Correspondence Division of Cardiology, Sakurabashi Watanabe Hospital, 2-4-32 Umeda, Kita-ku, Osaka 530-001, Japan

Email itomd@osk4.3web.ne.jp

Introduction

After acute myocardial infarction (AMI), the immediate therapeutic goal is to establish patency of the infarct-related artery. The successful restoration of epicardial coronary artery patency, however, does not necessarily translate into improved tissue perfusion. Structural disruption or obstruction of the microvasculature, the so-called no-reflow phenomenon, could occur before or because of percutaneous coronary intervention (PCI) and might impair coronary flow. With the advancement of imaging modalities, the number of patients in whom microvascular obstruction is detected has increased compared with that based on clinical judgment alone.

Patients with the no-reflow phenomenon have a poor clinical prognosis.¹ Attention has shifted, therefore, away from merely achieving epicardial artery patency and towards the status of the microvasculature. Advances in our understanding of the pathophysiology of microvascular dysfunction in patients with AMI could aid the development of preventive and therapeutic strategies. In this article, I attempt to provide an in-depth understanding of the no-reflow phenomenon from the bench to the bedside.

Pathophysiology of microvascular dysfunction

The no-reflow phenomenon in the myocardium was originally described in 1974 by Kloner et al.² The capillary structure becomes disorganized in the no-reflow zone because of endothelial swelling, compression by tissue, myocyte edema, and neutrophil infiltration.³ This pathologic process can be accelerated by coronary reperfusion, leading to progressive decline of coronary flow.⁴ Tissue edema, endothelial disruption, plugging of capillaries by neutrophils and microthrombi, inflammation due to the generation of oxygen-free radicals and activation of complement components, and contracture of neighboring myocytes are all promoted by coronary reperfusion.⁵ Thus, the no-reflow phenomenon results partly from reperfusion injury.

Microthromboemboli and particles of plaque gruel are thought to be showered downstream after plaque rupture, leading to the obstruction of small arteries and arterioles. Progressive microvascular dysfunction could, therefore, result from some embolic events in the ipsilateral microvasculature, but also in the contralateral microvasculature through the collateral circulation.^{6, 7} PCI potentially accelerates this pathologic process, which can cause small periprocedural infarctions.

The factors related to the development of the no-reflow phenomenon differ according to whether the cause is destruction or obstruction of capillaries, or the introduction of microemboli to small arteries or arterioles. Determinants of capillary obstruction are similar to those of myocardial necrosis after AMI, and include duration of coronary occlusion, extent of myocardium supplied by the occluded artery, patency of infarct-related artery, the quality of collateral circulation, and the presence of preinfarction angina.⁸ If preinfarction angina is present it produces a preconditioning-like effect and might correlate with collateral function. The quality of collateral channels is important to maintain microvascular integrity. Myocardial territory supplied by collateral channels can be successfully visualized by myocardial contrast echocardiography, and this territory is salvaged after sustained coronary ischemia.⁹

Hyperglycemia in AMI is associated with an increased risk of in-hospital mortality, as well as with the no-reflow phenomenon.^{10, 11} Endothelium-dependent vasodilatation is impaired by hyperglycemia, which leads to increased adhesion of leukocytes to the endothelial cells because of an increase in the numbers of circulating adhesion molecules. This change could lessen the effect of ischemic preconditioning.

Microemboli are likely to arise during PCI from lipid-rich vulnerable plaques. Liberation of plaque components, including platelet-fibrin complex, macrophages, and cholesterol crystals, could provoke arteriole spasm, leading to further microvascular congestion, thrombosis, and sluggish coronary flow; such restriction is usually transient.^{12, 13} Coronary arterial blood flow is reduced after intracoronary administration of particles smaller than 45 m in dogs, but immediately rises to higher than the baseline level after adenosine-related hyperemia of the myocardium surrounding the embolized microregions.¹⁴ Only when embolic particles occlude more than 50% of the coronary microvascular bed is coronary flow reduced. Okamura et al.¹⁵ used a Doppler guide wire to detect high-intensity transient signals, which allowed them to count the number of embolic particles. The average number of embolic particles was 20–30 throughout the PCI procedure in patients with AMI. If the number of embolic particles is within this range, any notable derangement of coronary microcirculation is unlikely. If embolic particles are large (>200 m diameter), however, they can lodge in coronary perforators, creating so-called infarctlets and reducing myocardial blood flow.

Diagnosis of the no-reflow phenomenon

Myocardial contrast echocardiography

Myocardial contrast echocardiography uses intravascular contrast agents that contain tracers. This modality can be used to assess microvascular perfusion (Figure 1), and hence has become the gold standard investigative technique for the no-reflow phenomenon. This form of echocardiography was first performed during coronary angiography after injection of sonicated microbubbles into recanalized infarct-related arteries. Substantially sized no-reflow zones were seen in 25–30% of patients with AMI, despite open arteries on angiography.¹⁶ Myocardial contrast echocardiography can be performed at the bedside with intravenous injection of commercially available contrast agents (Figure 1).

Figure 1 Myocardial contrast echocardiograms in a patient with reperfused anterior myocardial infarction.

These end-systolic myocardial contrast echocardiograms show the apical four-chamber view in a patient with anterior myocardial infarction. (A) After the intravenous injection of a microbubble contrast medium, the mid-ventricular to distal ventricular septum and apical segment show contrast perfusion defects, indicating the no-reflow phenomenon. (B) After the quantitative analysis with commercially available software (VoluMap-445, Ikoma, Japan), the contrast defect area is represented as the area of low myocardial blood volume fraction (blue colors, estimated myocardial blood volume <1.586 ml/100g myocardium).

Full figure and legend (33K)Figures & Tables indexDownload Power Point slide (238K)

The perfusion defects observed on contrast echocardiography should reflect the regions of microvascular obstruction, but the infarct size is underestimated. After a vasodilator stress, the defects should match infarct size.¹⁷ The spatial extent of the affected region varies over time. Visualization of the microvasculature to assess myocardial viability might, therefore, be best done 48–72 h after AMI. The microvascular damage can be quantified by measurement of regional myocardial blood volume fraction. The background-subtracted acoustic intensity for the myocardium correlates with the number of microbubbles. When the intensity is normalized to acoustic intensity for the left ventricular cavity, myocardial blood volume fraction can be measured. Since 90% of myocardial blood volume in end systole exists in capillaries, enough data to allow assessment of microvascular integrity can be collected in one myocardial contrast echocardiography image. The findings adequately reflect myocardial viability.¹⁸

Coronary Doppler imaging

The study of coronary blood flow velocity patterns is helpful in understanding the mechanism of microvascular dysfunction. The no-reflow phenomenon has a characteristic coronary blood flow pattern that has three main components: systolic flow reversal; reduced antegrade systolic flow; and forward diastolic flow with a rapid deceleration slope.²⁴ This to-and-fro nature of blood flow causes coronary forward flow to be reduced and leads to TIMI II flow on imaging. The coronary blood flow velocity pattern is caused by extensive capillary damage, which is associated with increased capillary resistance and a reduced myocardial blood pool. The recognition of this characteristic pattern is helpful deciding whether PCI should be performed. If TIMI II flow remains after PCI, the to-and-fro flow velocity pattern implies the presence of the no-reflow phenomenon, and additional stenting would not reverse impaired coronary flow.²⁵

The coronary blood flow velocity pattern helps to differentiate between individuals with microemboli and those without. Characteristic features of those with emboli are slow forward flow and an increase in diastolic-to-systolic flow ratio, implicating increased coronary arterial resistance. At least two different coronary blood flow velocity patterns can, therefore, be seen in patients with slow coronary flow after PCI (Table 1).²⁶

Table 1 The two mechanisms of TIMI II flow, indicating sluggish coronary flow, associated with PCI.

Full tableFigures & Tables indexDownload Power Point slide (259K)

Clinical implications of the no-reflow phenomenon

As well as correlating with infarct size, no reflow can provide prognostic information.³¹ The no-reflow phenomenon occurs after the myocytes in the area are already dead and, therefore, later recovery of function is almost impossible. A large no-reflow zone is associated with reduced left ventricular contractile function. In addition to predicting recovery of systolic function, the presence of no reflow predicts acute complications after AMI. Patients with the no-reflow phenomenon form the highest-risk subgroup of patients undergoing reperfusion, with raised associated risks of early and sustained congestive heart failure and death.¹⁶ A large region of no reflow might impede the ability of the infarct to heal and prevent delivery of pharmacologic agents into that area. Transmural damage is frequently seen and, if this is substantial, infarct expansion and early left ventricular dilation are likely to occur. The no-reflow phenomenon has been linked to ventricular arrhythmias and even to cardiac rupture. Evidence also suggests that it might lead to adverse effects on left ventricular remodeling after AMI. Follow-up studies have documented that the no-reflow phenomenon is associated with malignant arrhythmias, reduced ejection fraction, and a raised risk of cardiac death,^{29, 32} all of which have important therapeutic implications.

Treatment of microvascular dysfunction

The focus of reperfusion therapy is moving towards improving the patency of the microvasculature in the affected area rather than merely opening the target vessel. The improvement of tissue perfusion could promote functional recovery of viable muscle, reduce infarct expansion, and possibly increase the delivery of blood-borne components. Bone marrow components contain endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts. These components have been shown to directly induce new blood vessel formation in the infarct bed (vasculogenesis) and proliferation of pre-existing vasculature (angiogenesis) after experimental myocardial infarction.³³ Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling, and improves cardiac function.

Treatment of microemboli

Promising adjunctive therapies to reduce microemboli include intensive antiplatelet therapy with aspirin and clopidogrel, platelet glycoprotein-IIb/IIIa-receptor inhibitors, coronary vasodilators, and devices to protect against embolization. Thrombolytic agents seem not to improve microvascular function.

Aggressive treatment of platelet microembolism with glycoprotein-IIb/IIIa-receptor inhibitors has yielded encouraging results. In an experimental study, administration of tirofiban before coronary reperfusion was associated with improved myocardial perfusion and reduced infarct size.³⁴ The Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up (ADMIRAL) trial³⁵ provided preliminary evidence that intravenous abciximab is associated with a high incidence of TIMI III flow; an 80% reduction in adverse cardiac events was seen compared with controls among AMI patients undergoing primary PCI. Whether the improvement in coronary flow is mediated by inhibition of platelet aggregation or by faster establishment of epicardial artery recanalization, however, remains unknown.

A more direct method to reduce thrombus or plaque burden is to retrieve embolic materials with catheter-based devices. Some devices directly aspirate thrombus and plaque contents at the occlusion site and others are distal protection devices designed to trap embolic materials. Devices are classified into two types: balloon-occlusion devices, which are deployed to the distal site of a vulnerable plaque during PCI to temporarily occlude the vessel, followed by removal of debris with an aspiration catheter; and filter wire devices that trap debris during PCI and can be collapsed and withdrawn from the artery containing the trapped debris. Both types of systems retrieve embolic debris effectively in most patients with AMI undergoing emergency PCI. Nonetheless, distal embolic protection does not necessarily result in improved microvascular flow or reperfusion success, reduced infarct size, or increased event-free survival.^{36, 37} The patients in whom these devices are to be used should, therefore, be selected carefully. Identification of ruptured plaques by intravascular angioscopy might be useful to identify patients who could respond to distal protection.³⁸ The AngioJet^® rheolytic thrombectomy system (Possis Medical Inc., Minneapolis, MN) is designed to remove thrombus using the Venturi-Bernoulli effect, by shooting multiple high-velocity, high-pressure saline jets through orifices in the distal tip of a catheter to create a localized low-pressure zone. The result is a vacuum effect with the entrainment and dissociation of the bulky thrombus.³⁹ Rheolytic thrombectomy with the AngioJet^® catheter can reduce thrombus burden in patients with AMI. In a small population study, long-term follow-up results seemed favorable in AMI patients treated with rheolytic thrombectomy compared with conventional primary angioplasty. The findings in larger populations are, however, unclear,⁴⁰ and further studies are needed.

Experimental studies have demonstrated that multiple, short, induced coronary occlusions immediately after sustained myocardial ischemia are associated with reduced myocardial infarct size compared with sudden reperfusion.⁴¹ This cardioprotective intervention is called postconditioning. The mechanism of protection involves activation of extracellular-signal-regulated kinase, production of nitric oxide, opening of mitochondrial potassium channels, and inhibition of opening of the mitochondrial permeability transition pore. A similar approach could be applied in the cardiac catheterization laboratory to protect reperfused myocardium after primary angioplasty in patients with AMI. Staat et al.⁴² performed postconditioning during PCI for AMI in humans, starting within 1 min of reflow and achieved by inflation of an angioplasty balloon for 1 min followed by deflation for 1 min, carried out four times. Improvements were seen in myocardial perfusion and functional outcomes compared with those in patients who did not undergo postconditioning. This catheter-based technique may be clinically applicable in PCI, CABG surgery, organ transplantation, and peripheral revascularization where reperfusion injury is expressed.

Treatment of the no-reflow phenomenon

If myocytes and the microvasculature could be protected against ischemic injury, reperfusion injury, or both, postischemic microvascular flow would be augmented and functional and clinical outcomes improved. Adenosine yields benefits beyond simple vasodilation that make it a possible therapy to achieve this goal. Adenosine lowers neutrophil counts in infarct zones, maintains endothelial integrity, and might exert cardioprotective effects that are similar to ischemic preconditioning. In patients with AMI, intracoronary administration of 24–48 g adenosine is well tolerated and improves microvascular and ventricular function in the infarct zone, leading to an improved clinical course after PCI.⁴³ Intravenous administration of adenosine is not powerful enough to reduce infarct size. The AMISTAD II trial⁴⁴ assessed clinical outcomes and infarct size in 21,118 patients with ST-segment elevation myocardial infarction undergoing reperfusion therapy with adenosine as an adjunct therapy. Clinical outcomes were not significantly improved with adenosine, although infarct size was reduced with a high-dose infusion (70 g kg^-1 min^-1). Nicorandil is a mitochondrial potassium-channel opener that has a nitrate component and has shown promising results in patients with AMI when given before reperfusion. This drug reduces preload and afterload, dilates coronary resistance vessels, reduces calcium overload of myocytes and attenuates neutrophil activation. Since the mitochondrial potassium channel is an end effector of the ischemic preconditioning pathway, nicorandil could protect the myocardium against ischemic injury. Studies have demonstrated that among reperfused patients who received intravenously administered nicorandil, improvement in microvascular perfusion was observed, infarct size was reduced, and clinical outcomes improved.^{45, 46} An associated improvement in microvascular perfusion was observed in the nicorandil treatment groups.

The use of vasodilators, including nitrates, verapamil, papaverine, nicardipine and sodium nitroprusside, might have a role in improving microvascular function after AMI. Administration of intracoronary sodium nitroprusside or verapamil was associated with significant improvements in coronary flow with an increase being seen in TIMI flow grade.^{47, 48, 49} Intracoronary verapamil was associated with better functional recovery in wall motion abnormalities.^{50, 51} In cases of TIMI II flow after PCI, however, these strategies could be tried to restore coronary blood flow, which is essential for an improved left ventricular function and a good cardiac outcome. Sodium–hydrogen pump inhibitors can reduce reperfusion injury by attenuating intracellular calcium overload. In an experimental study, use of such an agent improved microvascular function and myocardial blood flow, and reduced infarct size.⁵¹ Large-scale, multicenter trials did not, however, show any benefit with cariporide or eniporide on functional and clinical outcomes in patients with a wide range of ischemic risk.^{52, 53} The usefulness of these drugs to reduce no reflow has, therefore, not been established in a clinical setting. Other adjunctive agents, including monoclonal antibodies to leukocytes, complement-receptor inhibitors, adhesion molecule antibodies, endothelin-A selective antagonists, and erythropoietin,⁵⁴ might have potential therapeutic roles. Double-blind, randomized, multicenter trials should be conducted to assess the potential of these agents to treat the no-reflow phenomenon and to determine the appropriate dosage.

Conclusions

The no-reflow phenomenon occurs in a notable proportion of patients with AMI, despite aggressive reperfusion therapy, and is associated with a poor prognosis. Looking beyond epicardial artery patency and assessing microvascular perfusion is useful for risk stratification in patients with AMI. The identification of mechanisms of microvascular dysfunction is the key to defining specific therapeutic strategies for reperfusion. To accelerate the development of the new reperfusion regimens, an integrated approach that incorporates multiple efficacy variables to assess the success or failure of tissue perfusion is required.

Acknowledgments

I thank Dr S Kaul, Oregon Health & Science University, Portland, OR, USA, for valuable discussion and suggestions.

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Subject areas under which this article appears: Acute coronary syndromes | Vascular disease