectin,66 CD11 and CD,18,67 the intercellular adhesion molecule 168; and pharmacologic inhibitors of complement activation.69 However, the corresponding clinical studies have not shown any cardioprotective benefits.70–72 Adenosine. Experimental studies have shown that pretreatment with adenosine reduces ischemia reperfusion damage, limits infarct size and improves ventricular function.73 Marzilli et al74 found that patients on adenosine demonstrated a lower incidence of no-reflow phenomenon and a significant improvement in final TIMI grade flow. To the contrary, the ADMIRE (AmP579 Delivery for Myocardial Infarction Reduction) study of 311 patients undergoing primary PCI demonstrated that adenosine had no significant effect on infarct size.75 Adenosine is not only an antiinflammatory agent, but also has other actions (antiplatelet, vasodilatory, angiogenic, vasculogenic and antifibrotic).76 The Acute Myocardial Infarction Study of Adenosine (AMISTAD) I and II showed reductions in infarct size in anterior infarction (67% and 57%, respectively).76,77 AMISTAD II showed that adenosine given within 3 hours after the onset of symptoms decreased mortality.78 After inconclusive experimental studies,79,80 clinical studies using the antiinflammatory agent adenosine as an adjunct to PCI have shown an 11% reduction in the size of myocardial infarcts.77,78 Currently, the use of intracoronary adenosine is limited to the treatment of patients with established no-reflow. Endothelial cells. Endothelial cells may also play a role in reperfusion injury. These cells can trigger the development of neutrophil and platelet aggregates that plug the cardiac microvasculature, leading to the no-reflow phenomenon. Hypoxia-reoxygenation activates endothelial cells to secrete Weibel-Palade bodies, containing granules of von Willebrand factor and P-selectin.81 Release of von Willebrand factor induces platelet rolling; activated platelets can release chemokines, which in turn increase inflammation and damage to cardiac myocytes. New strategies aimed at blocking the exocytosis of these bodies from the endothelial cells may prove useful in preventing reperfusion injury.82 Metabolic modulation using glucose and insulin. Several experimental and numerous clinical studies have examined the cardioprotective potential of using glucose, insulin and potassium (GIK) as an adjunct to myocardial reperfusion.83,84 These studies have been conducted on the premise that ischemic myocardium benefits more from metabolizing glucose than from fatty acids.85 A recent very large, randomized, controlled study from several centers reported no cardioprotective benefit from therapy with glucose, insulin and potassium as an adjunct to myocardial reperfusion in patients with AMI.86 The delay in initiating this therapy, the prolonged period of myocardial ischemia, and high and potentially damaging glucose levels have all been cited as reasons for the lack of cardioprotection.84 A separate study, the Organization for the Assessment of Strategies for Ischemic Syndromes-6 (OASIS-6) trial, evaluated the effect of GIK infusion versus no infusion on 6-month clinical outcomes in 2,748 patients with acute STEMI.87 The combined OASIS-6 and CREATE-ECLA trial analysis of almost 23,000 patients with STEMI demonstrates that GIK infusion has no effect on any important clinical endpoint through 30 days following STEMI. Magnesium therapy. Experimental studies have reported that intravenous magnesium administered during myocardial reperfusion can reduce myocardial infarct size, but the mechanism of this effect is unclear.85 Initial clinical studies of adjunctive therapy with magnesium during reperfusion in patients with AMI were inconclusive.88,89 However, subsequent trials with magnesium administered immediately before PCI have also not shown cardioprotection.90,91 Therapeutic hypothermia. Mild hypothermia (33–35°C) has been reported to benefit patients surviving a cardiac arrest.92 Experimental studies have shown a 10% reduction in myocardial infarct size for every 1°C decrease in body temperature93 and that mild hypothermia reduces myocardial infarct size in pigs.94 However, these beneficial effects were not reproduced in initial clinical studies of therapeutic hypothermia in patients with AMI who are undergoing primary PCI.95,96 The COOL-MI (COOLing as an Adjunctive Therapy to Percutaneous Intervention in Patients with Acute Myocardial Infarction) trial (Presented at the 2003 Transcatheter Cardiovascular Therapeutics conference, by William O’Neill, MD) enrolled 392 patients with AMI presenting within 6 hours of symptom onset. The results of this trial showed that treatment with endovascular cooling in patients with AMI undergoing PCI was not associated with a reduction in infarct size compared with controls, but was associated with a reduction in infarct size in a subset of patients with an anterior MI cooled to Mechanical Intervention (Table 6) There were various trials performed to improve microvascular function after PCI. The different studies on mechanical devices were based on three methods: firstly, distal protection devices; secondly, thrombectomy; and finally, thrombus aspiration to prevent thrombus migration. All these methods have varying results, most of which are still in experimental stages and not widely used. 1. Distal protection devices Two types of distal protection devices are approved by the U.S. Food and Drug Administration for use in PCI:114 1) The FilterWire™-EX system (Boston Scientific Corp. Natick, Massachusetts) is an intravascular filtration device that is placed distal to the PCI site without obstructing antegrade blood flow. 2)The PercuSurge GuardWire (Medtronic Corp., Santa Rosa, California) and FilterWire-EX. Both work by temporary inflation of a low-pressure occlusion balloon distal to the PCI site, followed by removal of debris using an aspiration catheter after which the balloon is deflated and antegrade flow is reestablished. The FilterWire-EX is a 0.014 inch guidewire that incorporates a nonoccluding polyurethane porous membrane filter (80 µm pores) in the shape of a windsock to allow retention and removal of embolized particles.115 Distal protection devices like the FilterWire and the FilterWire-EX used in the PROMISE trial6 did not result in improved reperfusion, reduced infarct size, or improved clinical outcome, despite a high procedural success rate. The results of larger trials including EMERALD, AIMI and PROMISE did not favor using these devices. The various devices used in AIMI, EMERALD and PROMISE trials are shown in Figure 2. The EMERALD (Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris) trial7 used a distal balloon occlusion and aspiration system which effectively retrieved embolic debris in most patients with acute STEMI undergoing emergent PCI. Nonetheless, distal embolic protection did not result in improved microvascular flow, greater reperfusion success, reduced infarct size or enhanced event-free survival. Of note in this study, infarct size increased with distal protection in thrombotic lesions which were performed by occluding the infarcted artery prior to reperfusion. It is more likely that the distal embolization that can be prevented by protection devices exerts only minor effects when compared to the consequences of ischemic microvascular damage116,117 or spontaneous distal embolization from plaques during the natural course of myocardial infarction.118,119 The difficulty in finding explanations for the lack of efficacy of the distal protection strategy used in these trials may imply that both the relevance and the nature of the mechanisms interfering with microcirculatory function in AMI need to be reassessed. 2. Thrombectomy The X-Sizer is a thrombectomy device using an intracoronary helical cutter connected to an external passive vacuum source allowing fragmentation and removal of intracoronary thrombotic material.120 In the setting of ACS, this device may allow removal of soft material immediately before PCI to avoid or minimize distal embolization. Studies by Beran et al,120 Napadano et al121 and Lefevre et al122 reported that thrombectomy with the X-Sizer before PCI has the potential to minimize thrombus dislodgement and distal embolization. These studies showed improvement in coronary epicardial flow and microvascular function. In the AIMI (AngioJet rheolytic thrombectomy in patients undergoing primary angioplasty for acute myocardial infarction) trial [Ali A. AngioJet rheolytic thrombectomy in patients undergoing primary angioplasty for acute myocardial infarction (TCT abstract presentation), 2004], patients treated with the AngioJet showed larger infarct sizes in comparison with control patients. Although rheolytic therapy (RT) is approved for use in thrombotic coronary lesions, the results of this study do not support its routine use with primary PCI in all STEMI patients. The observed difference in MACE is statistically significant and driven by mortality. Additional studies are planned to further evaluate the safety and clinical value of the use of RT in patients with STEMI/thrombotic lesions. 3. Thrombus aspiration In thrombus aspiration, the first procedural step is the passing of a floppy, steerable guidewire through the target lesion. This step is then followed by advancing the 6 Fr Export Aspiration Catheter (Medtronic; crossing profile, 0.068 inch) into the target coronary segment, continuously aspirating in the process. When necessary for stent delivery, balloon dilatation can be performed before stenting.123 In REMEDIA (The Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus Aspiration in Primary and Rescue Angioplasty ) trial,124 manual thrombus aspiration with the Diver CE in patients with acute STEMI resulted in improved angiographic and ECG myocardial reperfusion rates. A new study, TAPAS (Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study), has been designed to determine whether aspiration of thrombotic material by means of a 6 Fr Export aspiration catheter before stent implantation of the infarct-related coronary artery will result in improved myocardial perfusion compared with conventional primary PCI. This study showed that thrombus aspiration is applicable in a large majority of patients with myocardial infarction with ST-segment elevation, and it results in better reperfusion and clinical outcomes than conventional PCI, irrespective of clinical and angiographic characteristics at baseline.123 Conclusion Developing new therapies to salvage jeopardized myocardium, limit infarct size and preserve left ventricular function is of primary importance in the treatment of patients with myocardial infarction. While most of the studies have shown that distal microcirculatory embolization may occur during primary PCI and be preventable, such intervention may be too little or too late to achieve meaningful myocardial salvage. This could be due to systemic and local mediators of inflammation and endothelial dysfunction, capillary leakage causing interstitial edema and reperfusion injury.7 In the setting of ACS, thrombotic embolization and activation of platelets with release of vasoconstrictors into the downstream microvasculature may occur before cardiac catheterization.112 Lethal reperfusion injury would be expected to adversely affect clinical outcomes after an AMI, and it may contribute to mortality despite early and successful reperfusion. Until recently, most cardioprotective agents used in animal models have had difficulty in reproducing the same effects in clinical trials. General agreement now is that ischemic preconditioning and postconditioning are cardioprotective, not only in animals, but also in humans. The newer mechanisms of cardiac protection, particularly with regard to the RISK pathway and the inhibition of mitochondrial PTP opening, has led to the development of new pharmacologic interventions to improve microvascular dysfunction. These clinical results have regenerated interest in the reperfusion phase as a target for cardioprotection. Preliminary clinical data indicate that these new cardioprotective strategies confer a benefit to patients with AMI, but this has to be confirmed in large-scale clinical studies. Therefore, future studies need to consider not only ways to restore epicardial circulation, but also methods of reducing microvascular dysfunction and improving microvascular circulation.

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