Associate Editor: Gregory DustingManagement of the no-reflow phenomenon
Introduction
Cardiovascular disease remains the biggest killer in the developed world, with the majority of morbidity and mortality attributable to the catastrophic effects of acute myocardial infarction (MI). Whilst treatment strategies for MI have understandably focused on restoration of patency to the infarct-related artery (IRA), in many instances myocardial perfusion remains poor despite the successful restoration of IRA patency. The lack of reperfusion of myocardium after prolonged ischaemia that may occur despite opening of the IRA is termed “no reflow” or “reperfusion no reflow” (Kloner et al., 1974, Eeckhout and Kern, 2001, Galiuto, 2004, Jaffe et al., 2008). This phenomenon was initially described in the heart in an experimental model in 1966 by Krug et al. (1966) and further defined by Kloner et al. (1974). It was reported clinically in 1985 by Schofer et al. (1985) in the setting of thrombolysis using scintigraphic methods to define the reperfusion injury. In experimental models and in clinical research no reflow is determined by myocardial imaging techniques including myocardial contrast echocardiography, cardiac magnetic resonance imaging (CMRI), nuclear scintigraphy, positron emission tomography or histology (Eeckhout and Kern, 2001, Reffelmann and Kloner, 2002). In 1986, Bates et al. (1986) described the angiographic correlation of no reflow after observing slow contrast flow in the IRA. However, vessel patency (with normal angiographic flow) and normal myocardial perfusion are not necessarily synonymous (Ito, Maruyama, et al., 1996a, Ito, Okamura, et al., 1996b), leading to some confusion with respect to definitions (Eeckhout & Kern, 2001). Indeed with more sensitive assessment of myocardial perfusion, impaired myocardial perfusion despite successful restoration of IRA patency may be the rule rather than the exception (Taylor, Al-Saadi, et al., 2004, Taylor, Bobik, et al., 2004).
Clinically, no reflow is usually defined angiographically. The “no/slow-reflow” phenomenon manifests as an acute reduction in coronary blood flow in the absence of epicardial vessel obstruction, flow-limiting dissection, conduit vessel spasm, or apparent in-situ thrombosis. A recent review suggested that “no reflow” be reserved to angiographically defined Thrombolysis in Myocardial Infarction (TIMI) (TIMI Study Group, 1985) grade 0 or 1 flow in the absence of other aetiologies with “slow flow” referring to TIMI grade 2 flow (Table 1) (Klein et al., 2003). In previously reported series, no reflow or slow flow occurs in up to 3.2% of all percutaneous coronary interventions (PCI) (Piana et al., 1994, Frederic et al., 2003). We recently reported an incidence of transient or persistent no reflow of 4.8% in 5286 unselected patients undergoing PCI (Butler et al., 2008). In acute MI the incidence is higher, and is reported to occur in 30% to 40% of interventions when defined by myocardial perfusion techniques such as myocardial contrast echocardiography and technetium-99m scintigraphy (Ito, Maruyama, et al., 1996a, Ito, Okamura, et al., 1996b, Iwakura et al., 1996, Kondo et al., 1998). A similar process of myocardial tissue hypoperfusion, sometimes termed “interventional (or angiographic) no reflow” (Eeckhout and Kern, 2001, Jaffe et al., 2008), may also occur without preceding acute myocardial ischaemia in patients undergoing PTCA and stenting of saphenous vein bypass grafts (SVGs) or in patients undergoing rotational atherectomy (Safian et al., 1993, Ellis et al., 1994). In these settings, the incidence of no-reflow is between 10% and 20% (Abbo et al., 1995, Kaplan et al., 1996, Michaels et al., 2002, Resnic et al., 2003). No reflow occurs less commonly after coronary intervention for an acute coronary syndrome (ACS) without ST-segment elevation or stable angina (Abbo et al., 1995).
The most common clinical situation where no reflow is observed is acute MI. The cornerstone of treatment of MI is to restore myocardial blood flow and thus limit myocardial infarct size (Braunwald, 1993). Reperfusion is generally achieved pharmacologically by thrombolysis and anti-platelet agents or mechanically by PCI (along with anti-platelet therapy). Vessel patency rates with emergency percutaneous mechanical reperfusion are in the vicinity of 95% (Stone et al., 2002), compared to 81% with thrombolysis (de Bono et al., 1992, Keeley et al., 2003), and superior medium-term outcomes have been demonstrated, making percutaneous revascularization the therapy of choice (Keeley et al., 2003). Despite excellent rates of epicardial vessel patency post MI, myocardial salvage is often still incomplete, with abnormal TIMI flow rates (less than 3) not uncommon. When myocardial reperfusion is assessed by more sensitive techniques such as myocardial contrast echocardiography (Ito et al., 1996a) or myocardial blush grade (Costantini et al., 2004), the results are less than optimal. The CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) study investigators recently published their analysis of myocardial perfusion (as opposed to TIMI flow or TIMI frame counts) in the setting of coronary stenting with abciximab for MI (Costantini et al., 2004). They found that despite achieving a TIMI flow grade of 3 in 96.1% of patients, that myocardial perfusion (as defined by myocardial blush grade) was normal in only 17.4% of patients. Myocardial perfusion was reduced in 33.9% and absent in 48.7% (Costantini et al., 2004). Finally, following restoration of epicardial blood flow, myocardial reperfusion per se may cause injury beyond the previous myocardial ischaemic insult (Braunwald and Kloner, 1985, Ito, 2006, Camici and Crea, 2007, Yellon and Hausenloy, 2007).
No reflow is clinically important as it is independently associated with increased in-hospital mortality, malignant arrhythmias and cardiac failure (Abbo et al., 1995, Frederic et al., 2003, Ito, Maruyama, et al., 1996a). If persistent, no/slow reflow may result in post-procedural MI, or extension of MI, and is associated with a poor long-term prognosis (Gibson et al., 1999, Kenner et al., 1995, Mehta et al., 2003). Additionally, we recently reported that transient no reflow is even more common than persistent no reflow and results in significantly increased 30-day morbidity and mortality (Butler et al., 2008). When no reflow is detected by myocardial contrast echocardiography it is associated with a threefold increase in the risk of heart failure one month post MI (Ito et al., 1996a), and also predicts a lack of recovery of left ventricular function of affected myocardial segments (Kenner et al., 1995).
The pathophysiology of no reflow may vary depending on the clinical circumstance and is likely multifactorial (Fig. 1) (Reffelmann & Kloner, 2002). The restoration of epicardial blood flow does not necessarily mean flow is restored to the microcirculation. “Structural” or “anatomical” no reflow relates to obstruction from cellular oedema and compression of the microcirculation directly leading to cellular ischaemia (Reffelmann and Kloner, 2002, Galiuto, 2004), as well as destruction of the local microvascular architecture (Gerber et al., 2000). “Functional” no-reflow relates to microvascular spasm probably from neurohumoural activation and local vascular endothelial paracrine dysfunction, along with distal plaque atherothrombotic embolisation (Reffelmann and Kloner, 2002, Galiuto, 2004). It is probable that multiple other factors contribute and therefore numerous strategies must be employed to counteract this phenomenon.
As no reflow is difficult to treat successfully and has potentially serious adverse outcomes, early or even preventive measures by pharmacological or mechanical means have been advocated, as once no-reflow is established the cascade of microvascular circulatory changes becomes more refractory to treatment (Klein et al., 2003). Distal protection devices for prevention of microembolisation have been disappointing in the setting of native vessel acute MI but have shown some promise in intervention on SVGs (Mauri et al., 2006). A more effective mechanical therapy may be the technique of thrombus aspiration with an intracoronary catheter during PCI (Svilaas et al., 2006, Svilaas et al., 2008, Vlaar et al., 2008). Anti-platelet therapy may play a preventative role by decreasing thrombus burden and therefore distal embolisation of debris to avert reduction in microvascular flow (De Luca et al., 2005). However, several studies have somewhat conflicting results regarding anti-platelet agents. Vasodilators may be used in the prevention or treatment of no reflow (Ito, 2006), with those agents that are more selective for resistance vessels appearing to be more effective. However, evidence for most vasodilator agents is largely restricted to studies with small numbers of patients (Ito, 2006). Despite a recent improvement in the understanding of the mechanisms of no reflow and therefore potential preventative treatments, prevention and therapeutic targets of no reflow are still evolving.
Section snippets
Mechanical obstruction from embolisation
Although no reflow has previously been described in multiple animal models, microembolisation of plaque debris is not a likely mechanism as these models generally do not have atherosclerosis (Reffelmann & Kloner, 2002). In contrast, in clinical scenarios, atherothrombotic microembolisation appears to be an important contributor to no reflow, particularly in the setting of primary PCI for acute MI or SVG PCI (Abbo et al., 1995, Cura et al., 2000, Webb et al., 1999). No reflow is easily
Epicardial vessel flow versus myocardial perfusion
In some circumstances, despite restoration of normal antegrade epicardial vessel flow (TIMI 3 flow) there is ongoing obstruction to microvascular flow with a consequent perfusion defect when assessed by imaging studies. A significant number of patients following MI PCI have reduced TIMI flow (with increased TIMI frame counts) related to increased microvascular resistance and/or obstruction. Recognition of microvascular obstruction despite seemingly adequate epicardial flow is important as it is
Prevention and treatment of no reflow
Early catheterization laboratory intra-coronary strategies to treat no reflow were largely based on intravenous therapies that were useful in ACS, such as thrombolytics and nitroglycerin. Failure of these treatments to improve outcomes in the setting of no reflow gave rise to the sentiment that once established the no-reflow phenomenon was untreatable. However, greater understanding of the pathophysiology of no reflow has led to new pharmacological and mechanical treatments that show promise,
Preconditioning, postconditioning, cyclosporine and newer therapies
Upon being subjected to transient nonlethal periods of ischemia, the heart quickly adapts (‘preconditions’) itself to become more resistant to subsequent infarction from a more prolonged ischemic insult (Nakano et al., 2000). This cardiac adaptation, known as ischaemic pre-conditioning, was first described by Murry in 1986, who observed a reduction in MI size in canine hearts after applying four 5-minute alternate episodes of circumflex artery occlusion and reperfusion prior to 40 min of
Conclusion and future directions
No reflow is a common consequence of PCI, particularly in the setting of MI. TIMI flow is the most commonly used method to assess for coronary reflow in the setting of MI and PCI, but TIMI 3 flow does not equate with normal myocardial perfusion. To improve clinical outcomes following MI we need to focus on salvaging the ischaemic penumbra by increasing microvascular flow to ischaemic (but not infarcted) myocardium and reducing ischaemia-reperfusion injury. Recent studies show promise for a
Acknowledgments
Dr. Chan is supported by a postgraduate scholarship from the National Health and Medical Research Council of Australia. Drs. Duffy, Taylor, and Dart are supported by a National Health and Medical Research Council of Australia Program Grant.
References (162)
- et al.
Features and outcome of no-reflow after percutaneous coronary intervention
Am J Cardiol
(1995) - et al.
Demonstration of the “no-reflow” phenomenon by digital coronary arteriography
Am J Cardiol
(1986) - et al.
Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials
Lancet
(2002) - et al.
Coronary no-reflow is caused by shedding of active tissue factor from dissected atherosclerotic plaque
Blood
(2002) - et al.
Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial
Lancet
(2010) - et al.
An increased platelet-leukocytes interaction at the culprit site of coronary artery occlusion in acute myocardial infarction: a pathogenic role for “no-reflow” phenomenon?
Int J Cardiol
(2007) - et al.
Manual thrombus-aspiration improves myocardial reperfusion: the randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus-aspiration in primary and rescue angioplasty (REMEDIA) trial
J Am Coll Cardiol
(2005) - et al.
Predictors and outcomes of the no-reflow phenomenon
Heart Lung Circ
(2008) - et al.
Cardiac-derived thromboxane A2. An initiating mediator of reperfusion injury?
J Thorac Cardiovasc Surg
(1993) - et al.
Reduction in infarct size by the prostacyclin analogue iloprost (ZK 36374) after experimental coronary artery occlusion-reperfusion
Am Heart J
(1988)
Sodium nitroprusside exacerbates myocardial ischemia-reperfusion injury
Ann Thorac Surg
Frequency, correlates, and clinical implications of myocardial perfusion after primary angioplasty and stenting, with and without glycoprotein IIb/IIIa inhibition, in acute myocardial infarction
J Am Coll Cardiol
Adjunctive mechanical devices to prevent distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction: a meta-analysis of randomized trials
Am Heart J
Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation
Am J Pathol
Evaluation of dynamic changes in microvascular flow during ischemia-reperfusion by myocardial contrast echocardiography
J Am Coll Cardiol
Postischemic left ventricular dysfunction is abolished by alpha-adrenergic blocking agents
J Am Coll Cardiol
Early administration of intracoronary verapamil improves myocardial perfusion during percutaneous coronary interventions for acute myocardial infarction
Chest
Preconditioning and postconditioning: united at reperfusion
Pharmacol Ther
Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience
J Am Coll Cardiol
Role of pre-infarction angina and inflammatory status in the extent of microvascular obstruction detected by MRI in myocardial infarction patients treated by PCI
Int J Cardiol
Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials
Lancet
Ability of the no-reflow phenomenon during an acute myocardial infarction to predict left ventricular dysfunction at one-month follow-up
Am J Cardiol
Translation of remote ischaemic preconditioning into clinical practice
Lancet
Inflammatory and vasoactive factors in the aspirate from the culprit coronary artery of patients with acute myocardial infarction
Int J Cardiol
Assessment of “microvascular no-reflow phenomenon” using technetium-99m macroaggregated albumin scintigraphy in patients with acute myocardial infarction
J Am Coll Cardiol
Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion: a quantitative myocardial contrast echocardiography study
J Am Coll Cardiol
Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) Trial
J Am Coll Cardiol
Prognostic significance of transient no-reflow during primary percutaneous coronary intervention for ST-elevation acute myocardial infarction
Am J Cardiol
Effect of cyclosporine on left ventricular remodeling after reperfused myocardial infarction
J Am Coll Cardiol
Improvement in microvascular reflow and reduction of infarct size with adenosine in patients undergoing primary coronary stenting
Am J Cardiol
Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14
Nature
Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial
Am Heart J
Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes
Circulation
The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study Group
N Engl J Med
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group
Lancet
Effect of locally-applied active site-blocked activated factor VII (ASIS) on experimental arterial thrombosis
Blood Coagul Fibrinolysis
Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts
Circulation
Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries
Circulation
The open-artery theory is alive and well-again
N Engl J Med
Myocardial reperfusion: a double-edged sword?
J Clin Invest
Controlled reperfusion of the regionally ischemic myocardium with leukocyte-depleted blood reduces stunning, the no-reflow phenomenon, and infarct size
J Thorac Cardiovasc Surg
Coronary microvascular dysfunction
N Engl J Med
Embolic protection of saphenous vein graft percutaneous interventions
J Interv Cardiol
Adenosine: trigger and mediator of cardioprotection
Basic Res Cardiol
Adjunctive intracoronary thrombolysis in complicated coronary angioplasty
Ann Pharmacother
Pronounced benefit of coronary stenting and adjunctive platelet glycoprotein IIb/IIIa inhibition in complex atherosclerotic lesions
Circulation
Calcium-channel blockers preserve coronary endothelial reactivity after ischemia-reperfusion
Ann Thorac Surg
‘Postconditioning’ the human heart: multiple balloon inflations during primary angioplasty may confer cardioprotection
Basic Res Cardiol
Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial
Br Heart J
Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials
JAMA
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