Microvascular dysfunction in acute myocardial infarction: focus on the roles of platelet and inflammatory mediators in the no-reflow phenomenon☆
Section snippets
Incidence of microvascular hypoperfusion after immediate reperfusion therapy
Acute ST-segment elevation myocardial infarction is typically caused by rupture of a coronary atherosclerotic plaque with subsequent thrombosis of an epicardial vessel. Immediate reperfusion therapy refers to fibrinolytic agents or mechanical transcatheter techniques that remove thrombus and open the IRA. “Reflow” is achieved when blood flow is restored beyond the site of the previous coronary occlusion.
The quality of coronary flow seen during coronary angiography has been quantified by the
Impact of microvascular dysfunction on clinical outcome
Numerous thrombolytic and angioplasty studies have demonstrated improvement in clinical outcome in patients with AMI who have early coronary reperfusion.
Pathophysiology of the no-reflow phenomenon
There are 2 potential explanations of TIMI 2 flow rates after immediate reperfusion therapy in patients with AMI. Residual thrombus, stenosis, or coronary dissection may give the appearance of a widely patent vessel and yet reduce coronary flow to the distal segment. Coronary angiography, however, can often identify these epicardial artery problems that may reduce coronary flow. In the current era of stenting, it is believed that residual luminal stenosis is not responsible for the development
Epidemiologic evidence: immune function in AMI patients
In addition to the vast body of experimental evidence suggesting a central role of neutrophil function in AMI patients, there is growing epidemiologic evidence supporting the role of the immune system in patients with ischemia and reperfusion injury.
Quantitative assessment of microvascular perfusion
Several diagnostic testing strategies have evolved that provide quantitative, objective assessment of microvascular flow.
Is no-reflow modifiable?
Management of myocardial hypoperfusion in AMI patients should be directed at the potential pathophysiologic mechanisms involved. Treating the phenomenon of platelet microembolism-related microvascular obstruction with aggressive antiplatelet therapy has yielded encouraging results. Therapeutic strategies addressing reperfusion injury appear promising in animal studies, but clinical trial data are still lacking.
The use of glycoprotein IIb/IIIa receptor inhibitors may improve microvascular
Conclusions
Despite optimal therapy with thrombolytic agents or primary angioplasty or stenting, a considerable number of patients are left with impaired epicardial coronary flow. An even greater proportion of patients has impaired microvascular perfusion, indicating a poorer prognosis with a higher adverse cardiac event rate. Current therapy is not successful in addressing the pathophysiology of microvascular dysfunction due to microvascular obstruction and reperfusion injury.
Looking beyond epicardial
References (141)
- et al.
Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapyresults of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study
J Am Coll Cardiol
(1993) - et al.
Meta analysis of five reported studies on the relation of early coronary patency grades with mortality and outcomes after acute myocardial infarction
Am J Cardiol
(1996) - et al.
Six- and twelve-month follow-up of the Phase I Thrombolysis in Myocardial Infarction (TIMI) Trial
Am J Cardiol
(1988) - et al.
Does Thrombolysis in Myocardial Infarction (TIMI) perfusion grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electrocardiographic evidence from the TEAM-2 study
J Am Coll Cardiol
(1992) - et al.
Importance of infarct-related artery patency for recovery of left ventricular function and late survival after primary angioplasty for acute myocardial infarction
J Am Coll Cardiol
(1996) - et al.
Incidence and importance of thrombolysis in myocardial infarction grade 3 flow after primary percutaneous transluminal coronary angioplasty for acute myocardial infarction
Am J Cardiol
(1996) - et al.
Long-term outcome after primary angioplastyreport from the Primary Angioplasty in Myocardial Infarction (PAMI-I) trial
J Am Coll Cardiol
(1999) - et al.
Microvascular involvement in cardiac pathology
J Mol Cell Cardiol
(1998) - et al.
Endothelial cell “swelling” is ischaemia and reperfusion
J Mol Cell Cardiol
(1995) - et al.
Cytokines and the microcirculation in ischemia and reperfusion
J Mol Cell Cardiol
(1998)
Detection of the terminal complement complex in patient plasma following acute myocardial infarction
Atherosclerosis
Increased expression of neutrophil and monocyte adhesion molecules LFA-1 and Mac-1 and their ligand ICAM-1 and VLA-4 throughout the acute phase of myocardial infarctionpossible implications for leukocyte aggregation and microvascular plugging
J Am Coll Cardiol
Serial changes in plasma levels of soluble P-selectin in patients with acute myocardial infarction
Am J Cardiol
Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the β2-integrin CD11b/CD18
Blood
Continuous activation and deactivation of integrin CD11b/CD18 during de novo expression enables rolling neutrophils to immobilize on platelets
Blood
A chimeric IgG4 monoclonal antibody directed against CD18 reduces infarct size in a primate model of myocardial ischemia and reperfusion
J Am Coll Cardiol
An anti-CD18 antibody limits infarct size and preserves left ventricular function in dogs with ischemia and 48-hour reperfusion
J Am Coll Cardiol
Does reperfusion injury exist in humans?
J Am Coll Cardiol
Myocardial malondialdehyde and uric acid release after short-lasting coronary occlusions during coronary angioplastypotential mechanisms for free radical generation
Am J Cardiol
Transient release of lipid peroxides after coronary artery balloon angioplasty
Lancet
Demonstration of myocardial reperfusion injury in humansresults of a pilot study utilizing acute coronary angioplasty with perfluorochemical in anterior myocardial infarction
J Am Coll Cardiol
Combined tissue-type plasminogen activator and prostacyclin therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 4 Study Group
J Am Coll Cardiol
White blood cell count, coronary heart disease, and deaththe NHANES I epidemiologic follow-up study
Am Heart J
Association between leukocyte count and the presence and extent of coronary atherosclerosis as determined by coronary angiography
Am J Cardiol
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromesa TIMI 11A substudy
J Am Coll Cardiol
Extended mortality benefit of early postinfarction reperfusionGlobal Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries Trial
Circulation
A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction
N Engl J Med
Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifibanresults of the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trial
J Am Coll Cardiol
Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarctionresults of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI investigators
Circulation
Abciximab facilitates the rate and extent of thrombolysisresults of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 investigators
Circulation
Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarctionReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators
Circulation
The Thrombolysis in Myocardial Infarction (TIMI) trialphase I findings
N Engl J Med
An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction
N Engl J Med
A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction
N Engl J Med
Angiographic findings and catheterization laboratory events in patients with primary coronary angioplasty or streptokinase therapy for acute myocardial infarction
Eur Heart J
Coronary angioplasty with or without stent implantation for acute myocardial infarctionStent Primary Angioplasty in Myocardial Infarction Study Group
N Engl J Med
The Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction
N Engl J Med
Thrombolysis in Myocardial Infarction (TIMI) Trial, phase Ia comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge
Circulation
TIMI perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarctionventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 study
Circulation
Benefit of thrombolytic therapy is sustained throughout five years and is related to TIMI perfusion grade 3 but not grade 2 flow at discharge
Circulation
Clinical and angiographic follow-up after primary stenting in acute myocardial infarctionthe Primary Angioplasty in Myocardial Infarction (PAMI) stent pilot trial
Circulation
Adjunctive stenting following thrombolysis in TIMI 10A & B
Circulation
Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog
Am J Pathol
Neutrophil accumulation in ischemic canine myocardiuminsights into the time course, distribution, and mechanism of localization during early reperfusion
Circulation
Free radical and granulocyte-mediated injury during myocardial ischemia and reperfusion
Am J Cardiol
Neutrophil-mediated vasoconstriction and endothelial dysfunction in low-flow perfusion-reperfused cat coronary artery
Circ Res
Endogenous adenosine inhibits P-selectin-dependent format of coronary microemboli during hypoperfusion in dogs
J Clin Invest
Platelet accumulation in regions of low blood flow during the postischemic period
Stroke
Transient platelet accumulation in the rat brain after common carotid artery thrombosisan Indium-111 labeled platelet study
Stroke
Cited by (125)
Vitamin D deficiency and periprocedural myocardial infarction in patients undergoing percutaneous coronary interventions
2018, Cardiovascular Revascularization MedicinePrevention of coronary microvascular obstruction by addressing distal embolization
2018, Coronary Microvascular Obstruction in Acute Myocardial Infarction: From Mechanisms to TreatmentIncreased Platelet-leukocyte Aggregates Are Associated With Myocardial No-reflow in Patients With ST Elevation Myocardial Infarction
2016, American Journal of the Medical SciencesCitation Excerpt :Cross talk between platelets and leukocytes is now regarded as a crucial pathophysiological mechanism linking thrombosis and inflammation. Recent study has focused on the critical roles of platelet and inflammatory mediators leading to microvascular obstruction.18 Botto et al19 reported that an increased PLA level at the site of the plaque rupture may be one of the pathogenetic mechanisms for myocardial “no-reflow.”
- ☆
Supported by Genentech, Inc., South San Francisco, California. Dr. Michaels also received support from the 1999–2000 American Heart Association Postdoctoral Fellowship Award.