Circulation. 2008;117:3152-3156
doi: 10.1161/CIRCULATIONAHA.107.742312
(Circulation. 2008;117:3152-3156.)
© 2008 American Heart Association, Inc.
Microvascular Obstruction and the No-Reflow Phenomenon After Percutaneous Coronary Intervention
Ronen Jaffe, MD;
Thierry Charron, MD;
Geoffrey Puley, MD;
Alexander Dick, MD;
Bradley H. Strauss, MD, PhD
From the Schulich Heart Programme (R.J., A.D., B.H.S.), Sunnybrook Health Sciences Centre, and Roy and Ann Foss Interventional Cardiology Research Program (R.J., T.C., G.P.), St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada.
Correspondence to Dr Bradley H. Strauss, Reichmann Chair in Cardiovascular Sciences, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Suite A-253, Toronto, Ontario, Canada MYN 3MD. E-mail bradley.strauss{at}sunnybrook.ca
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Introduction
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C
ase presentation A: A 50-year-old diabetic man presented to
the hospital after 8 hours of continuous chest pain. Because
of acute myocardial infarction of the anterior wall, he underwent
direct stenting to an occlusion in the left anterior descending
coronary artery. Despite revascularization, suboptimal coronary
flow was achieved, and he subsequently developed heart failure.
Case presentation B: A 77-year-old man underwent elective stenting of a significant stenosis in a degenerated saphenous vein coronary bypass graft. After the procedure, coronary flow in the graft was severely reduced, and he sustained a myocardial infarction in the subtended myocardial territory.
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Introduction and Definition
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The concept of "no reflow" refers to a state of myocardial tissue
hypoperfusion in the presence of a patent epicardial coronary
artery. The underlying cause of no reflow is microvascular obstruction,
which may be produced by various mechanisms.
No reflow can be classified according to the duration of the preceding myocardial ischemia (Figure 1). "Reperfusion no reflow" occurs after primary percutaneous coronary intervention (PCI) for reperfusion of an infarct artery in the setting of acute myocardial infarction (AMI) and may be asymptomatic or may present clinically with continued chest pain and ST-segment elevation. Reperfusion no reflow is preceded by ischemic cell injury, is confined to the irreversibly damaged necrotic zone, and may be exacerbated at the time of reperfusion. Reperfusion no reflow is an independent predictor of adverse clinical outcome after AMI regardless of infarct size and is associated with heart failure and increased mortality.1
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Figure 1. Schematic illustrating the effect of duration of preceding myocardial ischemia on mechanism of no reflow (NR).
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"Interventional no reflow" follows noninfarct PCI and affects myocardium that was not subjected to prolonged ischemia before the procedure. Clinically recognized interventional no reflow that complicates PCI is typically sudden in onset, presenting as acute ischemia with chest pain and ECG changes, and may resolve over the course of several minutes. Patients sustaining interventional no reflow have higher rates of myocardial infarction and mortality.2 Because interventional no reflow is unpredictable and uncommonly recognized in clinical practice, much of the current understanding of this phenomenon originates from studies of reperfusion no reflow in animal models and AMI patients.
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Diagnosis of No Reflow
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Although ECG ST-segment resolution is a readily available marker
of tissue-level reperfusion, persistence of ST-segment elevation
in an AMI patient may reflect either epicardial artery occlusion
or microvascular obstruction. Coronary angiography allows a
semiquantitative grading of epicardial coronary flow according
to the Thrombolysis In Myocardial Infarction (TIMI) flow grades.
The no-reflow phenomenon is recognized angiographically in >20%
of patients undergoing primary angioplasty for AMI and in <2%
of elective PCI cases. Reduced coronary flow after primary angioplasty
(TIMI flow 0 to 2) is associated with worse outcome than normal
(TIMI 3) flow, even when no significant epicardial obstruction
remains.
1 More sensitive markers of tissue perfusion have now
been identified and provide prognostic information beyond that
of TIMI flow grade. The TIMI frame count assesses the number
of angiographic frames required for the contrast medium to reach
standardized distal landmarks of the coronary tree, and the
myocardial blush grade is a quantitative assessment of myocardial
contrast density. Angiographic epicardial flow is a poor surrogate
for tissue perfusion, which is the clinically important end
point of coronary interventions, and microvascular no reflow
occurs much more commonly than is recognized. Myocardial contrast
echocardiography has greatly advanced the noninvasive assessment
of myocardial perfusion and may demonstrate microvascular no
reflow even among patients with angiographic TIMI 3 flow after
primary PCI, which predicts worse outcome.
3 Tissue hypoenhancement
on contrast-enhanced MRI and CT reflects impaired myocardial
perfusion and correlates with histological evidence of microvascular
obstruction. A rise in serum cardiac biomarkers after PCI reflects
myocardial necrosis secondary to tissue hypoperfusion and ischemia.
More than 70% of patients may exhibit elevated troponin values
after an otherwise successful elective PCI.
4
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Pathophysiology of No Reflow
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No reflow results from obstruction of the myocardial microcirculation,
defined as vessels <200 µm in diameter. The pathophysiology
and treatment of microvascular obstruction in the setting of
reperfusion and interventional no reflow likely differ (
Figure 2).
Preexisting microvascular dysfunction may exacerbate the degree
of microvascular obstruction that develops after both elective
and infarct-related PCI, which may explain the association of
diabetes mellitus and hyperlipidemia with no reflow.
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Figure 2. A, Schematic representation of pathophysiological mechanisms that may contribute to reperfusion no reflow in the setting of primary angioplasty for AMI. The vasculature within the necrotic zone is subjected to additional injury after reperfusion. Microvascular spasm and plugging, intravascular thrombus, endothelial swelling, and capillary compression by edema within the adjacent myocardial tissue may lead to microvascular obstruction. Angioplasty-induced distal coronary embolization of plaque and thrombus may compound the vascular obstruction. An inflammatory response may exacerbate this process, which leads to further myocardial ischemia and cell death. B, Interventional no reflow after noninfarct angioplasty is induced by distal coronary embolization of plaque components. Mechanical obstruction of the microvasculature may be accompanied by an inflammatory vascular response that leads to vascular spasm. These mechanisms result in myocardial ischemia and cell death.
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Myocardial Infarction Reperfusion No Reflow
Myocardial ischemia-reperfusion injury and endothelial damage underlie the development of reperfusion no reflow. Infarct size and microvascular hypoperfusion may increase at the time of coronary reperfusion beyond that observed during the ischemic period. Endothelial injury is induced by an acute inflammatory response, generation of reactive oxygen species, intracellular calcium overload, and opening of the mitochondrial permeability transition pore. Ultrastructural changes are confined to the necrotic zone, appear first in the subendocardium, and subsequently progress toward the subepicardium after longer periods of occlusion. Endothelial cellular swelling and protrusions, as well as myocyte swelling and tissue edema, may occlude the microvasculature. Vasospasm and downstream embolization of thrombus compound the microvascular obstruction.
Interventional No Reflow
Distal embolization of thrombus and atherosclerotic gruel are the most likely culprits in no reflow complicating noninfarct angioplasty. Microembolization leads to platelet and inflammatory cell activation and to vasospasm, which reduce coronary flow in combination with mechanical plugging of the microcirculation.
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Predictors of No Reflow
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The degree of reperfusion no reflow that develops after infarct
angioplasty is associated with the duration of the preceding
myocardial ischemia, infarct size, procedural variables, and
patient characteristics. Coronary stenting may lead to reduced
tissue perfusion compared with balloon angioplasty.
5 Larger
plaque area and eccentric or fissured plaque predict no reflow.
These findings reflect the importance of distal embolization
in this setting. Diabetes mellitus, absence of preinfarction
angina, and advanced age predict no reflow, which reflects the
impact of preexisting microvascular damage and dysfunction,
as well as ischemic preconditioning, on the subsequent development
of no reflow. Interventional no reflow occurs more commonly
after angioplasty in degenerated saphenous vein grafts and thrombus-containing
lesions and after coronary atherectomy.
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Prevention and Treatment of No Reflow
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Multiple therapies for no reflow have been tested in animals
and to a lesser degree in humans. Interventions for no reflow
that were efficacious in preclinical research often have failed
to translate into effective human therapies owing to limitations
of the available animal models. Most research has focused on
the setting of AMI, and randomized clinical trials have been
confined to preventative therapy. Consequently, data relating
to reversal of established no reflow are limited. Because no
reflow is dynamic by nature and may spontaneously resolve over
time, the contribution of nonrandomized studies to the current
understanding of treatment options is limited.
Several pharmacological agents have been studied. Adenosine is an endogenous purine nucleoside that decreases arteriolar resistance and activates intracellular cardioprotective signaling pathways. Its mechanism of action may involve opening ATP-sensitive potassium channels (KATP), inhibition of neutrophil migration, prevention of superoxide generation, or blockade of coronary endothelin release. Nitroprusside and nitroglycerin are nitric oxide donors that vasodilate conductance vessels; however, microvessels are unable to metabolize nitroglycerin to nitric oxide, whereas nitroprusside does not require metabolism. Nicorandil is a hybrid of a KATP opener and nitrate and may prevent reperfusion injury by blocking the mitochondrial permeability transition pore. Calcium channel blockade has several potentially beneficial effects in the setting of no reflow in addition to attenuation of microvascular spasm. Reduction of heart rate and blood pressure may reduce myocardial ischemia and infarct size. Verapamil may inhibit platelet aggregation and thrombus formation in the microvasculature and may have a direct effect on calcium flux across the sarcolemmal membrane or within intracellular compartments that could protect reversibly injured myocytes. Platelet inhibition with glycoprotein IIb/IIIa inhibitors could reduce downstream embolization and in situ microvascular generation of thrombus and reduce the release of vasoactive and chemotactic mediators from platelets.
Myocardial Infarction Reperfusion No Reflow
Randomized trials have suggested that the vasodilators verapamil and adenosine may reduce the no-reflow phenomenon after primary PCI. Prevention of upstream and in situ microvascular thrombosis with intravenous abciximab and intracoronary thrombolysis has been shown to improve microvascular perfusion.6,7 Mechanical devices for prevention of embolization and removal of plaque and thrombus may have a role in the setting of primary PCI. Although thrombus aspiration improves tissue perfusion,8 deployment of a distal arterial protection device does not.9
The concept of ischemic preconditioning and postconditioning refers to a variety of pharmacological and nonpharmacological cardioprotective interventions implemented before the onset of ischemia or at the time of reperfusion. Intracellular signaling is complex and incompletely defined and appears to involve the activation of various survival protein kinase cascades (eg, ERK1/2 and PI3K-Akt), antiapoptotic pathways (eg, Bcl-2 and BAX), protein kinases C and G, intracellular generation of nitric oxide, mitochondrial generation of reactive oxygen species, opening of mitochondrial (and possibly sarcolemmal) KATP, and blockade of the mitochondrial permeability transition pore.10 These various events culminate in reduction of both necrotic and apoptotic cell death (Figure 3), reduce the degree of no reflow and infarct size, and are suppressed in the presence of diabetes and hyperlipidemia. Intravenous nicorandil, started before PCI, and myocardial postconditioning after direct coronary stenting by intermittent low-pressure balloon inflations in the infarct-related artery have been shown to improve tissue perfusion, reduce infarct size, and improve patient outcome.11,12 Papaverine, nitroprusside, and abciximab have been reported to be effective for reversal of existing no reflow after primary PCI; however, no randomized trials have been performed in this setting.
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Figure 3. Simplified diagram depicting representative participants in the process of cardioprotection secondary to ischemic preconditioning and postconditioning. Extracellular triggering and intracellular signaling result in prevention of cell death. sKATP indicates sarcolemmal KATP; mKATP, mitochondrial KATP; mPTP, mitochondrial permeability transition pore; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; and PKC/G, protein kinase C and G.
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Interventional No Reflow
Prophylactic measures that protect against no reflow after noninfarct PCI include deployment of an embolic protection device for coronary bypass angioplasty13 and administration of glycoprotein IIb/IIIa inhibitors to patients undergoing PCI to native coronary arteries14 but not to bypass grafts. Among patients undergoing rotational coronary atherectomy, intracoronary nicorandil reduced no reflow compared with verapamil. As in the case of reperfusion no reflow, treatment of existing interventional no reflow is confined to retrospective reports and case series. Beneficial effects of intracoronary diltiazem, verapamil, epinephrine, nitroprusside, and adenosine have been reported.
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How Could No Reflow Have Been Prevented in Our Patients?
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In patient A, upstream administration of a glycoprotein IIb/IIIa
inhibitor, use of a thrombus aspiration device, and possibly
administration of nicorandil or ischemic postconditioning after
coronary stenting may have prevented the development of microvascular
no reflow in the setting of infarct angioplasty. In patient
B, deployment of an embolic protection device may have prevented
microvascular obstruction after stenting of the bypass graft.
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Conclusions
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Myocardial hypoperfusion is common after both elective and infarct-related
PCI, is underdiagnosed, and is associated with adverse outcome.
Recent advances in noninvasive imaging of microvascular perfusion
have enhanced the diagnosis of no reflow. Several prophylactic
measures have been identified; however, no treatment has demonstrated
proven efficacy for the treatment of existing no reflow. Future
directions in no-reflow research include elucidation and targeted
activation of intracellular cardioprotective signaling pathways.
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Acknowledgments
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Disclosures
None.
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Introduction
Introduction and Definition